Change search
Refine search result
12 1 - 50 of 62
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Ali, Imran
    et al.
    Damdimopoulou, Pauliina
    Stenius, Ulla
    Adamsson, Annika
    Mäkelä, Sari I
    Åkesson, Agneta
    Berglund, Marika
    Håkansson, Helen
    Halldin, Krister
    Cadmium-induced effects on cellular signaling pathways in the liver of transgenic estrogen reporter mice.2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 127, no 1, p. 66-75Article in journal (Refereed)
    Abstract [en]

    Estrogen-like effects of cadmium (Cd) have been reported in several animal studies, and recent epidemiological findings suggest increased risk of hormone-dependent cancers after Cd exposure. The mechanisms underlying these effects are still under investigation. Our aim was to study the effects of Cd on cellular signaling pathways in vivo with special focus on estrogen signaling and to perform benchmark dose analysis on the effects. Transgenic adult ERE-luciferase male mice were exposed subcutaneously to 0.5-500 μg CdCl(2) per kg body weight (bw) or 17α-ethinylestradiol (EE2) for 3 days. These doses had no effects on organ and bw or testicular histology, indicating subtoxic exposure levels. The transgene luciferase, reporting genomic estrogen response, was significantly increased by EE2 but not by Cd. However, Cd significantly affected kinase phosphorylation and endogenous gene expression. Interestingly, gene expression changes displayed a traditional dose-response relationship, with benchmark dose levels for the expression of Mt1, Mt2, p53, c-fos, and Mdm2 being 92.9, 19.9, 7.6, 259, and 25.9 μg/kg bw, respectively, but changes in kinase phosphorylation were only detected at low exposure levels. Phosphorylation of Erk1/2 was significantly increased even in the lowest dose group, 0.5 μg/kg bw, rendering pErk1/2 a more sensitive sensor of exposure than changes in gene expression. Collectively, our data suggest that the effects triggered by Cd in vivo are markedly concentration dependent. Furthermore, we conclude that the estrogen-like effects of Cd are likely to result from a mechanism different from steroidal estrogens.

  • 2.
    Ankarberg, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Increased susceptibility to adult paraoxon exposure in mice neonatally exposed to nicotine2004In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 82, no 2, p. 555-561Article in journal (Refereed)
    Abstract [en]

    Low-dose exposure of neonatal mice to nicotine has earlier been shown to induce an altered behavioral response to nicotine in adulthood. Organophosphorus insecticides are known to affect the cholinergic system by inhibition of acetylcholinesterase. This study was undertaken to investigate whether neonatal exposure to nicotine makes mice more susceptible to a known cholinergic agent. Neonatal, 10-day-old, male mice were exposed to nicotine-base (33 microg/kg body weight) or saline s.c. twice daily on five consecutive days. At 5 months of age the animals were exposed to paraoxon (0.17 or 0.25 mg/kg body weight [29% and 37% inhibition of cholinesterase, respectively]) or saline sc every second day for 7 days. Before the first paraoxon injection, the animals were observed for spontaneous motor behavior. The spontaneous motor behavior test did not reveal any differences in behavior between the treatment groups. Immediately after the spontaneous behavior test, the animals received the first injection of paraoxon and were observed for acute effects of paraoxon on spontaneous motor behavior. The acute response to paraoxon in the spontaneous motor behavior test was a decreased level of activity in mice neonatally exposed to nicotine. Control animals showed no change in activity. Two months after the paraoxon treatment, the animals were again tested for spontaneous motor behavior. Animals neonatally exposed to nicotine and exposed to paraoxon as adults showed a deranged spontaneous motor behavior, including hyperactivity and lack of habituation.

  • 3.
    Bahrami, Fariba
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, EB
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergman, A
    Larsson, C
    Brandt, I
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Localization and comparative toxicity of methylsulfonyl-2,5-and 2,6-dichlorobenzene in the olfactory mucosa of mice1999In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 49, no 1, p. 116-123Article in journal (Refereed)
    Abstract [en]

    Several methylsulfonyl (MeSO2) metabolites formed from chlorinated aromatic hydrocarbons have been identified in human milk, lung, and body fat, as well as in the tissues of Baltic grey seals and arctic polar bears. The tissue localization and nasal toxicity of two methylsulfonyl-substituted dichlorobenzenes (diCl-MeSO2-B), with the chlorine atoms in the 2,5-, and 2,6- positions, were investigated in female NMRI and C57B1 mice. Using tape-section autoradiography, animals dosed i.v. with 14C-labeled 2,5-, or 2,6-(diCl-MeSO2-B) showed a preferential uptake of radioactivity in the olfactory mucosa and the tracheobronchial epithelium. Histopathology showed that 2,6-(diCl-MeSO2- B) is a potent toxicant that induces necrosis in the olfactory mucosa following a single dose as low as 4 mg/kg (i.p. injection), whereas 2,5- (diCl-MeSO2-B) induced no signs of toxicity in the olfactory mucosa at doses as high as 130 mg/kg (i.p. injection). Necrosis of the Bowman's glands was the first sign of 2,6-(diCl-MeSO2-B)-induced toxicity followed by degeneration of the neuroepithelium, which implies that the Bowman's gland may be the primary site of toxicity and degeneration of the neuroepithelium may be a secondary effect. Administration of the parent compounds, 1,3-dichlorobenzene and 1,4-dichlorobenzene, or the chlorinated analog 1,2,3-trichlorobenzene (85, 85, and 105 mg/kg, respectively; i.p. injection), induced no signs of toxicity in the olfactory mucosa. These and previous results suggest that 2,6- positioned chlorine atoms and an electron withdrawing substituent in the primary position is an arrangement that predisposes for toxicity in the olfactory mucosa.

  • 4.
    Barath, Stefan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Langrish, Jeremy P.
    Centre for Cardiovascular Science, Edinburgh University, Edinburgh, United Kingdom.
    Lundbäck, Magnus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Bosson, Jenny A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Goudie, Colin
    Newby, David E.
    Centre for Cardiovascular Science, Edinburgh University, Edinburgh, United Kingdom.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Mills, Nicholas L.
    Centre for Cardiovascular Science, Edinburgh University, Edinburgh, United Kingdom.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Short-Term Exposure to Ozone Does Not Impair Vascular Function or Affect Heart Rate Variability in Healthy Young Men2013In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 135, no 2, p. 292-299Article in journal (Refereed)
    Abstract [en]

    Air pollution exposure is associated with cardiovascular morbidity and mortality, yet the role of individual pollutants remains unclear. In particular, there is uncertainty regarding the acute effect of ozone exposure on cardiovascular disease. In these studies, we aimed to determine the effect of ozone exposure on vascular function, fibrinolysis, and the autonomic regulation of the heart. Thirty-six healthy men were exposed to ozone (300 ppb) and filtered air for 75min on two occasions in randomized double-blind crossover studies. Bilateral forearm blood flow (FBF) was measured using forearm venous occlusion plethysmography before and during intra-arterial infusions of vasodilators 2–4 and 6–8h after each exposure. Heart rhythm and heart rate variability (HRV) were monitored during and 24h after exposure. Compared with filtered air, ozone exposure did not alter heart rate, blood pressure, or resting FBF at either 2 or 6h. There was a dose-dependent increase in FBF with all vasodilators that was similar after both exposures at 2–4h. Ozone exposure did not impair vasomotor or fibrinolytic function at 6–8h but rather increased vasodilatation to acetylcholine (p = .015) and sodium nitroprusside (p = .005). Ozone did not affect measures of HRV during or after the exposure. Our findings do not support a direct rapid effect of ozone on vascular function or cardiac autonomic control although we cannot exclude an effect of chronic exposure or an interaction between ozone and alternative air pollutants that may be responsible for the adverse cardiovascular health effects attributed to ozone.

  • 5.
    Bergander, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Öberg, Mattias
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Helene
    Rannug, Agneta
    Identification of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole in cell culture medium, as a factor that controls the constitutive aryl hydrocarbon receptor activity2005In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 85, no 2, p. 935-943Article in journal (Refereed)
    Abstract [en]

    The presence of high affinity ligands for the aryl hydrocarbon receptor (AhR) in cell culture medium has generally been overlooked. Such compounds may confound mechanistic studies of the important AhR regulatory network. Numerous reports have described that light exposed cell culture medium induces AhR-dependent activity. In this study, we aimed at identifying the causative substance(s). A three-dimensional factorial design was used to study how the background activity of CYP1A1 in a rat hepatoma cell line (MH1C1) was controlled by photoproducts formed in the medium exposed to normal laboratory light. The light induced activity was found to be tryptophan dependent, but independent of riboflavin and other components in the medium. The light exposed medium showed the same transient enzyme inducing activity in vitro as the AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). This substance, which we have previously identified as being formed in UV-exposed tryptophan solutions, is a substrate for CYP1A1 and it has a higher AhR binding affinity than TCDD. Several tryptophan related photoproducts were detected in the light-exposed medium. For the first time one of the formed photoproducts was identified as FICZ with bioassay driven fractionation coupled with HPLC/MS. These results clearly show that tryptophan derived AhR ligands, which have been suggested to be endogenous AhR ligands, influence the background levels of CYP1A1 activity in cells in culture.

  • 6. Bäcklin, Britt-Marie
    et al.
    Bredhult, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Proliferative Effects of Estradiol, Progesterone, and Two CB Congeners and Their Metabolites on Gray Seal (Halichoerus grypus) Uterine Myocytes in Vitro2003In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 75, no 1, p. 154-160Article in journal (Refereed)
    Abstract [en]

    Gray seal females living in the Baltic Sea have been found to exhibit a high prevalence of uterine leiomyomas. These animals are also known to accumulate lipid-soluble PCBs in their blubber. PCBs have documented endocrine-disrupting effects; to investigate whether the PCBs could be part of the genesis of uterine smooth muscle tumors in this species, gray seal myometrial cell cultures were exposed to two CBs and their metabolites, as well as to estradiol and progesterone, after which the effects were analyzed in terms of proliferative activity by measurements of BrdU absorbance and protein content. Progesterone was found to have an inhibitory effect, whereas one CB acted as a stimulant on the myometrial cell proliferation. One of the CB metabolites also seemed to have an inhibitory effect, although this could not be statistically verified. These results suggest that some CBs have effects on uterine myometrial cell proliferation in gray seals and, thus, may also take part in the growth regulation of uterine leiomyomas.

