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  • 1. Beronius, Anna
    et al.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Håkansson, Helen
    Hanberg, Annika
    Risk to all or none? A comparative analysis of controversies in the health risk assessment of Bisphenol A2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 29, no 2, p. 132-146Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA) is an endocrine disruptor for which health risk assessment has proven controversial. Conclusions regarding health risks of BPA vary between assessments from "there is no risk to any part of the population" to "there is risk to the entire population". We have carried out a literature study investigating what might be the scientific and/or policy-related reasons for these differences. Ten risk assessments for BPA were scrutinized and several factors were compared between assessments, including estimations of exposure levels, identification of critical study and NOAEL, assessment factors and significance attributed to reports of low-dose effects. Differences in conclusions were mainly influenced by the evaluation of low-dose effects and the uncertainties surrounding the significance of these data for health risk assessment. The results illustrate the impact of differences in risk assessment policy and expert judgment on the risk assessment process and highlight the importance of transparency in this process.

  • 2. Björk, Christel
    et al.
    Nenonen, Hannah
    Giwercman, Aleksander
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Rylander, Lars
    Giwercman, Yvonne Lundberg
    Persistent organic pollutants have dose and CAG repeat length dependent effects on androgen receptor activity in vitro2011In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 32, p. 293-297Article in journal (Refereed)
    Abstract [en]

    Recently, the effect of exposure to persistent organic pollutants (POPS) on sperm concentration was only seen in men with a short androgen receptor (AR) gene CAG repeat. In order to investigate whether these effects could be observed also in vitro, we tested the impact of 2,2’,4,4’,5,5’-hexachlorobiphenyl (CB-153) and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (4,4’-DDE) on 5 alpha-dihydrotestosterone activated ARs containing 16,22 and 28 CAG repeats, respectively. Single exposure to 4,4’-DDE had the most pronounced effect on the AR activity containing 16 CAG repeats, whereas 28 CAG was the most sensitive variant when a mixture of the two compounds was added. Thus, our in vitro results have confirmed the in vivo data indicating a CAG repeat length dependent effect of endocrine disrupters on the AR activity.

  • 3. Bondesson, Maria
    et al.
    Jönsson, Jill
    Pongratz, Ingemar
    Olea, Nicholas
    Cravedi, Jean-Pierre
    Zalko, Daniel
    Håkansson, Helen
    Halldin, Krister
    Institutet för miljömedicin, Karolinska Institutet.
    Di Lorenzo, Diego
    Behl, Christian
    Manthey, Dieter
    Balaguer, Patrick
    Demeneix, Barbara
    Fini, Jean Baptiste
    Laudet, Vincent
    Gustafsson, Jan-Ake
    A CASCADE of effects of bisphenol A.2009In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 28, no 4, p. 563-7Article in journal (Refereed)
  • 4. Borg, D.
    et al.
    Bogdanska, J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sundström, Maria
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Nobel, S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Håkansson, H.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    DePierre, J. W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Halldin, K.
    Bergstrom, U.
    Tissue distribution of S-35-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 4, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to S-35-PFOS (12 5 mg/kg) we determined the distribution in dams fetuses (GD18 and GD20) and pups (postnatal day 1 PND1) employing whole-body autoradiography and liquid scintillation counting In dams levels were highest in liver and lungs After placental transfer S-35-PFOS was present on GD18 at 2-3 times higher levels in lungs liver and kidneys than in maternal blood In PND1 pups levels in lungs were significantly higher than in GD18 fetuses A heterogeneous distribution of S-35-PFOS was observed in brains of fetuses and pups with levels higher than in maternal brain This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.

  • 5.
    Borg, Daniel
    et al.
    Karolinska Institutet.
    Bogdanska, Jasna
    Stockholms Universitet.
    Sundström, Maria
    Stockholms Universitet.
    Nobel, Stefan
    Stockholms Universitet.
    Håkansson, Helen
    Karolinska Institutet.
    Bergman, Åke
    Stockholms Universitet.
    Depierre, Jospeh W
    Stockholms Universitet.
    Halldin, Krister
    Karolinska Institutet.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Tissue distribution of (35)S-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 4, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival. Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to (35)S-PFOS (12.5mg/kg), we determined the distribution in dams, fetuses (GD18 and GD20) and pups (postnatal day 1, PND1) employing whole-body autoradiography and liquid scintillation counting. In dams, levels were highest in liver and lungs. After placental transfer, (35)S-PFOS was present on GD18 at 2-3 times higher levels in lungs, liver and kidneys than in maternal blood. In PND1 pups, levels in lungs were significantly higher than in GD18 fetuses. A heterogeneous distribution of (35)S-PFOS was observed in brains of fetuses and pups, with levels higher than in maternal brain. This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.

  • 6.
    Bredhult, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bäcklin, Britt-Marie
    Bignert, Anders
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Study of the relation between the incidence of uterine leiomyomas and the concentrations of PCB and DDT in Baltic gray seals2008In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 25, no 2, p. 247-255Article in journal (Refereed)
    Abstract [en]

    Exposure to environmental contaminants is believed to be associated with the previously described decrease in the reproduction rate of Baltic gray seals. In the present study the prevalence of uterine leiomyomas was investigated in 257 Baltic gray seal females examined during 1973-2007, in relation to the levels of polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) in Baltic biota, using an estimated exposure index. Additionally, the proliferative activity in leiomyomas, occurrence of corpora lutea, and blubber concentrations of PCB and DDT were investigated in a subset of females. Leiomyomas were only found in females 22-41 years old, at a prevalence of 65%. No differences in blubber concentrations of PCB or DDT were detected between the subset of leiomyoma-bearing females and reference females, but the estimated exposure index indicated that the PCB level in Baltic biota might be related to the leiomyoma prevalence in Baltic gray seal females.

  • 7.
    Bredhult, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bäcklin, Britt-Marie
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Effects of some endocrine disruptors on the proliferation and viability of human endometrial endothelial cells in vitro2007In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 23, no 4, p. 550-559Article in journal (Refereed)
    Abstract [en]

    Endocrine disrupting chemicals (EDCs) pose a potential threat to human reproductive health. We studied the proliferation and viability of human endometrial endothelial cells (HEECs) in vitro after exposure to 2,2-bis(o,p-chlorophenyl)-1,1,1-trichloroethane (o,p′-DDT), 3,3′,4,4′-tetrachlorobiphenyl (CB 77), 3,3′,4,4′,5-pentachlorobiphenyl (CB 126), di-n-butyl phthalate (DBP), bisphenol A (BPA), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and 17β-oestradiol, progesterone, 17α-ethynyl oestradiol and levonorgestrel. Cell proliferation was studied using immunocytochemistry for PCNA expression and a 5-bromo-2′-deoxyuridine assay. Cell viability was studied by vital staining with propidium iodide and Hoechst 33258. HEECs in primary culture responded with increased proliferation to oestradiol and with decreased proliferation to levonorgestrel and the EDCs. Some EDCs also affected cell viability and increased the proportion of necrotic cells. However, the decrease in proliferation in response to DBP and TCDD cannot be explained by cell death. In light of these results, it is possible that the EDCs could have effects in vivo as well as in vitro, and influence processes involving for example endometrial angiogenesis.

  • 8.
    Bredhult, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sahlin, Lena
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Gene expression analysis of human endometrial endothelial cells exposed to Bisphenol A2009In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 28, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA) can affect reproductive tissues in several species. Recently, treatment of human endometrial endothelial cells (HEECs) with 100 microM BPA decreased their proliferation and viability. In the present study, 50 microM BPA decreased HEEC proliferation, and microarray analyses of five HEEC cultures revealed that BPA affected biological processes associated with proliferation. Expression of three of the most differentially expressed genes identified in the gene array analysis, SPBC25, SGOL2 and CDCA8, was verified by real-time qRT-PCR in five HEEC cultures obtained from women in the proliferative phase and in five cultures obtained from women in the secretory phase of the menstrual cycle after treatment with BPA. This study supports our previous findings of decreased cell proliferation and increased cell death in response to BPA, and may offer important clues to the mechanisms of action of BPA. Furthermore, the study implies a possible impact of BPA on female fertility functions.

  • 9. Carlsson, Gunnar
    et al.
    Patring, Johan
    Ullerås, Erik
    Oskarsson, Agneta
    Developmental toxicity of albendazole and its three main metabolites in zebrafish embryos.2011In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 32, no 1, p. 129-37Article in journal (Refereed)
    Abstract [en]

    Albendazole (ABZ) is used as an anthelmintic drug in humans and animals. ABZ has been shown to cause developmental toxicity in experimental animals, however it is not clear if this is caused by the parent compound or a metabolite. Zebrafish embryos were exposed from 1 to 144hpf (hours post fertilization) to investigate the developmental toxicity of ABZ, the first metabolite albendazole sulphoxide and the subsequent metabolites albendazole sulphone (ABZSO(2)) and albendazole-2-aminosulphone (ABZSO(2)NH(2)). The results showed that ABZ caused malformations of head and tail and embryonic lethality from 0.3μM. In contrast, the metabolites did not display developmental toxicity at any tested concentration. Dechorionation did not influence the developmental toxic potential of ABZ and ABZSO, indicating that bioavailability was not a limiting factor. Chemical analysis showed that at sublethal concentrations, most of ABZ was metabolized to ABZSO. The results demonstrate that in zebrafish embryos ABZ rather than ABZSO displays developmental toxicity.

  • 10.
    Danielsson, Bengt R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Danielsson, Christian
    Nilsson, Mats F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Embryonic cardiac arrhythmia and generation of reactive oxygen species: common teratogenic mechanism for IKr blocking drugs2007In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 24, no 1, p. 42-56Article in journal (Refereed)
    Abstract [en]

    In the adult organism, it is well established that hypoxia followed by reperfusion may be fatal and result in generation of reactive oxygen species (ROS) and subsequent tissue damage. There is also considerable evidence that temporary decrease or interruption in oxygen supply to the embryo and ROS generation during reperfusion result in tissue damage in embryonic tissues. A wide spectrum of different malformations by transient embryonic hypoxia could be produced, depending on the duration, extent, and timing of the hypoxic event. It is the contention of this paper that drugs that block the potassium channel IKr, either as an intended pharmacologic effect or as an unwanted side-effect, are potentially teratogenic by a common ROS related mechanism. Drugs blocking the IKr channel, such as almokalant, dofetilide, phenytoin, cisapride and astemizole, do all produce a similar pattern of hypoxia-related malformations. Mechanistic studies show that the malformations are preceded by embryonic cardiac arrhythmia and periods of hypoxia/reoxygenation in embryonic tissues. Pretreatment or simultaneous treatment with radical scavengers with capacity to capture ROS, markedly decrease the teratogenicity of different IKr blocking drugs. A second aim of this review is to demonstrate that the conventional design of teratology studies is not optimal to detect malformations caused by IKr blocking drugs. Repeated high doses result in high incidences of embryonic death due embryonic cardiac arrhythmia, thus masking their teratogenic potential. Instead, single dosing on specific days is proposed to be a better way to characterize the teratogenic potential of Ikr blocking drugs.