  • 7.
    Carvalho, Raquel N.
    et al.
    Institute for Environment and Sustainability, European Commission-DG Joint Research Centre, Ispra, Italy.
    Arukwe, Augustine
    Norwegian University of Science & Technology, Trondheim, Norway.
    Ait-Aissa, Selim
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Bado-Nilles, Anne
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France; Reims University, Reims, France.
    Balzamo, Stefania
    Istituto Superiore per la Protezione e la Ricerca Ambientale (ISPRA), Rome, Italy.
    Baun, Anders
    Department of Environmental Engineering,Technical University of Denmark, Kgs Lyngby, Denmark.
    Belkin, Shimshon
    Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
    Blaha, Ludek
    Faculty of Science, RECETOX, Masaryk University, Brno, Czech Republic.
    Brion, Francois
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Conti, Daniela
    Istituto Superiore per la Protezione e la Ricerca Ambientale (ISPRA), Rome, Italy.
    Creusot, Nicolas
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Essig, Yona
    Analytical and Environmental Sciences Division, King's College, London, UK.
    Ferrero, Valentina E. V.
    European Commission-DG Joint Research Centre, Institute for Environment and Sustainability, Ispra, Italy.
    Flander-Putrle, Vesna
    Marine Biology Station Piran, National Institute of Biology, Ljubljana, Slovenia.
    Furhacker, Maria
    University of Natural Resources and Life Sciences, Vienna, Austria.
    Grillari-Voglauer, Regina
    University of Natural Resources and Life Sciences, Vienna, Austria.
    Hogstrand, Christer
    Diabetes and Nutritional Sciences Division, King's College London, London, UK.
    Jonas, Adam
    Faculty of Science, RECETOX, Masaryk University, Brno, Czech Republic.
    Kharlyngdoh, Joubert B.
    Örebro University, School of Science and Technology.
    Loos, Robert
    European Commission-DG Joint Research Centre, Institute for Environment and Sustainability, Ispra, Italy.
    Lundebye, Anne-Katrine
    National Institute of Nutrition and Seafood Research, Bergen, Norway.
    Modig, Carina
    Örebro University, School of Science and Technology. Life Science Center, Örebro University, Örebro, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology. Life Science Center, Örebro University, Örebro, Sweden.
    Pillai, Smitha
    University of Natural Resources and Life Sciences, Vienna, Austria.
    Polak, Natasa
    Analytical and Environmental Sciences Division, King's College, London, UK.
    Potalivo, Monica
    Istituto Superiore per la Protezione e la Ricerca Ambientale (ISPRA), Rome, Italy.
    Sanchez, Wilfried
    National Institute for Industrial Environment and Risks, Verneuil en Halatte, France.
    Schifferli, Andrea
    Swiss Centre for Applied Ecotoxicology, Eawag-EPFL, Dübendorf, Switzerland.
    Schirmer, Kristin
    Swiss Centre for Applied Ecotoxicology, Eawag-EPFL, Dübendorf, Switzerland.
    Sforzini, Susanna
    Department of Environmental and Life Sciences, Universita del Piemonte Orientale Vercelli Novara Alessandria, Alessandria, Italy.
    Sturzenbaum, Stephen R.
    Analytical and Environmental Sciences Division, King's College, London, UK.
    Søfteland, Liv
    National Institute of Nutrition and Seafood Research, Bergen, Norway.
    Turk, Valentina
    Marine Biology Station Piran, National Institute of Biology, Ljubljana, Slovenia.
    Viarengo, Aldo
    Department of Environmental and Life Sciences, Università del Piemonte Orientale Vercelli Novara Alessandria, Alessandria, Italy.
    Werner, Inge
    Swiss Centre for Applied Ecotoxicology, Swiss Federal Institute of Aquatic Science and Technology ( Eawag-EPFL), Dübendorf, Switzerland.
    Yagur-Kroll, Sharon
    Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
    Zounkova, Radka
    Faculty of Science, RECETOX, Masaryk University, Brno, Czech Republic.
    Lettieri, Teresa
    European Commission-DG Joint Research Centre, Institute for Environment and Sustainability, Rome, Italy.
    Mixtures of chemical pollutants at European legislation safety concentrations: how safe are they?2014In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 141, no 1, p. 218-233Article in journal (Refereed)
    Abstract [en]

    The risk posed by complex chemical mixtures in the environment to wildlife and humans is increasingly debated, but has been rarely tested under environmentally relevant scenarios. To address this issue, two mixtures of 14 or 19 substances of concern (pesticides, pharmaceuticals, heavy metals, polyaromatic hydrocarbons, a surfactant, and a plasticizer), each present at its safety limit concentration imposed by the European legislation, were prepared and tested for their toxic effects. The effects of the mixtures were assessed in 35 bioassays, based on 11 organisms representing different trophic levels. A consortium of 16 laboratories was involved in performing the bioassays. The mixtures elicited quantifiable toxic effects on some of the test systems employed, including i) changes in marine microbial composition, ii) microalgae toxicity, iii) immobilization in the crustacean Daphnia magna, iv) fish embryo toxicity, v) impaired frog embryo development, and vi) increased expression on oxidative stress-linked reporter genes. Estrogenic activity close to regulatory safety limit concentrations was uncovered by receptor-binding assays. The results highlight the need of precautionary actions on the assessment of chemical mixtures even in cases where individual toxicants are present at seemingly harmless concentrations.

  • 8. Dingemans, Milou M. L.
    et al.
    Heusinkveld, Harm J.
    de Groot, Aart
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    van den Berg, Martin
    Westerink, Remco H. S.
    Hexabromocyclododecane Inhibits Depolarization-Induced Increase in Intracellular Calcium Levels and Neurotransmitter Release in PC12 Cells2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 107, no 2, p. 490-497Article in journal (Refereed)
    Abstract [en]

    Environmental levels of the brominated flame retardant (BFR) hexabromocyclododecane (HBCD) have been increasing. HBCD has been shown to cause adverse effects on learning and behavior in mice, as well as on dopamine uptake in rat synaptosomes and synaptic vesicles. For other BFRs, alterations in the intracellular Ca2+ homeostasis have been observed. Therefore, the aim of this study was to investigate whether the technical HBCD mixture and individual stereoisomers affect the intracellular Ca2+ concentration ([Ca2+](i)) in a neuroendocrine in vitro model (PC12 cells). [Ca2+](i) and vesicular catecholamine release were measured using respectively single-cell Fura-2 imaging and amperometry. Exposure of PC12 cells to the technical HBCD mixture or individual stereoisomers did neither affect basal [Ca2+](i), nor the frequency of basal neurotransmitter release. However, exposure to HBCD (0-20 mu M) did cause a dose-dependent reduction of a subsequent depolarization-evoked increase in [Ca2+](i). This effect was apparent only when HBCD was applied at least 5 min before depolarization (maximum effect after 20 min exposure). The effects of alpha- and beta-HBCD were comparable to that of the technical mixture, whereas the inhibitory effect of gamma-HBCD was larger. Using specific blockers of L-, N- or P/Q-type voltage-gated Ca2+ channels (VGCCs) it was shown that the inhibitory effect of HBCD is not VGCC-specific. Additionally, the number of cells showing depolarization-evoked neurotransmitter release was markedly reduced following HBCD exposure. Summarizing, HBCD inhibits depolarization-evoked [Ca2+](i) and neurotransmitter release. As increasing HBCD levels should be anticipated, these findings justify additional efforts to establish an adequate exposure, hazard and risk assessment.

  • 9. Dingemans, Milou M. L.
    et al.
    van den Berg, Martin
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Westerink, Remco H. S.
    Calcium-Related Processes Involved in the Inhibition of Depolarization-Evoked Calcium Increase by Hydroxylated PBDEs in PC12 Cells2010In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 114, no 2, p. 302-309Article in journal (Refereed)
    Abstract [en]

    In vitro studies indicated that hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have an increased toxic potential compared to their parent congeners. An example is the OH-PBDE–induced increase of basal intracellular Ca2+ concentration ([Ca2+]i) by release of Ca2+ from endoplasmic reticulum (ER) and mitochondria and/or influx of extracellular Ca2+. ER and mitochondria regulate Ca2+ homeostasis in close association with voltage-gated Ca2+ channels (VGCCs). Therefore, effects of (OH-)PBDEs on the depolarization-evoked (100mM K+) net increase in [Ca2+]i (depolarization-evoked [Ca2+]i) were measured in neuroendocrine pheochromocytoma cells using the Ca2+-responsive dye Fura-2. OH-PBDEs dose dependently inhibited depolarization-evoked [Ca2+]i. This inhibition was potentiated by a preceding increase in basal [Ca2+]i. Especially at higher concentrations of OH-PBDEs (5–20μM), large increases in basal [Ca2+]i strongly inhibited depolarization-evoked [Ca2+]i. The inhibition appeared more sensitive to increases in basal [Ca2+]i by Ca2+ release from intracellular stores (by 3-OH-BDE-47 or 6′-OH-BDE-49) compared to those by influx of extracellular Ca2+ (by 6-OH-BDE-47 or 5-OH-BDE-47). The expected [Ca2+]i difference close to the membrane suggests involvement of Ca2+-dependent regulatory processes close to VGCCs. When coapplied with depolarization, some OH-PBDEs induced also moderate direct inhibition of depolarization-evoked [Ca2+]i. Polybrominated diphenyl ethers and methoxylated BDE-47 affected neither basal nor depolarization-evoked [Ca2+]i, except for BDE-47, which moderately increased fluctuations in basal [Ca2+]i and depolarization-evoked [Ca2+]i. These findings demonstrate that OH-PBDEs inhibit depolarization-evoked [Ca2+]i depending on preceding basal [Ca2+]i. Related environmental pollutants that affect Ca2+ homeostasis (e.g., polychlorinated biphenyls) may thus also inhibit depolarization-evoked [Ca2+]i, justifying further investigation of possible mixture effects of environmental pollutants on Ca2+ homeostasis.

  • 10.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Response to: Use of the Pup as the Statistical Unit in Developmental Neurotoxicity Studies: Overlooked Model or Poor Research Design?2008In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 103, no 2, p. 411-413Article in journal (Other academic)
  • 11.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fischer, Celia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Polybrominated diphenyl ethers, a group of brominated flame retardants, can interact with polychlorinated biphenyls in enhancing developmental neurobehavioral defects2006In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 94, no 2, p. 302-309Article in journal (Refereed)
    Abstract [en]

    The present study shows that polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) can interact and enhance developmental neurobehavioral defects when the exposure occurs during a critical stage of neonatal brain development. PBDEs are used in large quantities as flame-retardant additives in polymers, especially in the manufacture of a great variety of electrical appliances, and textiles. In contrast to the well-known persistent compounds PCBs and DDT, the PBDEs have been found to increase in the environment and in human mother's milk. We have previously shown that low-dose exposure to environmental toxic agents such as PCB can cause developmental neurotoxic effects when present during a critical stage of neonatal brain development. Epidemiological studies indicate the adverse neurobehavioral impact of PCBs. Recently, we reported that neonatal exposure to PBDEs causes developmental neurotoxic effects. In the present study, 10-day-old Naval Medical Research Institute male mice were given one single oral dose of PCB 52 (1.4 mu mol/kg body weight [bw]) + PBDE 99 (1.4 mu mol), PCB 52 (1.4 mu mol or 14 mu mol), or PBDE 99 (1.4 mu mol or 14 mu mol). Controls received a vehicle (20% fat emulsion). Animals exposed to the combined dose of PCB 52 (1.4 mu mol) + PBDE 99 (1.4 mu mol) and the high dose of PCB 52 (14 mu mol) or PBDE 99 (14 mu mol) showed significantly impaired spontaneous motor behavior and habituation capability at the age of 4 and 6 months. The neurobehavioral defects were also seen to worsen with age in mice neonatally exposed to PCB 52 + PBDE 99.

  • 12.
    Faulkner, Lee
    et al.
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Martinsson, Klara
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Santoyo-Castelazo, Anahi
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Cederbrant, Karin
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, S-151 85 Södertälje, Sweden.
    Schuppe-Koistinen, Ina
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, S-151 85 Södertälje, Sweden.
    Powell, Helen
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, Alderley Park, Macclesfield SK10 4TG, U.K.
    Tugwood, Jonathan
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, Alderley Park, Macclesfield SK10 4TG, U.K.
    Naisbitt, Dean J
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Park, B Kevin
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    The development of in vitro culture methods to characterize primary T-cell responses to drugs.2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 127, no 1, p. 150-8Article in journal (Refereed)
    Abstract [en]

    Adverse drug reactions represent a major stumbling block to drug development and those with an immune etiology are the most difficult to predict. We have developed an in vitro T-cell priming culture method using peripheral blood from healthy volunteers to assess the allergenic potential of drugs. The drug metabolite nitroso sulfamethoxazole (SMX-NO) was used as a model drug allergen to establish optimum assay conditions. Naive T cells were cocultured with monocyte-derived dendritic cells at a ratio of 25:1 in the presence of the drug for a period of 8 days, to expand the number of drug-responsive T cells. The T cells were then incubated with fresh dendritic cells, and drug and their antigen responsiveness analyzed using readouts for proliferation, cytokine secretion, and cell phenotype. All five volunteers showed dose-dependent proliferation as measured by 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester content and by (3)H-thymidine uptake. CD4 T cells that had divided in the presence of SMX-NO had changed from a naive phenotype (CD45RA+) to a memory phenotype (CD45RO+). These memory T cells expressed the chemokine receptors CCR2, CCR4, and CXCR3 suggesting a mixture of T(H)1 and T(H)2 cells in the responding population, with a propensity for homing to the skin. Drug stimulation was also associated with the secretion of a mixture of T(H)1 cytokines (interferon γ) and T(H)2 cytokines (interleukin [IL]-5 and IL-13) as detected by ELISpot. We are currently developing this approach to investigate the allergenic potential of other drugs, including those where an association between specific human leucocyte antigen alleles and susceptibility to an immunological reaction has been established.

  • 13. Fernandes, Elsa C Antunes
    et al.
    Hendriks, Hester S
    van Kleef, Regina G D M
    Reniers, Ad
    Andersson, Patrik L
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    van den Berg, Martin
    Westerink, Remco H S
    Activation and potentiation of human GABAA receptors by non-dioxin-like PCBs depends on chlorination pattern2010In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 118, no 1, p. 183-90Article in journal (Refereed)
    Abstract [en]

    The neurotoxic potential of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is characterized by disruption of presynaptic processes, including calcium homeostasis and neurotransmitter transport. Recently, using a limited set of congeners, we demonstrated that PCB28 and PCB52 can potentiate postsynaptic GABA(A) receptors. In the present study, effects of 20 NDL-PCBs and 2 dioxin-like PCBs, selected based on their chemical variation and abundance in the environment, on human GABA(A) receptors were investigated. GABA(A) receptors were expressed in Xenopus oocytes, and NDL-PCB effects were determined using the two-electrode voltage-clamp technique. Results demonstrate that lower chlorinated PCB19, PCB28, PCB47, PCB51, PCB52, PCB95, and PCB100 act as a partial agonists (at low receptor occupancy), i.e., potentiating the receptor response during coapplication with GABA (at EC(20)). Importantly, PCB19, PCB47, PCB51, and PCB100 can also act as full agonist, i.e., activate the GABA(A) receptor in the absence of GABA. Potentiation and activation of the GABA(A) receptor is concentration dependent and limited to NDL-PCBs that have 3-5 chlorine atoms, 1-3 ortho-substitutions, an equal number (0-1) of meta-substitutions on both phenyl rings, and do not have an adjacent para- and meta-substitution on the same phenyl ring. Activation and potentiation of the GABA(A) receptor by PCB47, the most potent congener (lowest observed effect concentration of 10nM), is attenuated when coapplied with PCB19, PCB28, PCB153, or PCB180, indicative for competitive binding. Considering the importance of GABA-ergic signaling for brain development, motor coordination, learning, and memory, this mode of action can contribute to the previously observed NDL-PCB-induced neurobehavioral and neurodevelopmental effects and should be included in human risk assessment.

  • 14.
    Fischer, Celia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Co-exposure of neonatal mice to a flame retardant PBDE 99 (2,2',4,4',5-pentabromodiphenyl ether) and methylmercury enhances developmental neurotoxic defects2008In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 101, no 2, p. 275-285Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies indicate that exposure to environmental pollutants during early human development can have deleterious effects on cognitive development. The interaction between environmental pollutants is suggested as one reason for the observed defective neurological development in children from the Faeroe Islands as compared to children from the Seychelles. We have previously seen in mice that polychlorinated biphenyls (PCBs) can interact together with methyl mercury (MeHg), as well as PCB together with polybrominated diphenyl ether (PBDE 99) to exacerbate developmental neurotoxic effects when present during a critical period of neonatal brain development. PBDEs are a new class of global environmental contaminants. The present study shows that neonatal coexposure to PBDE 99 (0.8 mg/kg body weight) and MeHg (0.4 or 4.0 mg/kg body weight) can exacerbate developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, reduced habituation, and impaired learning/memory abilities. This is seen in the low dose range, where the sole compounds do no give rise to developmental neurotoxic effects. The effects seen are more than just additive. Furthermore, a significant effect of interaction was seen on the cholinergic nicotinic receptors in the cerebral cortex and hippocampus. This suggests that a mechanism for the observed cognitive defects is via the cholinergic system. Furthermore, PBDE can interact with MeHg causing developmental neurotoxic effects similar to those we previously have observed between PCB 153 + MeHg and PCB 52 + PBDE 99. This is of vital importance, as the levels of PBDEs are increasing in mother's milk and in the environment generally.

  • 15. Fletcher, Nick
    et al.
    Giese, Norbert
    Schmidt, Carsten
    Stern, Natalia
    Lind, Monica
    Institute of Environmental Medicine, Karolinska Institutet.
    Viluksela, Matti
    Tuomisto, Jouni T
    Tuomisto, Jouko
    Nau, Heinz
    Håkansson, Helen
    Altered retinoid metabolism in female Long-Evans and Han/Wistar rats following long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treatment2005In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 86, no 2, p. 264-272Article in journal (Refereed)
    Abstract [en]

    This study investigated the effects of long-term low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on retinoid, thyroid hormone, and vitamin D homeostasis in Long-Evans and Han/Wistar rats using a tumor promotion exposure protocol. Female rats (ten/group) were partially hepatectomized, initiated with nitrosodiethylamine (NDEA), and given TCDD once per week by sc injection for 20 weeks at calculated daily doses of 0, 1, 10, 100, or 1000 ng/kg bw/day. Groups of nonhepatectomized/uninitiated rats (five/group) were identically maintained. After 20 weeks, the rats were killed, and apolar retinoid levels were determined in the liver and kidneys. No consistent differences were seen between partially hepatectomized/initiated and nonhepatectomized/uninitiated animals with respect to apolar retinoid levels or hepatic TCDD concentration. Further analyses of polar and apolar retinoid levels in liver, plasma, and kidney, as well as free thyroxine (FT4) and vitamin D (25-OH-D(3)) concentrations were carried out in partially hepatectomized/inititated animals. In Long-Evans rats, TCDD exposure dose-dependently decreased hepatic retinyl ester concentrations at doses of 1-100 ng/kg bw/day. Likewise, hepatic all-trans-retinoic acid (all-trans-RA) concentration was decreased 39 and 54% at 10 and 100 ng/kg bw/day respectively, whereas 9-cis-4-oxo-13,14-dihydro-retinoic acid (9-cis-4-oxo-13,14-dihydro-RA), a recently discovered retinoic acid metabolite, was decreased approximately 60% in the liver at 1 ng/kg bw/day. TCDD dose-dependently increased plasma retinol and kidney retinol concentrations, whereas all-trans-RA concentration was also increased in the plasma and kidney at 10 and 100 ng/kg bw/day. Plasma 9-cis-4-oxo-13,14-dihydro-RA was decreased to below detection limits from doses of 1 ng/kg bw/day TCDD. A qualitatively similar pattern of retinoid disruption was observed in the Han/Wistar rat strain following TCDD exposure. FT4 was decreased to a similar extent in both strains, whereas 25-OH-D(3) was decreased only at 100 ng/kg bw/day in Long-Evans rats. Together these results show that TCDD disrupts both retinoid storage and metabolism of retinoic acid and retinoic acid metabolites in liver, kidney, and plasma from doses as low as 1 ng/kg bw/day. Furthermore, 9-cis-4-oxo-13,14-dihydro-RA was identified as a novel and sensitive indicator of TCDD exposure, in a resistant and sensitive rat strain, thereby extending the database of low-dose TCDD effects.

  • 16.
    Forsby, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Norman, Kimberly G.
    EL Andaloussi-Lilja, Johanna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Walczak, Vincent
    Curren, Rodger
    Martin, Katharine
    Tierney, Neena K.
    Using Novel In Vitro NociOcular Assay Based on TRPV1 Channel Activation for Prediction of Eye Sting Potential of Baby Shampoos2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 129, no 2, p. 325-331Article in journal (Refereed)
    Abstract [en]

    The transient receptor potential vanilloid type 1 (TRPV1) channel is one of the most well-characterized pain-inducing receptors. The purpose of this study was to predict human eye stinging of 19 baby bath and shampoo formulations by studying TRPV1 activity, as measured by increase in intracellular free Ca2+. The NociOcular test, a novel recombinant neuronal in vitro model with high expression of functional TRPV1 channels, was used to test formulations containing a variety of surfactants, preservatives, and fragrances. TRPV1-specific Ca2+ influx was abolished when the TRPV1 channel antagonist capsazepine was applied to the cells prior to shampoo samples. The positive control, an adult shampoo that contains cocamide monoethanolamine (CMEA), a known stinging ingredient, was the most active sample tested in the NociOcular test. The negative control, a marketed baby shampoo, was negative in the NociOcular and human tests. Seven of the formulations induced stinging in the human test, and of those six were positive in the NociOcular test. Twelve formulations were classified as nonstinging in the human test, and of those ten were negative in the NociOcular test. There was no correlation between the clinical stinging results for the baby formulations and the data generated from other in vitro eye irritation assays (cytosensor microphysiometer, neutral red uptake, EpiOcular, transepithelial permeability). Our data support that the TRPV1 channel is a principal mediator of eye-stinging sensation induced by baby bath and shampoo formulations and that the NociOcular test may be a valuable in vitro tool to predict human eye stinging sensation.

  • 17.
    Guruge, K S
    et al.
    Toxico-Biochemistry Section, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki, Japan.
    Yeung, L W Y
    Toxico-Biochemistry Section, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki, Japan;Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, Hong Kong.
    Yamanaka, N
    Toxico-Biochemistry Section, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki, Japan.
    Miyazaki, S
    Toxico-Biochemistry Section, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki, Japan.
    Lam, P K S
    Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, Hong Kong.
    Giesy, J P
    Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, Hong Kong;Zoology Dept., National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI, United States.
    Jones, P D
    Zoology Dept., National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI, United States.
    Yamashita, N
    Environmental Measurement Group, National Institute of Advance Industrial Science and Technology, Onogawa 16-1, Tsukuba, Ibaraki, Japan.
    Gene expression profiles in rat liver treated with perfluorooctanoic acid (PFOA)2006In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 89, no 1, p. 93-107Article in journal (Refereed)
    Abstract [en]

    Perfluorooctanoic acid (PFOA; Pentadecafluorooctanoic acid) is widely used in various industrial applications. It is persistent in the environment and does not appear to undergo further degradation or transformation. PFOA is found in tissues including blood of wildlife and humans; however, the environmental fate and biological effects of PFOA remain unclear. Microarray techniques of gene expression have become a powerful approach for exploring the biological effects of chemicals. Here, the Affymetrix, Inc. rat genome 230 2.0 GeneChip was used to identify alterations in gene regulation in Sprague-Dawley rats treated with five different concentrations of PFOA. Male rats were exposed by daily gavage to 1, 3, 5, 10, or 15 mg PFOA/kg, body weight (bw)/day for 21 days and at the end of the exposure, liver was isolated and total liver RNA were used for the gene chip analysis. Over 500 genes, whose expression was significantly (p < 0.0025) altered by PFOA at two-fold changes compared to control, were examined. The effects were dose-dependent with exposure to 10 mg PFOA/kg, bw/day, causing alteration in expression of the greatest number of genes (over 800). Approximately 106 genes and 38 genes were consistently up- or down-regulated, respectively, in all treatment groups. The largest categories of induced genes were those involved in transport and metabolism of lipids, particularly fatty acids. Other induced genes were involved in cell communication, adhesion, growth, apoptosis, hormone regulatory pathways, proteolysis and peptidolysis and signal transduction. The genes expression of which was suppressed were related to transport of lipids, inflammation and immunity, and especially cell adhesion. Several other genes involved in apoptosis; regulation of hormones; metabolism; and G-protein coupled receptor protein signaling pathways were significantly suppressed.