  • 11.
    Ejdesjö, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Brings, Sebastian
    Fleming, Thomas
    Fred, Rikard G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nawroth, Peter P
    University of Heidelberg.
    Eriksson, Ulf J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Receptor for Advanced Glycation End products (RAGE) knockout reduces fetal dysmorphogenesis in murine diabetic pregnancy2016In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 62, p. 62-70Article in journal (Other academic)
    Abstract [en]

    Background & Aim: The receptor for Advanced Glycation End products (RAGE) is implicated in the pathogenesis of diabetic complications, but its importance for the induction of congenital malformations in diabetic pregnancy is unclear. The aim of the present study was to investigate a possible role of RAGE activation in the induction of diabetic embryopathy.

    Methods: Female non-diabetic and diabetic wildtype (WT) C57Bl/6 mice and RAGE knockout C57Bl/6 (RAGE‑/-) mice were mated with males of the same genotype. Diabetes was induced by daily streptozotocin (STZ) injections (50 mg/kg STZ i.p.) on five consecutive days. On gestational day 18, pregnant mice were anesthetized and blood was drawn from the heart to measure maternal metabolic parameters. Fetuses and placentas were excised, weighed, and examined for morphological anomalies, and fetal livers were analyzed for 8‑iso‑PGF levels.

    Results: There were no malformations in non-diabetic WT or non-diabetic RAGE‑/- mice. However, resorption rates were higher in non-diabetic WT (10%) than in non-diabetic RAGE‑/- mice (4%). Diabetic WT mice had higher malformation (22%) and resorption (43%) rates than diabetic RAGE‑/- mice (3% malformations and 21% resorptions). Maternal diabetes decreased fetal weight more in WT fetuses (44%) than in RAGE‑/- fetuses (36%). There were no differences in plasma glucose levels between the diabetic WT and RAGE‑/- mice, but plasma levels of triglycerides and cholesterol were lower in diabetic WT mice than in diabetic RAGE-/- mice. Diabetes increased maternal plasma levels of methylglyoxal in WT and RAGE‑/- mice, and increased fetal hepatic levels of 8-iso-PGF in WT fetuses, but not in RAGE‑/- fetuses.

    Discussion: Knockout of RAGE diminished the rates of fetal malformations and resorptions, despite similar levels of hyperglycemia in pregnant diabetic mice. An anti-teratogenic effect was present in RAGE‑/- mice despite having a more severe diabetic state than diabetic WT mice. As 8-iso-PGF, a marker of oxidative stress, only increased in diabetic WT offspring, this suggested a pivotal role of RAGE activation and oxidative stress in the pathogenesis of diabetic embryopathy.

  • 12.
    Fernández, Estíbaliz L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Tallkvist, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Expression of ZnT-1 (Slc30al) and MT-1 (Mt1) in the conceptus of cadmium treated mice2007In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 24, no 3-4, p. 353-358Article in journal (Refereed)
    Abstract [en]

    There are indications that Cd-induced malformations in rodents are related to a disrupted flux of Zn to the developing embryo. The aim of the present study was to detect ZnT-1 (Slc30al) and MT (Mt1) protein in structures within the decidua, yolk sac and embryo of mice and to determine whether Cd affects ZnT-1 or MT-1 gene expression in these tissues. ZnT-1 was detected in the placental labyrinth, in the ventral part around the floor plate, in the inner cell layers of the rhombencephalon and in the ventral area of the otic vesicle. MT protein was detected in the yolk sac and in the Surface ectoderm of some embryonic areas, such as the pharyngeal arches. ZnT-1 and MT-1 transcripts were most abundant in the decidua and yolk sac, whereas the abundance of these genes was relatively low in the embryo. Cd exposure down-regulated ZnT-1 and up-regulated MT-1 gene expression in all structures investigated, indicating that maternal Cd exposure may alter Zn homeostasis in the conceptus.

  • 13.
    Gardner, Renee M.
    et al.
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Nermell, Barbro
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Kippler, Maria
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Grandér, Margaretha
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Li, Li
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Ekström, Eva-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Rahman, Anisur
    International Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh.
    Lönnerdal, Bo
    Department of Nutrition, University of California, USA.
    Hoque, A. M. Waheedul
    International Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh.
    Vahter, Marie
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Arsenic methylation efficiency increases during the first trimester of pregnancy independent of folate status2011In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 31, no 2, p. 210-218Article in journal (Refereed)
    Abstract [en]

    Exposure to inorganic arsenic during pregnancy may negatively influence the offspring, though efficient metabolism of arsenic to dimethylarsinic acid (DMA) likely reduces the health risks. This study aimed to evaluate methylation of arsenic over the entire pregnancy and the influence of nutritional status. We studied longitudinally the arsenic metabolite pattern in the urine of 324 pregnant women exposed to arsenic via drinking water and food in rural Bangladesh. Metabolism of arsenic to DMA increased markedly over the course of pregnancy, with the greatest improvement occurring in the first trimester, along with a marked decrease in the most risk-associated monomethylated metabolite. This improvement in methylation was not associated with nutritional status, including vitamin B(12) and folate. Efficient methylation to DMA was associated with improved urinary excretion of arsenic, relative to blood arsenic concentrations, indicating that micronutrient-independent up-regulation of arsenic metabolism already in early pregnancy may provide protection for the fetus.

  • 14.
    Gäreskog, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cederberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wentzel, Parri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Maternal diabetes in vivo and high glucose concentration in vitro increases apoptosis in rat embryos2007In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 23, no 1, p. 63-74Article in journal (Refereed)
    Abstract [en]

    Apoptosis may be involved in diabetes-induced embryonic dysmorphogenesis. We estimated the occurrence of apoptosis in embryos of a rat model for diabetic pregnancy. We found decreased Bcl-2, increased Bax and cleaved Caspase 3 proteins in embryos from diabetic rats. Moreover, we found increased activation of Caspase 3 in cells from embryos previously exposed to a diabetes-like environment (in vivo, in vitro) compared to cells from control embryos, which was normalized by supplementation of N-acetylcysteine or apoptosis inhibitor. We detected increased propidium iodide uptake in embryonic cells exposed to maternal diabetes, a finding confirmed by vital staining. Additionally, we found increased dysmorphogenesis in embryos exposed to a diabetic environment in vivo and in vitro. Exposure to a diabetic milieu during organogenesis increases apoptosis in embryonic cells and dysmorphogenesis in embryos. Enhanced apoptotic rate may have a role in diabetic embryopathy by inducing disturbed embryonic maturation, increased rates of resorptions and congenital malformations.

  • 15.
    Hallberg, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU). Swedish Univ Agr Sci SLU, Dept Clin Sci, Box 7054, SE-7054 Uppsala, Sweden.
    Kjellgren, Jacklin
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Box 7054, SE-7054 Uppsala, Sweden.
    Persson, Sara
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Box 7054, SE-7054 Uppsala, Sweden;Swedish Museum Nat Hist, POB 50007, SE-10405 Stockholm, Sweden.
    Örn, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU). Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7036, SE-75007 Uppsala, Sweden.
    Sjunnesson, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU). Swedish Univ Agr Sci SLU, Dept Clin Sci, Box 7054, SE-7054 Uppsala, Sweden.
    Perfluorononanoic acid (PFNA) alters lipid accumulation in bovine blastocysts after oocyte exposure during in vitro maturation2019In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 84, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids present in human tissues. In this study, effects on early embryo development after PFNA exposure were investigated using the bovine in vitro production system. Oocytes were exposed to PFNA during maturation in vitro (10 μg mL-1 and 0.1 μg mL-1), and then fertilized and cultured in parallel with control groups. Developmental parameters (cleavage, blastocyst formation) were followed and embryo quality evaluated (stage, grade). Embryos developed after exposure to 0.1 μg mL-1 were stained to distinguish nuclei, active mitochondria and neutral lipids. 10 μg mL-1 of PFNA had a severe negative effect on blastocyst formation (OR: 0.27 p < 0.05), an effect not observed at 0.1 μg mL-1. However, lipid droplet distribution was significantly altered in embryos exposed to 0.1 μg mL-1, suggesting a disturbance of lipid metabolism after exposure to sublethal levels of PFNA during oocyte maturation in vitro.

  • 16.
    Helmestam, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Davey, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stavreus-Evers, Anne Li
    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.
    Bisphenol A affects human endometrial endothelial cell angiogenic activity in vitro2014In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 46, p. 69-76Article in journal (Refereed)
    Abstract [en]

    The widespread Bisphenol A (BPA) is classified as an endocrine-disrupting chemical (EDC) with estrogenic properties. Human endometrial endothelial cells (HEECs) play a key role in the endometrial angiogenesis that is under the control of estradiol. The hypothesis was that BPA may affect endometrial angiogenesis by disturbing some functional properties of the HEEC. To study this, primary HEECs were exposed to environmentally relevant doses of BPA. The HEECs were co-cultured with primary endometrial stromal cells to create conditions as similar to the in vivo situation as possible. The effects of BPA were evaluated by proliferation and viability assays, tube-formation assays, quantitative PCRs, Western blots and ELISAs. BPA slightly increased HEEC tube formation and VEGF-D protein expression compared with vehicle, without affecting HEEC viability or proliferation. Bisphenol A thus caused changes in HEEC activities in vitro, and may therefore have disturbing effects on endometrial angiogenesis. (C) 2014 Elsevier Inc. All rights reserved.

  • 17.
    Helmestam, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Cadmium chloride alters mRNA levels of angiogenesis related genes in primary human endometrial endothelial cells grown in vitro2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 3, p. 370-376Article in journal (Refereed)
    Abstract [en]

    Cadmium, is known to cause adverse reproductive effects, and classified as an endocrine disrupting chemical (EDC). Human endometrial endothelial cells (HEEC) have a key role in the regulation of endometrial angiogenesis. These cells are known to express estrogen receptors, a feature that makes them potential targets for EDCs such as cadmium. We have designed a co-culture system, in which HEEC were grown in the same cell culture medium as endometrial stromal cells but in separate, communicating chambers. With quantitative PCR, we investigated changes in mRNA expression of genes associated with angiogenesis, sex steroids and endothelial cell specific functions. We found that cadmium altered the mRNA expression of the two important angiogenic molecules VEGF-A and PLGF. Cadmium might thus affect endometrial angiogenesis and as a consequence cause endometrial dysfunction with an increased risk for fertility problems.

  • 18. Johansson, Stefan
    et al.
    Buchmayer, Susanne
    Harlid, Sophia
    Department of Medical Microbiology, Lund University, Malmö University Hospital, Sweden.
    Iliadou, Anastasia
    Sjöholm, Malin
    Grillner, Lena
    Norman, Mikael
    Sparén, Per
    Dillner, Joakim
    Cnattingius, Sven
    Infection with Parvovirus B19 and Herpes viruses in early pregnancy and risk of second trimester miscarriage or very preterm birth2008In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 26, no 3-4, p. 298-302Article in journal (Refereed)
    Abstract [en]

    We investigated whether infections with Parvovirus B19 and Herpes viruses in early pregnancy increase risks of second trimester miscarriage or delivery before 32 gestational weeks. Blood samples taken in early pregnancy were analyzed for Parvovirus B19 or Herpes viruses. Viremia was found in blood samples of 11 (4.7%) women with second trimester miscarriage and 10 (3.7%) women with very preterm birth, compared to 5 (1.7%) women who delivered at term, corresponding to adjusted odds ratios [95% CI] of 3.32 [0.93, 11.8] and 2.21 [0.71, 6.84], respectively. In stratified analyses, Parvovirus B19 viremia was associated with adjusted odds ratios of 3.76 [0.77, 18.3] for second trimester miscarriage and 2.66 [0.64, 11.1] for very preterm birth. Corresponding odds ratios for Human Herpes virus 6 viremia was 2.52 [0.33, 19.5] and 1.08 [0.14, 8.08], respectively. In conclusion, this study lends some support to the hypothesis that women with viremia in early pregnancy may face an increased risk of second trimester miscarriage or very preterm birth. Studies with larger sample sizes are needed.