  • 18. Hamers, Timo
    et al.
    Kamstra, Jorke H
    Cenijn, Peter H
    Pencikova, Katerina
    Palkova, Lenka
    Simeckova, Pavlina
    Vondracek, Jan
    Andersson, Patrik L
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stenberg, Mia
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Machala, Miroslav
    In Vitro toxicity profiling of ultrapure non-dioxin-like polychlorinated biphenyl congeners and their relative toxic contribution to PCB mixtures in humans2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 121, no 1, p. 88-100Article in journal (Refereed)
    Abstract [en]

    The toxic equivalency concept used for the risk assessment of polychlorinated biphenyls (PCBs) is based on the aryl hydrocarbon receptor (AhR)-mediated toxicity of coplanar dioxin-like (DL) PCBs. Most PCBs in the environment, however, are non-dioxin-like (NDL) PCBs that cannot adopt a coplanar structure required for AhR activation. For NDL-PCBs, no generally accepted risk concept is available because their toxicity is insufficiently characterized. Here, we systematically determined in vitro toxicity profiles for 24 PCBs regarding 10 different mechanisms of action. Prior to testing, NDL-PCB standards were purified to remove traces of DL compounds. All NDL-PCBs antagonized androgen receptor activation and inhibited gap junctional intercellular communication (GJIC). Lower chlorinated NDL-PCBs were weak estrogen receptor (ER) agonists, whereas higher chlorinated NDL-PCBs were weak ER antagonists. Several NDL-PCBs inhibited estradiol-sulfotransferase activity and bound to transthyretin (TTR) but with much weaker potencies than reported for hydroxylated PCB metabolites. AhR-mediated expression of uridine-glucuronyl transferase isozyme UGT1A6 was induced by DL-PCBs only. Hierarchical cluster analysis of the toxicity profiles yielded three separate clusters of NDL-PCBs and a fourth cluster of reference DL-PCBs. Due to small differences in relative potency among congeners, the highly abundant indicator PCBs 28, 52, 101, 118, 138, 153, and 180 also contributed most to the antiandrogenic, (anti)estrogenic, antithyroidal, tumor-promoting, and neurotoxic potencies calculated for PCB mixtures reported in human samples, whereas the most potent AhR-activating DL-PCB-126 contributed at maximum 0.2% to any of these calculated potencies. PCB-168 is recommended as an additional indicator congener, given its relatively high abundance and antiandrogenic, TTR-binding, and GJIC-inhibiting potencies.

  • 19.
    Hansson, Sven Ove
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Priority-Setting in the REACH System2006In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 90, no 2, p. 304-308Article in journal (Refereed)
    Abstract [en]

    Due to the large number of chemicals for which toxicological and ecotoxicological information is lacking, priority setting for data acquisition is a major concern in chemicals regulation. In the current European system, two administrative priority-setting criteria are used, namely novelty (i.e., time of market introduction) and production volume. In the proposed Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) system, the novelty criterion is no longer used, and production volume will be the main priority-setting criterion for testing requirements, supplemented in some cases with hazard indications obtained from QSAR modelling. This system for priority setting has severe weaknesses. In this paper we propose that a multicriteria system should be developed that includes at least three additional criteria: chemical properties, results from initial testing in a tiered system, and voluntary testing for which efficient incentives can be created. Toxicological and decision-theoretical research is needed to design testing systems with validated priority-setting mechanisms.

  • 20. Hendriks, Hester S.
    et al.
    Fernandes, Elsa C. Antunes
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    van den Berg, Martin
    Westerink, Remco H. S.
    PCB-47, PBDE-47, and 6-OH-PBDE-47 Differentially Modulate Human GABA(A) and alpha(4)beta(2) Nicotinic Acetylcholine Receptors2010In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 118, no 2, p. 635-642Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) and the structurally related polybrominated diphenyl ethers (PBDEs) are abundant persistent organic pollutants that exert several comparable neurotoxic effects. Importantly, hydroxylated metabolites of PCBs and PBDEs have an increased neurotoxic potency. Recently, we demonstrated that PCBs can act as (partial) agonist on GABA(A) neurotransmitter receptors, with PCB-47 being the most potent congener. It is, however, unknown whether PBDE-47 and its metabolite 6-OH-PBDE-47 exert similar effects and if these effects are limited to GABA(A) receptors only. We therefore investigated effects of PCB-47, PBDE-47, and 6-OH-PBDE-47 on the inhibitory GABA(A) and excitatory alpha(4)beta(2) nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Since human exposure is generally not limited to individual compounds, experiments with binary mixtures were also performed. The results demonstrate that PCB-47 and 6-OH-PBDE-47 act as full and partial agonist on the GABA(A) receptor. However, both congeners act as antagonist on the nACh receptor. PBDE-47 does not affect either type of receptor. Binary mixtures of PCB-47 and 6-OH-PBDE-47 induced an additive activation as well as potentiation of GABA(A) receptors, whereas this mixture resulted in an additive inhibition of nACh receptors. Binary mixtures of PBDE-47 and 6-OH-PBDE-47 yielded similar effects as 6-OH-PBDE-47 alone. These findings demonstrate that GABA(A) and nACh receptors are affected differently by PCB-47 and 6-OH-PBDE-47, with inhibitory GABA(A)-mediated signaling being potentiated and excitatory alpha(4)beta(2) nACh-mediated signaling being inhibited. Considering these opposite actions and the additive interaction of the congeners, these effects are likely to be augmented in vivo.

  • 21.
    Holmgren, Gustav
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Takara Bio Europe AB, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca Gothenburg, CVMD GMed, GMD, Mölndal, Sweden.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin - integration and visualization of multi omics data2018In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 163, no 1, p. 182-195Article in journal (Refereed)
    Abstract [en]

    Anthracyclines, such as doxorubicin, are highly efficient chemotherapeutic agents against a variety of cancers. However, anthracyclines are also among the most cardiotoxic therapeutic drugs presently on the market. Chemotherapeutic-induced cardiomyopathy is one of the leading causes of disease and mortality in cancer survivors. The exact mechanisms responsible for doxorubicin-induced cardiomyopathy are not completely known, but the fact that the cardiotoxicity is dose-dependent and that there is a variation in time-to-onset of toxicity, and gender- and age differences suggests that several mechanisms may be involved.In the present study, we investigated doxorubicin-induced cardiotoxicity in human pluripotent stem cell-derived cardiomyocytes using proteomics. In addition, different sources of omics data (protein, mRNA, and microRNA) from the same experimental setup were further combined and analyzed using newly developed methods to identify differential expression in data of various origin and types. Subsequently, the results were integrated in order to generate a combined visualization of the findings.In our experimental model system, we exposed cardiomyocytes derived from human pluripotent stem cells to doxorubicin for up to two days, followed by a wash-out period of additionally 12 days. Besides an effect on the cell morphology and cardiomyocyte functionality, the data show a strong effect of doxorubicin on all molecular levels investigated. Differential expression patterns that show a linkage between the proteome, transcriptome, and the regulatory microRNA network, were identified. These findings help to increase the understanding of the mechanisms behind anthracycline-induced cardiotoxicity and suggest putative biomarkers for this condition.

  • 22.
    Högberg, Helena T.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Kinsner-Ovaskainen, Agnieszka
    In vitro methods unit.
    Coecke, Sandra
    In vitro methods unit.
    Hartung, Thomas
    Johns Hopkins University.
    Bal-Price, Anna
    In vitro methods unit.
    mRNA Expression is a Relevant Tool to Identify Developmental Neurotoxicants Using an In Vitro Approach2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 113, no 1, p. 95-115Article in journal (Refereed)
    Abstract [en]

    So far, only a few industrial chemicals have been identified as developmental neurotoxicants. Because the current developmental neurotoxicity (DNT) guideline (Organisation for Economic Cooperation and Development TG 426) is based entirely on in vivo studies that are both time consuming and costly, there is a need to develop alternative in vitro methods for initial screening to prioritize chemicals for further DNT testing. In this study, gene expression at the mRNA level was evaluated to determine whether this could be a suitable endpoint to detect potential developmental neurotoxicants. Primary cultures of rat cerebellar granule cells (CGCs) were exposed to well known (developmental) neurotoxicants (methyl mercury chloride, lead chloride, valproic acid, and tri-methyl tin chloride) for different time periods. A significant downregulation of the mRNA level for the neuronal markers (NF- 68, NF-200, N-methyl D-aspartate glutamate receptor, and gamma amino butyric acid receptor) was observed after exposure to methyl mercury chloride, valproic acid, and tri-methyl tin chloride. Moreover, a significant increase of the neural precursor marker nestin mRNA was also observed. The mRNA expression of the astrocytic markers (glial fibrillary acidic protein [GFAP] and S100b) was unchanged. In contrast, exposure to lead chloride significantly decreased the mRNA level of the astrocytic marker GFAP, whereas the neuronal markers were less affected. These results suggest that gene expression could be used as a sensitive tool for the initial identification of DNT effects induced by different mechanisms of toxicity in both cell types (neuronal and glial) and at various stages of cell development and maturation.

  • 23.
    Jergil, Måns
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Forsberg, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salter, Hugh
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Nau, Heinz
    Center for Food Science, Department of Food Toxicology, Veterinary University, Hannover.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Short-Time Gene Expression Response to Valproic Acid and Valproic Acid analogs in Mouse Embryonic Stem Cells2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 121, no 2, p. 328-342Article in journal (Refereed)
    Abstract [en]

    The prediction of potential developmental toxicity in vitro could be based ontoxicogenomic endpoints a short time after exposure in cultured embryo-derived celllines. Our previous microarray studies in P19 mouse embryonal carcinoma cells andmouse embryos have indicated that the teratogen valproic acid (VPA), an inducerof neural tube defects, deregulates the expression of a large number of genes, manyof which have critical roles in neural tube formation and closure. In this study weexposed undifferentiated R1 mouse embryonic stem (ES) cells to VPA and VPA analogto define genes whose expression responses may be related to teratogenic potential.After 6 h of exposure, RNA samples were subjected to microarray analysis usingCodeLinkTM Mouse Whole Genome Bioarrays. VPA (1 mM) and the teratogenic VPAanalog (S)-2-pentyl-4-pentynoic (0.25 mM or 0.5 mM) deregulate a large numberof genes, whereas for the non-teratogenic (and potentially pharmacologically active)analog 2-ethyl-4-methyl-pentanoic acid (1 mM) the expression of only a few geneswas affected. Biological process ontology groups related to embryonic development,morphogenesis, and cell behavior were overrepresented among the affected teratogentarget genes. Multivariate analysis indicated that as few as five genes (out of ~2500array probes correlating with the separation) could separate the data set accordingto teratogenicity. Genes deregulated by the two teratogens showed a substantialoverlap with genes previously found to be deregulated by VPA in P19 cells and mouseembryos. A panel of candidate genes was defined as potential markers predictiveof teratogenicity and evaluated through TaqMan low density array analysis. Theteratogens butyrate and trichostatin A, which like VPA and (S)-2-pentyl-4-pentynoicacid are known histone deacetylase (HDAC) inhibitors, induced similar responsesas these two teratogens for a large subset of markers. This indicates that HDACinhibition may be a major mechanism by which VPA induces gene deregulation andpossibly teratogenicity. Other teratogenic compounds tested had no effect on thepanel of selected markers, indicating that they may not be predicitive of teratogenicityfor compounds acting through other mechanisms than VPA.