  • 19.
    Kallen, Bengt
    et al.
    Lund University, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Skåne University Hospital, Sweden.
    Use of tramadol in early pregnancy and congenital malformation risk2015In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 58, p. 246-251Article in journal (Refereed)
    Abstract [en]

    Only few studies exist regarding the risk of a teratogenic effect of tramadol when used in early pregnancy. Using the Swedish Medical Birth Register, women (deliveries in 1997-2013) who had reported the use of tramadol in early pregnancy were identified. Maternal characteristics and concomitant drug use were analyzed. Among 1,682,846 women (1,797,678 infants), 1751 (1776 infants) had used tramadol, 96 of the infants had a congenital malformation and 70 of them were relatively severe. The adjusted odds ratio for a relatively severe malformation was 1.33 (95% CI 1.05-1.70). The odds ratios for cardiovascular defects (1.56, 95% CI 1.04-2.29) and for pes equinovarus (3.63, 95% CI 1.61-6.89) were significantly increased. The study suggests a teratogenic effect of tramadol but the risk increase is moderate. (C) 2015 Elsevier Inc. All rights reserved.

  • 20.
    Kippler, Maria
    et al.
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Wagatsuma, Yukiko
    Department of Clinical Epidemiology, Faculty of Medicine, University of Tsukuba, Japan.
    Rahman, Anisur
    International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
    Nermell, Barbro
    International Centre for Diarrhoeal Disease Research, Mahakhali, Dhaka, Bangladesh.
    Persson, Lars-Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Raqib, Rubhana
    International Centre for Diarrhoeal Disease Research, Mahakhali, Dhaka, Bangladesh.
    Vahter, Marie
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Environmental exposure to arsenic and cadmium during pregnancy and fetal size: a longitudinal study in rural Bangladesh2012In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 34, no 4, p. 504-511Article in journal (Refereed)
    Abstract [en]

    Prenatal exposures to arsenic (As) and cadmium (Cd) have been associated with decreased size at birth. We here studied associations of prenatal As and Cd exposures with multiple fetal size parameters measured by ultrasound in gestational week (GW) 14 and 30 in a population-based mother-child cohort in rural Bangladesh. We measured As (n=1929) and Cd (n=1616) in urine during pregnancy. In the longitudinal evaluation of combined exposure, urinary Cd (UCd) showed an inverted U-shaped association (turning-point 1.5μg Cd/L) with all fetal size parameters, while UAs showed no significant association. Cross-sectional analyses indicated that associations with UCd were somewhat stronger in early gestation. Stratification indicated stronger associations between UCd and fetal size in girls than in boys, and in poorer than in richer families, while UAs was weakly associated with fetal size in boys. In conclusion, particularly Cd, but also As, appeared to influence fetal development in a sex-dependent manner.

  • 21.
    Kosmehl, Thomas
    et al.
    Aquatic Ecology and Toxicology Group, COS–Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Otte, Jens
    Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
    Yang, Lixin
    Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
    Legradi, Jessica
    Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
    Bluhm, Kerstin
    Department of Ecosystem Analysis, Institute for Environmental Research (Biology V), RWTH Aachen University, Aachen, Germany.
    Zinsmeister, Christian
    Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
    Keiter, Steffen
    Department of Ecosystem Analysis, Institute for Environmental Research (Biology V), RWTH Aachen University, Aachen, Germany.
    Reifferscheid, Georg
    German Federal Institute for Hydrology (BfG), Koblenz, Germany.
    Manz, Werner
    Institute of Integrated Natural Sciences, University of Koblenz-Landau, Koblenz, Germany.
    Braunbeck, Thomas
    Aquatic Ecology and Toxicology Group, COS–Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Strähle, Uwe
    Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
    Hollert, Henner
    Department of Ecosystem Analysis, Institute for Environmental Research (Biology V), RWTH Aachen University, Aachen, Germany.
    A combined DNA-microarray and mechanism-specific toxicity approach with zebrafish embryos to investigate the pollution of river sediments2012In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 33, no 2, p. 245-253Article in journal (Refereed)
    Abstract [en]

    The zebrafish embryo has repeatedly proved to be a useful model for the analysis of effects by environmental toxicants. This proof-of-concept study was performed to investigate if an approach combining mechanism-specific bioassays with microarray techniques can obtain more in-depth insights into theecotoxicity of complex pollutant mixtures as present, e.g., in sediment extracts. For this end, altered gene expression was compared to data from established bioassays as well as to results from chemical analysis. Mechanism-specific biotests indicated a defined hazard potential of the sediment extracts, and microarray analysis revealed several classes of significantly regulated genes which could be related to the hazard potential. Results indicate that potential classes of contaminants can be assigned to sediment extracts by both classical biomarker genes and corresponding expression profile analyses of known substances. However, it is difficult to distinguish between specific responses and more universal detoxification of the organism.

  • 22.
    Kultima, Kim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Fernández, Estíbaliz L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Gustafson, Anne-Lee
    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.
    Cadmium-induced gene expression changes in the mouse embryo, and the influence of pretreatment with zinc2006In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 22, no 4, p. 636-646Article in journal (Refereed)
    Abstract [en]

    Cadmium (Cd) administered to female C57BL/6 mice on gestation day 8 induces a high incidence of anterior neural tube defects (exencephaly). This adverse effect can be attenuated by maternal pretreatment with zinc (Zn). In this study we used replicated microarray analysis and real-time PCR to investigate gene expression changes induced in the embryo 5 and 10h after maternal Cd exposure in the absence or presence of Zn pretreatment. We report nine genes with a transcriptional response induced by Cd, none of which was influenced by Zn pretreatment, and two genes induced only by combined matemal Cd exposure and Zn pretreatment. We discuss the results in relation to the possibility that Cd is largely excluded from the embryo, that the teratogenic effects of Cd may be secondary to toxicity in extraembryonic tissues, and that the primary protective role of Zn may not be to reverse Cd-induced transcription in the embryo.

  • 23.
    Kultima, Kim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Jergil, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Salter, Hugh
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    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.
    Early transcriptional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicity2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 3, p. 457-468Article in journal (Refereed)
    Abstract [en]

    Cell-based in vitro assays would potentially reduce animal testing in preclinical drug development. Mouse embryos exposed to the teratogenic drug valproic acid (VPA) in utero for 1.5, 3 or 6h on gestational day 8 were analyzed using microarrays. Significant effects on gene expression were observed already at 1.5h, and 85 probes were deregulated across all time points. To find transcriptional markers of VPA-induced developmental toxicity, the in vivo data were compared to previous in vitro data on embryonal carcinoma P19 cells exposed to VPA for 1.5, 6 or 24h. Maximal concordance between embryos and cells was at the 6-h time points, with 163 genes showing similar deregulation. Developmentally important Gene Ontology terms, such as "organ morphogenesis" and "tube development" were overrepresented among putative VPA target genes. The genes Gja1, Hap1, Sall2, H1f0,Cyp26a1, Fgf15, Otx2, and Lin7b emerged as candidate in vitro markers of potential VPA-induced teratogenicity.

  • 24.
    Ljungvall, K
    et al.
    Swedish University of Agriculture Science, Sweden; .
    Spjuth, L
    Swedish University of Agriculture Science, Sweden; .
    Hulten, F
    Swedish University of Agriculture Science, Sweden; .
    Einarsson, S
    Swedish University of Agriculture Science, Sweden; .
    Rodriguez-Martinez, Heriberto
    Swedish University of Agriculture Science, Sweden; .
    Andersson, K
    Swedish University of Agriculture Science, Sweden; .
    Magnusson, U
    Swedish University of Agriculture Science, Sweden; .
    Early post-natal exposure to low dose oral di(2ethylhexyl) phthalate affects the peripheral LH-concentration in plasma, but does not affect mating behavior in the post-pubertal boar2006In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 21, no 2, p. 160-166Article in journal (Refereed)
    Abstract [en]

    In a split-litter design experiment, boars were exposed orally three times weekly to 300 mg/kg of di(2-ethylhexyl) phthalate (DEHP) between 3 and 7 weeks of age. Post-puberty, i.e. at 6 months of age the effects on endocrinology and mating behavior were examined. The response to stimulation with a synthetic GnRH-analogue at 9 months of age resulted initially in lower concentration of LH in the exposed animals, compared to the control animals. We did not find any effects of DEHP on the mating behavior. Also, the effects of DEHP during the treatment period on the plasma concentrations of testosterone, oestradiol and LH were examined. During the exposure period there was a transient decrease in plasma concentrations of LH in the control group, which did not occur in the boars exposed to DEHR The data suggest that DEHP in low repeated oral doses causes lasting effects on the hypothalamus-pituitary-gonadal axis. (c) 2005 Elsevier Inc. All rights reserved.

  • 25. Mattsson, Anna
    et al.
    Ullerås, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Patring, Johan
    Oskarsson, Agneta
    Albendazole causes stage-dependent developmental toxicity and is deactivated by a mammalian metabolization system in a modified zebrafish embryotoxicity test2012In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 34, no 1, p. 31-42Article in journal (Refereed)
    Abstract [en]

    The zebrafish embryotoxicity test has previously been combined with an external metabolic activation system (MAS) to assess developmental toxicity of metabolites produced by maternal metabolism. Due to toxicity of MAS the exposure was limited to one early and short period. We have modified the method and included additional testing time points with extended exposure durations. Using the anthelmintic drug albendazole as a model substance, we demonstrated stage-dependent toxic effects at three windows of zebrafish embryo development, i.e. 2-3, 12-14 and 24-28h post fertilization, and showed that MAS, by metabolic deactivation, reduced the toxicity of albendazole at all time points. Chemical analysis confirmed that albendazole was efficiently metabolized by MAS to the corresponding sulfoxide and sulfone, which are non-toxic to zebrafish embryos. To conclude, the modified zebrafish embryotoxicity test with MAS can be expanded for assessment of metabolites at different developmental stages.

  • 26. Møllerløkken, Ole J
    et al.
    Moen, Bente E
    Baste, Valborg
    Magerøy, Nils
    Oftedal, Gunnhild
    Neto, Emanuel
    Ersland, Lars
    Bjørge, Line
    Torjesen, Peter A
    Hansson Mild, Kjell
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    No effects of MRI scan on male reproduction hormones2012In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 34, no 1, p. 133-139Article in journal (Refereed)
    Abstract [en]

    Magnetic resonance imaging (MRI) is increasing around the world and the possible adverse effects on reproductive health of electromagnetic fields (EMFs) in MRI are not previously studied. A prospective randomized balanced cross-over study using a head scan in real MRI with whole-body transmitting coil and sham MRI among 24 healthy male volunteers was conducted. Serum-blood samples of inhibin B, testosterone, prolactine, thyreotropine, luteinizing hormone, follicle stimulating hormone, sex-hormone binding globuline and estradiol were taken before and after the different scans. Neither immediately after, nor after 11 days were there seen any differences in the hormone levels comparing real and sham MRI. The lack of effects of EMF on male reproductive hormones should be reassuring to the public and especially for men examined in MRI. Adverse effects on other endpoints than male reproduction or possible chronic effect of multiple MRI scans have not been investigated in this study.