  • 24.
    Jergil, Måns
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gustafson, Anne-Lee
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Valproic acid-induced deregulation in vitro of genes associated in vivo with neural tube defects2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 108, no 1, p. 132-148Article in journal (Refereed)
    Abstract [en]

    The utility of an in vitro system to search for molecular targets and markers of developmental toxicity was explored, using microarrays to detect genes susceptible to deregulation by the teratogen valproic acid (VPA) in the pluripotent mouse embryonal carcinoma cell line P19. Total RNA extracted from P19 cells cultured in the absence or presence of 1, 2.5, or 10mM VPA for 1.5, 6, or 24 h was subjected to replicated microarray analysis, using CodeLink UniSet I Mouse 20K Expression Bioarrays. A moderated F-test revealed a significant VPA response for 2972 (p < 10(-3)) array probes (19.4% of the filtered gene list), 421 of which were significant across all time points. In a core subset of VPA target genes whose expression was downregulated (68 genes) or upregulated (125 genes) with high probability (p < 10(-7)) after both 1.5 and 6 h of VPA exposure, there was a significant enrichment of the biological process Gene Ontology term transcriptional regulation among downregulated genes, and apoptosis among upregulated, and two of the downregulated genes (Folr1 and Gtf2i) have a knockout phenotype comprising exencephaly, the major malformation induced by VPA in mice. The VPA-induced gene expression response in P19 cells indicated that approximately 30% of the approximately 200 genes known from genetic mouse models to be associated with neural tube defects may be potential VPA targets, suggestive of a combined deregulation of multiple genes as a possible mechanism of VPA teratogenicity. Gene expression responses related to other known effects of VPA (histone deacetylase inhibition, G(1)-phase cell cycle arrest, induction of apoptosis) were also identified. This study indicates that toxicogenomic responses to a teratogenic compound in vitro may correlate with known in vitro and in vivo effects, and that short-time (< or =6 h) exposures in such an in vitro system could provide a useful component in mechanistic studies and screening tests in developmental toxicology.

  • 25.
    Johansson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Neonatal exposure to PFOS and PFOA in mice results in changes in proteins which are important for neuronal growth and synaptogenesis in the developing brain2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 108, no 2, p. 412-418Article in journal (Refereed)
    Abstract [en]

    Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) belong to the family of perfluorinated compounds (PFCs). They are used in industrial and consumer applications, e.g. clothing fabrics, carpets and food packaging. PFOS and PFOA are present in the environment and are found in dust and human milk, which implies that newborns and toddlers can be directly exposed to these agents during brain development. Recently, we reported that PFOS and PFOA can cause neurobehavioral defects and changes in the cholinergic system, in the adult animal, when given directly to neonatal mice, and thereby showing similarities with other investigated persistent organic pollutants (POPs), such as DDT, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). In recent studies, we have also seen that highly brominated PBDEs can affect the levels of proteins that are important for neuronal growth and synaptogenesis in the neonatal mouse brain. The present study shows that a single oral dose of either 21 µmol PFOS or PFOA/kg body weight (11.3 mg or 8.70 mg), given directly to the neonatal mice on postnatal day 10, significantly increased the levels of CaMKII, GAP-43, and synaptophysin in the hippocampus of the neonatal mouse. Both compounds significantly increased the levels of synaptophysin and tau in cerebral cortex and PFOA also increased the levels of tau in hippocampus. Since these proteins are important for normal brain development and altered levels of these proteins during a critical period of the brain growth spurts (BGS) could be one of the mechanisms behind earlier reported behavioral defects.

  • 26.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Jenny, Matthew J.
    Woodin, Bruce R.
    Hahn, Mark E.
    Stegeman, John J.
    Role of AHR2 in the expression of novel cytochrome P450 1 family genes, cell cycle genes, and morphological defects in developing zebra fish exposed to 3,3′,4,4′,5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo- p -dioxin2007In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 100, no 1, p. 180-193Article in journal (Refereed)
    Abstract [en]

    Halogenated agonists for the aryl hydrocarbon receptor (AHR), such as 3,3',4,4',5-pentachlorobiphenyl (PCB126) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause developmental toxicity in fish. AHR dependence of these effects is known for TCDD but only presumed for PCB126, and the AHR-regulated genes involved are known only in part. We defined the role of AHR in regulation of four cytochrome P450 1 (CYP1) genes and the effect of PCB126 on cell cycle genes (i.e., PCNA and cyclin E) in zebra fish (Danio rerio) embryos. Basal and PCB126-induced expression of CYP1A, CYP1B1, CYP1C1, and CYP1C2 was examined over time as well as in relation to cell cycle gene expression and morphological effects of PCB126 in developing zebra fish. The four CYP1 genes differed in the time for maximal basal and induced expression, i.e., CYP1B1 peaked within 2 days postfertilization (dpf), the CYP1Cs around hatching (3 dpf), and CYP1A after hatching (14–21 dpf). These results indicate developmental periods when the CYP1s may play physiological roles. PCB126 (0.3–100nM) caused concentration-dependent CYP1 gene induction (EC50: 1.4–2.7nM, Lowest observed effect concentration [LOEC]: 0.3–1nM) and pericardial edema (EC50: 4.4nM, LOEC: 3nM) in 3-dpf embryos. Blockage of AHR2 translation significantly inhibited these effects of PCB126 and TCDD. PCNA gene expression was reduced by PCB126 in a concentration-dependent manner, suggesting that PCB126 could suppress cell proliferation. Our results indicate that the four CYP1 genes examined are regulated by AHR2 and that the effect of PCB126 on morphology in zebra fish embryos is AHR2 dependent. Moreover, the developmental patterns of expression and induction suggest that CYP1 enzymes could function in normal development and in developmental toxicity of PCB126 in fish embryos.

  • 27.
    Jönsson, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jenny, Matthew J.
    Woodin, Bruce R.
    Hahn, Mark E.
    Stegeman, John J.
    Role of AHR2 in the expression of novel cytochrome p450 1 family genes, cell cycle genes, and morphological defects in developing zebra fish exposed to 3,3 ',4,4 ',5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin2007In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 100, no 1, p. 180-193Article in journal (Refereed)
  • 28.
    Karim, Md Rezaul
    et al.
    Rajshahi University, Bangladesh / Islamic University, Bangladesh.
    Rahman, Mashiur
    Rajshahi University, Bangladesh.
    Islam, Khairul
    Rajshahi University, Bangladesh.
    Al Mamun, Abdullah
    Rajshahi University, Bangladesh.
    Hossain, Shakhawoat
    Rajshahi University, Bangladesh.
    Hossain, Ekhtear
    Rajshahi University, Bangladesh.
    Aziz, Abdul
    Rajshahi University, Bangladesh.
    Yeasmin, Fouzia
    Rajshahi University, Bangladesh.
    Agarwal, Smita
    Rajshahi University, Bangladesh.
    Hossain, Md Imam
    Rajshahi University, Bangladesh.
    Saud, Zahangir Alam
    Rajshahi University, Bangladesh.
    Nikkon, Farjana
    Rajshahi University, Bangladesh.
    Hossain, Mostaque
    Rajshahi University, Bangladesh.
    Mandal, Abul
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Jenkins, Richard O.
    De Montfort University, United Kingdom .
    Haris, Parvez I.
    De Montfort University, United Kingdom .
    Miyataka, Hideki
    Tokushima Bunri University, Japan.
    Himeno, Seiichiro
    Tokushima Bunri University, Japan.
    Hossain, Khaled
    Rajshahi University, Bangladesh.
    Increases in Oxidized Low-Density Lipoprotein and Other Inflammatory and Adhesion Molecules With a Concomitant Decrease in High-Density Lipoprotein in the Individuals Exposed to Arsenic in Bangladesh2013In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 135, no 1, p. 17-25Article in journal (Refereed)
    Abstract [en]

    Elevated exposure to arsenic has been suggested to be associated with atherosclerosis leading to cardiovascular disease (CVD). However, biochemical events underlying the arsenic-induced atherosclerosis have not yet been fully documented. The aim of this study was to investigate the associations of circulating molecules involved in atherosclerosis with arsenic exposure in the individuals exposed to arsenic in Bangladesh. A total of 324 study subjects, 218 from arsenic-endemic areas and 106 from nonendemic areas in Bangladesh, were recruited. Drinking water, hair, nail, and blood samples were collected from the study subjects for analysis. Total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels were lower in arsenic-endemic subjects than those of nonendemic subjects. Oxidized LDL (Ox-LDL), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) levels were significantly higher in arsenic-endemic subjects than those in nonendemic subjects. All these circulating molecules showed significant correlations with arsenic exposure (water, hair, and nail arsenic concentrations), and all these relations were significant before and after adjusting for relevant covariates. Among the circulating molecules tested in this study, HDL, Ox-LDL, and CRP showed dose-response relationships with arsenic exposure. Ox-LDL/ HDL ratios were increased with the increasing concentrations of arsenic in the water, hair, and nails. Furthermore, non-HDL cholesterol and TC/ HDL ratios were significantly correlated with arsenic exposure before and after adjusting for relevant covariates. Thus, all the observed associations may be the major features of arsenic exposure-related atherosclerosis leading to CVD.

  • 29.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Lindström, Anna-Karin
    Hanrieder, Jorg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arnerup, Gunnel
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neonatal Exposure to the Cyanobacterial Toxin BMAA Induces Changes in Protein Expression and Neurodegeneration in Adult Hippocampus2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 130, no 2, p. 391-404Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin -N-methylamino-l-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 910) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460mg/kg) also induced changes in the expression of S100, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.

  • 30.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Selective Brain Uptake and Behavioral Effects of the Cyanobacterial Toxin BMAA (β-N-Methylamino-L-alanine) following Neonatal Administration to Rodents2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 109, no 2, p. 286-295Article in journal (Refereed)
    Abstract [en]

    Cyanobacteria are extensively distributed in terrestrial and aquatic environments all over the world. Most cyanobacteria can produce the neurotoxin ss-N-methylamino-L-alanine (BMAA), which has been detected in several water systems and could accumulate in food chains. The aim of the study was to investigate the transfer of BMAA to fetal and neonatal brains and the effects of BMAA on the development of behavioral characteristics during the brain growth spurt (BGS) in rodents Pregnant and neonatal mice were given an injection of (3)H-BMAA on gestational day 14 and postnatal day (PND) 10, respectively, and processed for tape-section autoradiography. The study revealed transplacental transfer of (3)H-BMAA and a significant uptake in fetal mouse. The radioactivity was specifically located in the hippocampus, striatum, brainstem, spinal cord and cerebellum of 10-day-old mice. The effect of repeated BMAA treatment (200 or 600 mg/kg sc) during BGS on rat behavior was also studied. BMAA treatment on PND 9-10 induced acute alterations, such as impaired locomotor ability and hyperactivity, in the behavior of neonatal rats. Furthermore, rats given the high dose of BMAA failed to habituate to the test environment when tested at juvenile age. In conclusion, the results demonstrated that BMAA was transferred to the neonatal brain and induced significant changes in the behavior of neonatal rats following administration during BGS. The observed behavioral changes suggest possible cognitive impairment. Increased information on the long-term effects of BMAA on cognitive function following fetal and neonatal exposure is required for assessment of the risk to children's health.

  • 31.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 112, no 1, p. 185-195Article in journal (Refereed)
    Abstract [en]

    Most cyanobacteria (blue-green algae) can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9-10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.

  • 32. Katchy, Anne
    et al.
    Pinto, Caroline
    Jonsson, Philip
    Nguyen-Vu, Trang
    Pandelova, Marchela
    Riu, Anne
    Schramm, Karl-Werner
    Samarov, Daniel
    Gustafsson, Jan-Åke
    Bondesson, Maria
    Williams, Cecilia
    University of Houston, United States .
    Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner2014In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 138, no 1, p. 21-35Article in journal (Refereed)
    Abstract [en]

    Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.

  • 33.
    Kia, Richard
    et al.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Kelly, Lorna
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Sison-Young, Rowena L. C.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Zhang, Fang
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Pridgeon, Chris S.
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Heslop, James A.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Metcalfe, Pete
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England.
    Kitteringham, Neil R.
    Univ Liverpool, Dept Mol & Clin Pharmacol, England / Stem Cells Safer Med, London, England.
    Baxter, Melissa
    Univ Manchester, Fac Life Sci, Manchester, England / Univ Cent Lancashire, Sch Med & Dent, Preston, England.
    Harrison, Sean
    Stem Cells Safer Med, London, England / Acad Hlth Sci Ctr, Fac Med & Human Sci, Ctr Endocrinol & Diabet,Inst Human Dev, Manchester, England.
    Hanley, Neil A.
    Stem Cells Safer Med, London, England / Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Med & Human Sci, Ctr Endocrinol & Diabet,Inst Human Dev, Manchester, England / Cent Manchester Univ Hosp NHS Fdn Trust, Endocrinol Dept, Manchester England.
    Burke, Zoe D.
    Stem Cells Safer Med, London, England / Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Storm,, Mike P.
    Stem Cells Safer Med, London, England / Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Welham, Melanie J.
    Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Tosh, David
    Stem Cells Safer Med, London, England / Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath, England.
    Küppers-Munther, Barbara
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Takara Bio Europe AB, Gothenburg, Sweden.
    Edsbagge, Josefina
    Takara Bio Europe AB, Gothenburg, Sweden.
    Lewis, Philip J. Starkey
    Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland.
    Bonner, Frank
    Stem Cells Safer Med, London, England.
    Harpur, Ernie
    Stem Cells Safer Med, London, England / Newcastle Univ, Inst Cellular Med, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
    Sidaway, James
    Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland / AstraZeneca R&D, Drug Safety & Metab, Cheshire, England.
    Bowes, Joanne
    Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland / AstraZeneca R&D, Drug Safety & Metab, Cheshire, England.
    Fenwick, Stephen W.
    Aintree Univ Hosp NHS Fdn Trust, North Western Hepatobiliary Unit, Liverpool, England.
    Malik, Hassan
    Aintree Univ Hosp NHS Fdn Trust, North Western Hepatobiliary Unit, Liverpool, England.
    Goldring, Chris E. P.
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England / Stem Cells Safer Med, London England.
    Park, B. Kevin
    Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, England / Stem Cells Safer Med, London, England.
    MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity2015In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 144, no 1, p. 173-185Article in journal (Refereed)
    Abstract [en]

    Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.

  • 34. Krementsov, Dimitry N
    et al.
    Katchy, Anne
    Case, Laure K
    Carr, Frances E
    Davis, Barbara
    Williams, Cecilia
    University of Houston, United States .
    Teuscher, Cory
    Studies in experimental autoimmune encephalomyelitis do not support developmental bisphenol a exposure as an environmental factor in increasing multiple sclerosis risk2013In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 135, no 1, p. 91-102Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS), a demyelinating immune-mediated central nervous system disease characterized by increasing female penetrance, is the leading cause of disability in young adults in the developed world. Epidemiological data strongly implicate an environmental factor, acting at the population level during gestation, in the increasing incidence of female MS observed over the last 50 years, yet the identity of this factor remains unknown. Gestational exposure to bisphenol A (BPA), an endocrine disruptor used in the manufacture of polycarbonate plastics since the 1950s, has been reported to alter a variety of physiological processes in adulthood. BPA has estrogenic activity, and we hypothesized that increased gestational exposure to environmental BPA may therefore contribute to the increasing female MS risk. To test this hypothesis, we utilized two different mouse models of MS, experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice (chronic progressive) and in SJL/J mice (relapsing-remitting). Dams were exposed to physiologically relevant levels of BPA in drinking water starting 2 weeks prior to mating and continuing until weaning of offspring. EAE was induced in adult offspring. No significant changes in EAE incidence, progression, or severity were observed with BPA exposure, despite changes in cytokine production by autoreactive T cells. However, endocrine disruption was evidenced by changes in testes development, and transcriptomic profiling revealed that BPA exposure altered the expression of several genes important for testes development, including Pdgfa, which was downregulated. Overall, our results do not support gestational BPA exposure as a significant contributor to the increasing female MS risk.

  • 35. Lei, Li-Jian
    et al.
    Chen, Liang
    Jin, Tai-Yi
    Nordberg, Monica
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Environmental Medicine.
    Chang, Xiu-Li
    Estimation of benchmark dose for pancreatic damage in cadmium-exposed smelters2007In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 97, no 1, p. 189-195Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to estimate the benchmark dose (BMD) for pancreas dysfunction caused by cadmium (Cd) exposure in smelters. Smelter workers who had been exposed to Cd for more than 1 year and matching nonoccupationally exposed subjects were asked to participate in this study. Urinary cadmium (UCd) was used as a biomarker for exposure, serum insulin and amylase were used as biomarkers for pancreatic effects. In this study, serum insulin and amylase were lower in the smelter workers than in the nonoccupationally exposed subjects. A significant dose-response relationship with UCd was displayed. BMI)s in terms of urinary Cd corrected for creatinine were calculated by use of BMDS (version 1.3.2). The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. It was found that the BMDL10 for serum insulin and serum amylase was 3.7 and 5.3 mu g/g Cr, respectively. Compared to the BMDL for renal damage caused by Cd exposure, identified by the effect biomarkers urinary beta(2)-microglobulin, urinary N-acetyl-beta-glucosaminidase, and urinary albumin (UALB), it was shown that BMDL10 for serum insulin is the lowest among all values and UALB gave the highest value (5.8 mu g/g Cr). This study indicates that Cd exposure can result in pancreatic dysfunction and the effect appears at lower urinary Cd level than renal dysfunction. The endocrine function of the pancreas was affected at lower urinary levels of Cd, compared to the exocrine function, which was seen at higher urinary levels of Cd than those giving rise to renal tubular dysfunction.

  • 36.
    Lilienthal, Hellmuth
    et al.
    Center of Toxicology, IPA – Institute for Prevention and Occupational Medicine, German Social Accident Insurance, Ruhr University of Bochum, 44789 Bochum, Germany.
    Heikkinen, Päivi
    Department of Environmental Health, THL – National Institute for Health and Welfare, 70701 Kuopio, Finland.
    Andersson, Patrik L
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    van der Ven, Leo T M
    Laboratory for Health Protection Research, RIVM - National Institute of Public Health and the Environment, 3720 BA Bilthoven, The Netherlands.
    Viluksela, Matti
    Department of Environmental Health, THL – National Institute for Health and Welfare, 70701 Kuopio, Finland.
    Auditory effects of developmental exposure to purity-controlled Polychlorinated Biphenyls (PCB52 and PCB180) in rats2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 122, no 1, p. 100-111Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are still present in the environment, with ongoing exposure in humans, including babies nursed by their mothers. Whereas toxicity of dioxin-like PCBs is well described, less systematic knowledge is available for non-dioxin-like PCBs (NDL-PCBs) which do not act via the Ah receptor. This study compared effects of developmental exposure to two ultrapure NDL-PCB congeners (PCB52 and PCB180) on auditory function in rats, using the brainstem auditory evoked potential (BAEP). Pregnant rats received repeated oral doses of PCB52 (total dose - 0, 30, 100, 300, 1000, or 3000 mg/kg body weight) or of PCB180 (total dose - 0, 10, 30, 100, 300, or 1000 mg/kg). BAEPs were recorded in adult male and female offspring after stimulation with clicks or pure tones in the frequency range from 0.5 kHz to 16 kHz. Significant elevation of BAEP thresholds were detected in the low-frequency range after developmental exposure to PCB52. Calculation of benchmark doses revealed lowest values in the frequency range of 0.5 - 2 kHz. Effects were more pronounced in male compared to female offspring. Latencies of waves II and IV were prolonged in exposed males, while only wave IV was affected in females. PCB180 increased thresholds only at few conditions and only in female offspring. These results confirm that developmental exposure to ultrapure NDL-PCBs affects auditory function, but different congeners exhibit differences in potencies.

  • 37.
    Lilja, Johanna
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lindegren, Helene
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Surfactant-Induced TRPV1 Activity—A Novel Mechanismfor Eye Irritation?2007In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 99, no 1, p. 174-180Article in journal (Refereed)
    Abstract [en]

    The pain receptor transient receptor potential vanilloid type 1 (TRPV1) has been reported as one of the key components in the pain pathway.  Activation of the receptor causes a Ca2+ influx with secondary effects leading to neurogenic inflammation. Here we report specific activation of TRPV1 by detergent-containing hygiene products measured as intracellular Ca2+ influxes in stably TRPV1-expressing neuroblastoma SH-SY5Y cells. Children products marketed as “painless” (containing lower concentration of detergents), and conditioners (without detergents) did not induce specific TRPV1 activation. Furthermore, low concentrations of the detergent sodium lauryl sulfate (SLS) dose-dependently induced Ca2+ influxes that could be addressed to TRPV1. These results reveal a novel mechanistic pathway for surfactant-induced nociception, which may be an important endpoint in in vitro test batteries as alternatives to Draize’s rabbit eye test for classification of eye irritating products.