  • 27.
    Nilsson, Mats F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Danielsson, C.
    Sköld, A.-C.
    Johansson, A.
    Blomgren, B.
    Wilson, J.
    Khan Niazi, Khalid Muhammad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Webster, W. S.
    Danielsson, Bengt R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 29, no 2, p. 156-163Article in journal (Refereed)
    Abstract [en]

    Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20nM, and arrhythmias at 200-400nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.

  • 28.
    Nordquist, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Luthman, Holger
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Linkage study of embryopathy-Polygenic inheritance of diabetes-induced skeletal malformations in the rat2012In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 33, no 3, p. 297-307Article in journal (Refereed)
    Abstract [en]

    We developed an inbred rat model of diabetic embryopathy, in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Our aim was to find genes controlling the embryonic maldevelopment in a diabetic environment.

    We contrasted the fetal outcome in inbred Sprague-Dawley L rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats (denoted W, no skeletal malformations in diabetic pregnancy). We used offspring from the backcross F-1 x L to probe for the genetic basis for malformation of the mandible in diabetic pregnancy. A set of 186 fetuses (93 affected, 93 unaffected) was subjected to a whole genome scan with 160 micro satellites. Analysis of genotype distribution indicated 7 loci on chromosome 4, 10 (3 loci), 14, 18, and 19 in the teratogenic process (and 14 other loci on 12 chromosomes with less strong association to the malformations), several of which contained genes implicated in other experimental studies of diabetic embryopathy. These candidate genes will be scrutinized in further experimentation.

    We conclude that the genetic involvement in rodent diabetic embryopathy is polygenic and predisposing for congenital malformations.

  • 29.
    Peddinghaus, Sabrina
    et al.
    Department of Ecosystem Analysis, Institute for Environmental Research, RWTH Aachen University, Aachen, Germany.
    Brinkmann, Markus
    Department of Ecosystem Analysis, Institute for Environmental Research, RWTH Aachen University, Aachen, Germany.
    Bluhm, Kerstin
    Department of Ecosystem Analysis, Institute for Environmental Research, RWTH Aachen University, Aachen, Germany.
    Sagner, Anne
    Department of Environmental Biotechnology, Water Technology Center (TZW), Karlsruhe, Germany.
    Hinger, Gunnar
    Aquatic Ecology and Toxicology, Centre for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Braunbeck, Thomas
    Aquatic Ecology and Toxicology, Centre for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Eisenträger, Adolf
    Dept. IV 2: Pharmaceuticals, Chemicals, Experimental Studies, Federal Environment Agency, Dessau, Germany; Institute of Hygiene and Environmental, Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany.
    Thiem, Andreas
    Department of Environmental Biotechnology, Water Technology Center (TZW), Karlsruhe, Germany.
    Hollert, Henner
    Department of Ecosystem Analysis, Institute for Environmental Research, RWTH Aachen University, Aachen, Germany.
    Keiter, Steffen
    Department of Ecosystem Analysis, Institute for Environmental Research, RWTH Aachen University, Aachen, Germany.
    Quantitative assessment of the embryotoxic potential of NSO-heterocyclic compounds using zebrafish (Danio rerio)2012In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 33, p. 224-232Article in journal (Refereed)
    Abstract [en]

    Heterocyclic aromatic compounds (NSO-HET) have frequently been detected in the environment. Several studies have concluded that NSO-HET pose a threat to organisms in waters, sediments and soils. However, few publications are available assessing the ecotoxicology of NSO-HET. The present study aims toassess the embryo toxicity of heterocycles using Danio rerio. A combination of the Fish Embryo Toxicity Test and analytical quantification should aid to determine the hazard potential. Changes of the total concentrations due to sorption or volatility were quantified by GC/MS. Loss of compounds during the testwas observed primarily for volatile or hydrophobic NSO-HET. The LC50 calculated with nominal concentrations underestimates the toxicity by a factor up to 16 (2 h), demonstrating that a chemical analysis for comparing nominal and measured concentrations is essential for such investigations.

  • 30.
    Ren, Hongzu
    et al.
    NHEERL, ORD, US EPA, Research Triangle Park, NC, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC, United States.
    Vallanat, Beena
    NHEERL, ORD, US EPA, Research Triangle Park, NC, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC, United States.
    Nelson, David M.
    Discovery Toxicology, Bristol-Myers Squibb Company, Princeton, NJ, United States.
    Yeung, Leo W. Y.
    Safety Research Team, 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.
    Guruge, Keerthi S.
    Safety Research Team, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki, Japan.
    Lam, Paul K. S.
    Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, Hong Kong.
    Lehman-McKeeman, Lois D.
    Discovery Toxicology, Bristol-Myers Squibb Company, Princeton, NJ, United States.
    Corton, J. Christopher
    NHEERL, ORD, US EPA, Research Triangle Park, NC, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC, United States.
    Evidence for the involvement of xenobiotic-responsive nuclear receptors in transcriptional effects upon perfluoroalkyl acid exposure in diverse species2009In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 27, no 3-4, p. 266-277Article in journal (Refereed)
    Abstract [en]