  • 38.
    Machtinger, Ronit
    et al.
    Tel Aviv Univ, Ramat Gan & Sackler Sch Med, Sheba Med Ctr, Tel Aviv, Israel.
    Zhong, Jia
    Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA.
    Mansur, Abdallah
    Tel Aviv Univ, Ramat Gan & Sackler Sch Med, Sheba Med Ctr, Tel Aviv, Israel.
    Adir, Michal
    Tel Aviv Univ, Ramat Gan & Sackler Sch Med, Sheba Med Ctr, Tel Aviv, Israel.
    Racowsky, Catherine
    Brigham & Womens Hosp, Boston, MA USA; Harvard Med Sch, Boston, MA USA.
    Hauser, Russ
    Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA.
    Brennan, Kasey
    Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden.
    Baccarelli, Andrea A
    Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA.
    Placental lncRNA Expression Is Associated With Prenatal Phthalate Exposure2018In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 163, no 1, p. 116-122Article in journal (Refereed)
    Abstract [en]

    Phthalates are endocrine-disrupting chemicals that can cross the placenta and affect the fetal epigenome. Among various epigenetic regulators of gene expression, long noncoding RNAs (lncRNAs) are important players that may also be involved in the manifestation of endocrine-disrupting chemical toxicity. We sought to explore the association between maternal urinary phthalate metabolite concentrations and lncRNA expression in human placenta to better understand potential mechanisms through which lncRNAs participate in mediating phthalate toxicity. Ten patients with uncomplicated dichorionic diamniotic twin pregnancies at term were included in this study. Urinary (n = 10) and placenta samples (n = 20) were collected for all participants. Urinary samples were analyzed for 15 phthalate metabolites and 2 phthalate alternative metabolites. Real-time PCR arrays were used to identify and quantify 87 lncRNAs from the placental samples. We tested the Spearman correlation matrix to compare prenatal phthalate measures against placental lncRNA levels. lncRNA levels showed large variations across samples, with no significant differences in lncRNA expression within twin pairs. Mono-(carboxynonyl) phthalate demonstrated consistently strong correlations with most lncRNAs. The strongest correlation was observed between mono-hydroxyisobutyl phthalate and LOC91450 (Rspearman = 0.88, p < .001). This correlation remained significant after Bonferroni adjustment. Other strong correlations were observed between mono-isobutyl phthalate, DPP10 and HOTTIP (Rspearman = −0.91, p < .001). AIRN, DACT3.AS1, DLX6, DPP10, HOTTIP, LOC143666, and LOC91450 were strongly correlated with the greatest number of phthalate metabolites. Further studies are needed to validate these results and understand if the altered expression of lncRNAs in human placenta has clinical significance.

  • 39. Montano, Mauricio
    et al.
    Cocco, Emmanuelle
    Guignard, Cedric
    Marsh, Göran
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Hoffmann, Lucien
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Gutleb, Arno Christian
    Murk, Albertinka Jacoba
    New Approaches to Assess the Transthyretin Binding Capacity of Bioactivated Thyroid Hormone Disruptors2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 130, no 1, p. 94-105Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) and polybrominated diphenyl-ethers (PBDEs) are metabolized into hydroxylated metabolites (OH-PCBs/PBDEs), which can disrupt the thyroid hormone homeostasis. Binding of these metabolites to transport proteins such as transthyretin (TTR) is an important mechanism of their toxicity. Several methods to quantify the competitive thyroxine (T-4) displacement potency of pure metabolites exist. However, quantification of the potency of in vitro metabolized PCBs and PBDEs has drawbacks related to the coextraction of compounds disturbing the T-4-TTR competitive binding assay. This study identifies and quantifies the major coextractants namely cholesterol, saturated and nonsaturated fatty acids (SFA and NSFA) at levels above 20 nmol per mg equivalent protein following various extraction methods. Their TTR binding potency was analyzed in a downscaled, nonradioactive fluorescence displacement assay. At concentration factors needed for TTR competitive binding, at least 10M of these coextracts is present, whereas individual SFA and NSFA disturb the assay from 0.3M. The effectiveness of the in vitro metabolism and extraction of the model compounds CB 77 and BDE 47 was chemically quantified with a newly developed chromatographic method analyzing silylated derivatives of the OH-metabolites and coextractants. A new method to selectively extract metabolites and limit coextraction of disturbing compounds to less than 5 nmol per mg equivalent protein is presented. It is now possible to make a dose-response curve up to 50% inhibition with bioactivated CB 77 and BDE 47. The toxic potencies of bioactivated persistent organic pollutants (POPs) should be taken into account to prevent serious underestimation of their hazard and risk.

  • 40.
    Pedersen, Jenny M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hoogstraate, Janet
    Acturum Life Science AB, Södertälje, Sweden.
    Norén, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    LeCluyse, Edward L.
    The Hamner Institutes for Health Sciences, North Carolina, USA.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Early Identification of Clinically Relevant Drug Interactions with the Human Bile Salt Export Pump (BSEP; ABCB11)2013In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 136, no 2, p. 328-343Article in journal (Other academic)
    Abstract [en]

    A comprehensive analysis was performed to investigate how inhibition of the human bile salt export pump (BSEP/ABCB11) relates to clinically observed drug induced liver injury (DILI). Inhibition of taurocholate (TA) transport was investigated in BSEP membrane vesicles for a dataset of 250 compounds, and 86 BSEP inhibitors were identified. Structure-activity modeling identified BSEP inhibition to correlate strongly with compound lipophilicity, while positive molecular charge was associated with a lack of inhibition. All approved drugs in the dataset (n=182) were categorized according to DILI warnings in drug labels issued by the FDA and a strong correlation between BSEP inhibition and DILI was identified. As many as 38 of the 61 identified BSEP inhibitors were associated with severe DILI, including nine drugs not previously linked to BSEP inhibition. Further, among the tested compounds, every second drug associated with severe DILI was a BSEP inhibitor. Finally, sandwich cultured human hepatocytes (SCHH) were used to investigate the relationship between BSEP inhibition, TA transport and clinically observed DILI in detail. BSEP inhibitors associated with severe DILI greatly reduced the TA canalicular efflux while BSEP inhibitors with less severe or no DILI resulted in weak or no reduction of TA efflux in SCHH. This distinction illustrates the usefulness of SCHH in refined analysis of BSEP inhibition. In conclusion, BSEP inhibition in membrane vesicles was found to correlate to DILI severity, and altered disposition of TA in SCHH  was shown to separate BSEP inhibitors associated with severe DILI from those with no or mild DILI. 

  • 41.
    Philippot, Gaetan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Hallgren, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)2018In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 166, no 1, p. 203-212Article in journal (Refereed)
    Abstract [en]

    Acetaminophen (AAP; also known as paracetamol) is the most used and only recommended analgesic and antipyretic among pregnant women and young children. However, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and adverse neurobehavioral effects later in life. We hypothesized that the cannabinoid receptor type 1 (CB1R) may be involved in the developmental neurotoxicity of AAP, owing to its interaction with the endocannabinoid system. Here we test if CB1R agonist WIN 55 212-2 (WIN) and AAP can interact when exposure occurs during a neurodevelopmental stage known for increased growth rate and for its vulnerability to AAP exposure. We exposed male NMRI mice on postnatal day 10 to different combinations of AAP and WIN. Adult mice, neonatally co-exposed to AAP and WIN, displayed a significant lack of habituation in the spontaneous behavior test, when compared with controls and single agent exposed mice. These adult adverse effects may at least in part be explained by a reduction of transcript levels of hippocampal synaptophysin (Syp) and tropomyosin receptor kinase B (Trkb), and cerebral cortical fatty acid amide hydroxylase (Faah), 24h after exposure. These findings are consistent with our hypothesis that AAP and WIN can interact when exposure occurs during early postnatal brain development in mice. Assuming our results are relevant for humans, they raise concerns on AAP safety because it is the only recommended analgesic and antipyretic during pregnancy and early life.

  • 42.
    Sand, Salomon
    et al.
    Swedish Natl Food Agcy, Sweden.
    Lindqvist, Roland
    Swedish Natl Food Agcy, Sweden.
    von Rosen, Dietrich
    Linköping University, Department of Mathematics, Mathematical Statistics . Linköping University, Faculty of Science & Engineering. Swedish Univ Agr Sci, Sweden.
    Ilback, Nils-Gunnar
    Swedish Natl Food Agcy, Sweden.
    Dose-Related Severity Sequence, and Risk-Based Integration, of Chemically Induced Health Effects2018In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 165, no 1, p. 74-89Article in journal (Refereed)
    Abstract [en]

    Risk assessment of chemical hazards is typically based on single critical health effects. This work aims to expand the current approach by characterizing the dose-related sequence of the development of multiple (lower- to higher-order) toxicological health effects caused by a chemical. To this end a "reference point profile" is defined as the relation between benchmark doses for considered health effects, and a standardized severity score determined for these effects. For a given dose of a chemical or mixture the probability for exceeding the reference point profile, thereby provoking lower- to higher-order effects, can be assessed. The overall impact at the same dose can also be derived by integrating contributions across all health effects following severity-weighting. In its generalized form the new impact metric relates to the probability of response for the most severe health effects. Reference points (points of departure) corresponding to defined levels of response can also be estimated. The proposed concept, which is evaluated for dioxin-like chemicals, provides an alternative for characterizing the low-dose region below the reference point for a severe effect like cancer. The shape and variability of the reference point profile add new dimensions to risk assessment, which for example extends the characterization of chemical potency, and the concept of acceptable effect sizes for individual health effects. Based on the present data the method shows high stability at low doses/responses, and is also robust to differences in severity categorization of effects. In conclusion, the novel method proposed enables risk-based integration of multiple dose-related health effects. It provides a first step towards a more comprehensive characterization of chemical toxicity, and suggests a potential for improved low-dose risk assessment.

  • 43.
    Schenk, Linda
    et al.
    KTH, Filosofi.
    Johanson, Gunnar
    Institute of environmental Medicine, Karolinska Institutet.
    A quantitative comparison of the safety margins in the European indicative occupational exposure limits and the derived no-effect levels for workers under REACH2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 121, no 2, p. 408-416Article in journal (Refereed)
    Abstract [en]

    The new European Union (EU) REACH legislation requires Derived No-Effect Levels (DNEL) to be calculated for substances produced in quantities above 10 tonnes/year. Meanwhile, the setting of occupational exposure limits (OEL) continues both at the member state and the EU level. According to REACH, Indicative OEL Values (IOELVs) from the Commission may under some circumstances be used as worker-DNELs. On the other hand, worker-DNELs will be derived for several thousand substances, far more than the roughly 100 substances for which IOELVs have been established. Thus, the procedure to set health-based OELs may become influential on that of DNELs and vice versa. In this study, we compare the safety margins of 88 SCOEL recommendations with those of the corresponding worker-DNELs, derived according to the default approach as described in the REACH guidance document. Overall, the REACH safety margins were approximately six times higher than those derived from the SCOEL documentation but varied widely with REACH/SCOEL safety margin ratios ranging by two orders of magnitude, from 0.3 to 58 (n=88). The discrepancies may create confusion in terms of legal compliance, risk management and risk communication. We also found that the REACH guidance document, although encompassing detailed advice on many issues, including default assessment factors for species and route extrapolation, gives no quantitative guidance on when and how to depart from defaults.

  • 44.
    Schenk, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Johanson, Gunnar
    Institute of environmental Medicine, Karolinska Institute.
    A quantitative comparison of the safety margins in the European indicative occupational exposure limits and the derived no-effect levels for workers under REACH2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 121, no 2, p. 408-416Article in journal (Refereed)
    Abstract [en]

    The new European Union (EU) REACH legislation requires Derived No-Effect Levels (DNEL) to be calculated for substances produced in quantities above 10 tonnes/year. Meanwhile, the setting of occupational exposure limits (OEL) continues both at the member state and the EU level. According to REACH, Indicative OEL Values (IOELVs) from the Commission may under some circumstances be used as worker-DNELs. On the other hand, worker-DNELs will be derived for several thousand substances, far more than the roughly 100 substances for which IOELVs have been established. Thus, the procedure to set health-based OELs may become influential on that of DNELs and vice versa. In this study, we compare the safety margins of 88 SCOEL recommendations with those of the corresponding worker-DNELs, derived according to the default approach as described in the REACH guidance document. Overall, the REACH safety margins were approximately six times higher than those derived from the SCOEL documentation but varied widely with REACH/SCOEL safety margin ratios ranging by two orders of magnitude, from 0.3 to 58 (n=88). The discrepancies may create confusion in terms of legal compliance, risk management and risk communication. We also found that the REACH guidance document, although encompassing detailed advice on many issues, including default assessment factors for species and route extrapolation, gives no quantitative guidance on when and how to depart from defaults.