    Humans and ecological species have been found to have detectable body burdens of a number of perfluorinated alkyl acids (PFAA) including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). In mouse and rat liver these compounds elicit transcriptional and phenotypic effects similar to peroxisome proliferator chemicals (PPC) that work through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). Recent studies indicate that along with PPARα other nuclear receptors are required for transcriptional changes in the mouse liver after PFOA exposure including the constitutive activated receptor (CAR) and pregnane X receptor (PXR) that regulate xenobiotic metabolizing enzymes (XME). To determine the potential role of CAR/PXR in mediating effects of PFAAs in rat liver, we performed a meta-analysis of transcript profiles from published studies in which rats were exposed to PFOA or PFOS. We compared the profiles to those produced by exposure to prototypical activators of CAR, (phenobarbital (PB)), PXR (pregnenolone 16 alpha-carbonitrile (PCN)), or PPARα (WY-14,643 (WY)). As expected, PFOA and PFOS elicited transcript profile signatures that included many known PPARα target genes. Numerous XME genes were also altered by PFOA and PFOS but not WY. These genes exhibited expression changes shared with PB or PCN. Reexamination of the transcript profiles from the livers of chicken or fish exposed to PFAAs indicated that PPARα, CAR, and PXR orthologs were not activated. Our results indicate that PFAAs under these experimental conditions activate PPARα, CAR, and PXR in rats but not chicken and fish. Lastly, we discuss evidence that human populations with greater CAR expression have lower body burdens of PFAAs.

  • 31.
    Rudén, Christina
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Hansson, Sven Ove
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Comment on: "A retrospective analysis of the two-generation study: What is the added value of the second generation?" by G. Janer, B.C. Hakkert, W. Slob, T. Vermeire, A.H. Piersma Reprod. Toxicol. 24 (2007) 97-1022008In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 25, no 4, p. 397-405Article in journal (Refereed)
  • 32. Spörndly-Nees, Ellinor
    et al.
    Boberg, Julie
    Ekstedt, Elisabeth
    Holm, Lena
    Fakhrzadeh, Azadeh
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Kushnir, Mark M
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Low-dose exposure to Bisphenol A during development has limited effects on male reproduction in midpubertal and aging Fischer 344 rats.2018In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 81, p. 196-206Article in journal (Refereed)
    Abstract [en]

    Low doses of Bisphenol A (BPA) during development may affect reproduction. In this study, Fischer 344 rats were exposed to 0.5 or 50 μg BPA/kg bw/day via drinking water from gestational day 3.5 to postnatal day 22. Anogenital distance, organ weight, histopathology of reproductive organs, hormone analysis and sperm morphology were evaluated in male offspring. In this study no major effects of BPA on male reproduction in midpubertal (postnatal day 35) or adult (12-month-old) rats were revealed, apart from a higher prevalence of mild inflammatory cell infiltrate in cauda epididymis in adult rats exposed to 50 μg BPA/kg bw/day. No BPA-related effects on sexual development were seen but care should be taken when evaluating histopathology in midpuberty testis due to large morphological variation. Results from the present study show no major signs of altered male reproduction in rats exposed to low doses of BPA during gestation and lactation.

  • 33.
    Sundström, Maria
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Chang, Shu-Ching
    Noker, Patricia E.
    Gorman, Gregory S.
    Hart, Jill A.
    Ehresman, David J.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Butenhoff, John L.
    Comparative pharmacokinetics of perfluorohexanesulfonate (PFHxS) in rats, mice, and monkeys2012In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 33, no 4, p. 441-451Article in journal (Refereed)
    Abstract [en]

    Perfluorohexanesulfonate (PFHxS) has been found in biological samples from wildlife and humans. The human geometric mean serum PFHxS elimination half-life has been estimated to be 2665 days. A series of studies was undertaken to establish pharmacokinetic parameters for PFHxS in rats, mice, and monkeys after single administration with pharmacokinetic parameters determined by WinNonlin (R) software. Rats and mice appeared to be more effective at eliminating PFHxS than monkeys. With the exception of female rats, which had serum PFHxS elimination half-life of approximately 2 days, the serum elimination half-lives in the rodent species and monkeys approximated 1 month and 4 months, respectively, when followed over extended time periods (10-24 weeks). Collectively, these studies provide valuable insight for human health risk assessment regarding the potential for accumulation of PFHxS in humans.

  • 34.
    Zabihi, Sheller
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wentzel, Parri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Folic acid supplementation affects ROS scavenging enzymes, enhances Vegf-A, and diminishes apoptotic state in yolk sacs of embryos of diabetic rats2007In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 23, no 4, p. 486-498Article in journal (Refereed)
    Abstract [en]

    We aimed to investigate the extent to which maternal diabetes with or without folic acid (FA) supplementation affects mRNA levels and protein distribution of ROS scavenging enzymes, vascular endothelial growth factor-A (Vegf-A), folate binding protein-1 (Folbp-1), and apoptosis-associated proteins in the yolk sacs of rat embryos on gestational days 10 and 11. Commencing at conception and throughout pregnancy, half of the streptozotocin-diabetic and half of the control rats received daily FA injections. Maternal diabetes impaired vascular morphology and decreased CuZnSOD and GPX-1 gene expression in yolk sacs. Maternal diabetes also increased the levels of CuZnSOD protein, increased the Bax/Bcl-2 protein ratio and decreased Vegf-A protein distribution. FA treatment normalized vascular morphology, decreased mRNA levels of all three SOD isoforms and increased Vegf-A mRNA levels, rectified CuZnSOD protein distribution and Bax/Bcl-2 ratio. A teratogenic diabetic environment produces a state of vasculopathy, oxidative stress, and mild apoptosis in the yolk sac. FA administration normalizes vascular morphology, diminishes apoptotic rate, and increases Vegf-A gene expression and protein distribution in the yolk sac of diabetic rats.

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