  • 45.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kramarova, Tatiana V.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mattsson, Charlotte L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Mousumi Rahman
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chang, Shu-Ching
    Butenhoff, John
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Environmental Pollutants Perfluorooctane Sulfonate and Perfluorooctanoic Acid Upregulate Uncoupling Protein 1 (UCP1) in Brown-Fat Mitochondria Through a UCP1-Dependent Reduction in Food Intake2015In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 146, no 2, p. 334-343Article in journal (Refereed)
    Abstract [en]

    The environmental pollutants perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) cause a dramatic reduction in the size of the major adipose tissue depots and a general body weight decrease when they are added to the food of mice. We demonstrate here that this is mainly due to a reduction in food intake; this reduction was not due to food aversion. Remarkably and unexpectedly, a large part of the effect of PFOA/PFOS on food intake was dependent on the presence of the uncoupling protein 1 (UCP1) in the mice. Correspondingly, PFOA/PFOS treatment induced recruitment of brown adipose tissue mitochondria: increased oxidative capacity and increased UCP1-mediated oxygen consumption (thermogenesis). In mice pair-fed to the food intake during PFOA/PFOS treatment in wildtype mice, brown-fat mitochondrial recruitment was also induced. We conclude that we have uncovered the existence of a regulatory component of food intake that is dependent upon brown adipose tissue thermogenic activity. The possible environmental consequences of this novel PFOA/PFOS effect (a possible decreased fitness) are noted, as well as the perspectives of this finding on the general understanding of control of food intake control and its possible extension to combatting obesity.

  • 46.
    Shi, Xiongjie
    et al.
    State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
    Yeung, Leo W. Y.
    Department of Biology and Chemistry, City University of Hong Kong, Hong Kong SAR, Hong Kong.
    Lam, Paul K. S.
    Department of Biology and Chemistry, City University of Hong Kong, Hong Kong SAR, Hong Kong.
    Wu, Rudolf S. S.
    State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
    Zhou, Bingsheng
    State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
    Protein Profiles in Zebrafish (Danio rerio) Embryos Exposed to Perfluorooctane Sulfonate2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 110, no 2, p. 334-340Article in journal (Refereed)
    Abstract [en]

    Perfluorooctane sulfonate (PFOS) is widely distributed and persistent in the environment and in wildlife, and it has the potential for developmental toxicity. However, the molecular mechanisms that lead to these toxic effects are not well known. In the present study, proteomic analysis has been performed to investigate the proteins that are differentially expressed in zebrafish embryos exposed to 0.5 mg/l PFOS until 192 h postfertilization. Two-dimensional electrophoresis coupled with mass spectrometry was employed to detect and identify the protein profiles. The analysis revealed that 69 proteins showed altered expression in the treatment group compared to the control group with either increase or decrease in expression levels (more than twofold difference). Of the 69 spots corresponding to the proteins with altered expression, 38 were selected and subjected to matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (TOF/TOF) analysis; 18 proteins were identified in this analysis. These proteins can be categorized into diverse functional classes such as detoxification, energy metabolism, lipid transport/steroid metabolic process, cell structure, signal transduction, and apoptosis. Overall, proteomic analysis using zebrafish embryos serves as an in vivo model in environmental risk assessment and provides insight into the molecular events in PFOS-induced developmental toxicity.

  • 47.
    Suuronen, Erik J.
    et al.
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    McLaughlin, Christopher R.
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    Stys, Peter K.
    Ottawa Health Research Institute — Division of Neuroscience, University of Ottawa, Ottawa, ON, Canada.
    Nakamura, Masatsugu
    Santen Pharmaceutical Company Ltd., Ikoma-shi, Nara,, Japan.
    Munger, Rejean
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    Functional innervation in tissue engineered models for in vitro study and testing purposes2004In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 82, no 2, p. 525-533Article in journal (Refereed)
    Abstract [en]

    The biotechnology industry is rapidly expanding and the emerging field of tissue engineering is projected to have a high impact in the near future. Recently the field of cellular, drug, and prosthetic delivery has melded with the field of tissue engineering to make simulated tissues. In addition to their roles as tissue substitutes for transplantation, these simulated tissues may provide more accurate models and environments for toxicology testing and the study of peripheral nerves. The current study demonstrates the importance of innervation, in general, for the function of engineered tissues. We observe that the presence of nerves in a tissue engineered (TE) human cornea model enhances the growth of the epithelium and the formation of its protective mucin layer. Innervation also confers protection to the epithelium from chemical insult, as determined by the level of post-treatment epithelial cell death. We demonstrate differential responses of the nerves to chemical stimuli by changes in intracellular sodium as measured by 2-photon microscopy. The 2-photon imaging techniques also allow for the visualization and study of the fine sensory axon fibers within the 3-dimensional tissue. This work demonstrates a role for innervation in the protective quality and function of the engineered tissue, and the potential to use the nerves themselves as indicators of the severity of an insult. These results are important to consider for the development of any optimized TE models for in vitro study and testing purposes.

  • 48. Tofighi, Roshan
    et al.
    Wan Ibrahim, Wan Norhamidah
    Rebellato, Paola
    Andersson, Patrik L
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uhlen, Per
    Ceccatelli, Sandra
    Non-dioxin like polychlorinated biphenyls interfere with neuronal differentiation of embryonic neural stem cells2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 124, no 1, p. 192-201Article in journal (Refereed)
    Abstract [en]

    Developmental exposure to food contaminants, such as polychlorinated biphenyls (PCBs), has been considered as a possible cause of neurodevelopmental disorders. We have investigated the effects of non-cytotoxic concentrations of PCB 153 and 180 on spontaneous differentiation of rat embryonic neural stem cells (NSCs). Upon removal of basic fibroblast growth factor to induce spontaneous differentiation, cells were exposed to 100 nM of the selected PCBs for 48 h and analyzed after 5 days. Both PCB 153 and 180 induced a significant increase in the number of neurite-bearing Tuj1 positive cells with a concomitant decrease in proliferating cells, as detected by Fucci-transfection and EdU-staining. Measurements of spontaneous Ca(2+) oscillations showed a decreased number of cells with Ca(2+) activity after PCB exposure, further confirming the increase in neuronal cells. Conversely, exposure to methylmercury (MeHg), which we evaluated in parallel, led to an increased number of cells with Ca(2+) activity, in agreement with the previously observed inhibition of neuronal differentiation. Analysis with q-PCR of the Notch pathway revealed that PCBs has a repressive action on Notch signaling, whereas MeHg activates it. All together, the data indicate that nM concentrations of the selected non-dioxin like PCBs and MeHg interfere in opposite directions with neuronal spontaneous differentiation of NSCs through Notch signaling. Combined exposures to PCBs and MeHg resulted in an induction of apoptosis and an antagonistic interaction on spontaneous neuronal differentiation. NSCs are further proven to be a valuable in vitro model to identify potential developmental neurotoxicants.

  • 49.
    Van den Berg, Martin
    et al.
    World Health Organization Collaborating Centre for Research on Environmental Health Risk Assessment and Institute for Risk Assessment Sciences, Faculties of Veterinary Medicine, Science and University Medical Center, Universiteit Utrecht, Utrecht, The Netherlands.
    Birnbaum, Linda S.
    National Health & Environmental Effects Research Laboratory, United States Environmental Protection Agency Research Triangle Park, North Carolina, USA.
    Denison, Michael
    Department of Environmental Toxicology, University of California at Davis, Davis, California, USA.
    De Vito, Mike
    National Health & Environmental Effects Research Laboratory, United States Environmental Protection Agency Research Triangle Park, North Carolina, USA.
    Farland, William
    Office of Research and Development, U.S. Environmental Protection Agency (EPA), NW, Washington, District of Columbia, USA.
    Feeley, Mark
    Chemical Health Hazard Assessment Division, Bureau of Chemical Safety, Health Canada, Tunney’s Pasture, Ottawa, Ontario, Canada.
    Fiedler, Heidelore
    United Nations Environment Program Chemicals, International Environment House, Châtelaine (GE), Switzerland.
    Håkansson, Helen
    Institute of Environmental Medicine, Karolinska Institutet, Unit of Environmental Health Risk Assessment, Stockholm, Sweden.
    Hanberg, Annika
    Institute of Environmental Medicine, Karolinska Institutet, Unit of Environmental Health Risk Assessment, Stockholm, Sweden.
    Haws, Laurie
    ChemRisk, Austin, Texas, USA.
    Rose, Martin
    Central Science Laboratory, Sand Hutton, York, United Kingdom.
    Safe, Stephen
    Veterinary Physiology and Pharmacology, Texas A&M University, Texas, USA.
    Schrenk, Dieter
    Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Kaiserslautern, Germany.
    Tohyama, Chiharu
    Division of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo Japan.
    Tritscher, Angelika
    nternational Programme on Chemical Safety, World Health Organization, Geneva, Switzerland.
    Tuomisto, Jouko
    National Public Health Institute, Department of Environmental Health, Kuopio, Finland.
    Tysklind, Mats
    Environmental Chemistry, Umeå University, Sweden.
    Walker, Nigel
    National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
    Peterson, Richard E.
    School of Pharmacy and Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin, USA.
    The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds2006In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 93, no 2, p. 223-241Article in journal (Refereed)
    Abstract [en]

    In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and "systemic" TEFs for blood and adipose tissue and TEQ for body burden.

  • 50. van den Berg, Martin
    et al.
    Denison, Michael S
    Birnbaum, Linda S
    DeVito, Michael J
    Fiedler, Heidelore
    Falandysz, Jerxy
    Rose, Martin
    Schrenk, Dieter
    Safe, Stephen
    Tohyama, Chiharu
    Tritscher, Angelika
    Tysklind, Mats
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Peterson, Richard E
    Polybrominated Dibenzo-p-Dioxins, Dibenzofurans, and Biphenyls: Inclusion in the Toxicity Equivalency Factor Concept for Dioxin-Like Compounds2013In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 133, no 2, p. 197-208Article, review/survey (Refereed)
    Abstract [en]

    In 2011 a joint World Health Organization (WHO) and United Nations Environment Programme (UNEP) expert consultation took place, during which the possible inclusion of brominated analogues of the dioxin-like compounds in the WHO Toxicity Equivalency Factor (TEF) scheme were evaluated. The expert panel concluded that polybrominated dibenzo-p-dioxins (PBDDs), dibenzofurans (PBDFs), and some dioxin-like biphenyls (dl-PBBs) may contribute significantly in daily human background exposure to the total dioxin toxic equivalencies (TEQs). These compounds are also commonly found in the aquatic environment. Available data for fish toxicity were evaluated for possible inclusion in the WHO-UNEP TEF scheme (Van den Berg et al., 1998). Because of the limited database it was decided not to derive specific WHO-UNEP TEFs for fish, but for ecotoxicological risk assessment the use of specific relative effect potencies (REPs) from fish embryo assays is recommended. Based on the limited mammalian REP database for these brominated compounds, it was concluded that sufficient differentiation from the present TEF values of the chlorinated analogues (Van den Berg et al., 2005) was not possible. However, the REPs for PBDDs, PBDFs, and non-ortho dl-PBBs in mammals closely follow those of the chlorinated analogues, at least within one order of magnitude. Therefore, the use of similar interim TEF values for brominated and chlorinated congeners for human risk assessment is recommended, pending more detailed information in the future.

12 1 - 50 of 62
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf