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  • 1.
    Berg, A. H.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Westerlund, L.
    Olsson, P-E.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of Arctic char (Salvelinus alpinus) egg shell proteins and vitellogenin during reproduction and in response to 17β-estradiol and cortisol2004In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 135, no 3, p. 276-285Article in journal (Refereed)
    Abstract [en]

    Estrogens induce both vitellogenin (Vtg) and egg shell (zona pellucida; ZP) protein synthesis in salmonids. However, while Vtg is strictly under estrogenic control, recent reports suggest that additional mechanisms are involved in ZP protein synthesis. During sexual maturation both estrogen and glucocorticoid levels increase in the circulation of female fish. As glucocorticoids have been shown to interfere with Vtg induction in fish we investigated whether cortisol (F) had similar effects on ZP regulation. In the present study we determined both the natural variation in Vtg and ZP during an annual reproductive cycle in female Arctic char (Salvelinus alpinus), and the effect of co-treatment of juvenile Arctic char with 17β-estradiol (E2) and F. During sexual maturation the expression of Vtg and ZP correlated to plasma levels of E2 and F. Determination of Vtg and ZP protein levels following co-treatment with E2 and F showed that F antagonized E2 induction of Vtg. However, F was observed to potentiate the expression of ZP protein in the same fish. These results indicate that in Arctic char Vtg and ZP proteins are not regulated by the same mechanisms and suggest that ZP protein expression does not necessarily imply exposure to estrogenic compounds alone, and may thus not be ideally suited as a biomarker of exposure to estrogenic compounds.

  • 2.
    Berg, A. H.
    et al.
    Örebro University, School of Science and Technology.
    Westerlund, L.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Regulation of Arctic char (Salvelinus alpinus) egg shell proteins and vitellogenin during reproduction and in response to 17beta-estradiol and cortisol2004In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 135, no 3, p. 276-285Article in journal (Refereed)
    Abstract [en]

    Estrogens induce both vitellogenin (Vtg) and egg shell (zona pellucida; ZP) protein synthesis in salmonids. However, while Vtg is strictly under estrogenic control, recent reports suggest that additional mechanisms are involved in ZP protein synthesis. During sexual maturation both estrogen and glucocorticoid levels increase in the circulation of female fish. As glucocorticoids have been shown to interfere with Vtg induction in fish we investigated whether cortisol (F) had similar effects on ZP regulation. In the present study we determined both the natural variation in Vtg and ZP during an annual reproductive cycle in female Arctic char (Salvelinus alpinus), and the effect of co-treatment of juvenile Arctic char with 17beta-estradiol (E2) and F. During sexual maturation the expression of Vtg and ZP correlated to plasma levels of E2 and F. Determination of Vtg and ZP protein levels following co-treatment with E2 and F showed that F antagonized E2 induction of Vtg. However, F was observed to potentiate the expression of ZP protein in the same fish. These results indicate that in Arctic char Vtg and ZP proteins are not regulated by the same mechanisms and suggest that ZP protein expression does not necessarily imply exposure to estrogenic compounds alone, and may thus not be ideally suited as a biomarker of exposure to estrogenic compounds.

  • 3.
    Blixt, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Niklasson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Characterization of β-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 154, no 1-3, p. 41-47Article in journal (Refereed)
    Abstract [en]

    Bank voles (Clethrionomys glareolus) kept in captivity develop diabetes mellitus to a significant extent. Also in wild bank voles, elevated blood glucose has been observed. A newly isolated picornavirus named Ljungan virus (LV) has been found in the pancreas of these bank voles. Moreover, LV infection in combination with environmental factors may cause glucose intolerance/diabetes (GINT/D) in normal mice. The aim of the present study was to investigate the functional characteristics of pancreatic islets, isolated from bank voles, bred in the laboratory but considered LV infected. About 20% of all males and females were classified as GINT/D following a glucose tolerance test. Of these animals the majority had become diabetic by 20 weeks of age, with a tendency towards an earlier onset in the males. GINT/D animals had increased serum insulin levels. Islets were tested on the day of isolation (day 0) and after 1 week of culture for their insulin content and their capacity to synthesize (pro)insulin, secrete insulin and metabolize glucose. Functional differences could be observed between normal and GINT/D animals as well as between genders. An elevated basal insulin secretion was observed on day 0 indicating β-cell dysfunction among islets isolated from diabetic males. In vitro culture could reverse some functional changes. The increased serum insulin level and the increased basal islet insulin secretion may suggest that the animals had developed a type 2 diabetes-like condition. It is likely that the putative stress imposed in the laboratory, maybe in combination with LV infection, can lead to an increased functional demand on the β-cells.

  • 4.
    Brunström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Mattsson, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Effects of estrogens on sex differentiation in Japanese quail and chicken2009In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 163, no 1-2, p. 97-103Article in journal (Refereed)
    Abstract [en]

    Estrogen production by the female avian embryo induces development of a female phenotype of the reproductive organs whereas the low estrogen concentration in the male embryo results in a male phenotype. Treatment of female embryos with exogenous estrogens disrupts Müllerian duct development resulting in malformations and impaired oviductal function. Exposure of male embryos to estrogens results in ovotestis formation and persisting Müllerian ducts in the embryos and testicular malformations, reduced semen production and partially developed oviducts in the adult bird. Furthermore, studies in Japanese quail show that the male copulatory behavior is impaired by embryonic estrogen treatment. Results from our experiments with selective agonists for ERalpha and ERbeta suggest that the effects of estrogens on the reproductive organs are mediated via activation of ERalpha. Abundant expression of ERalpha mRNA was shown in gonads and Müllerian ducts of early Japanese quail embryos. Both ERalpha and ERbeta transcripts were detected by real-time PCR in early embryo brains of Japanese quail indicating that both receptors may be involved in sex differentiation of the brain. However, in 9-day-old quail embryo brains in situ hybridization showed expression of ERbeta mRNA, but not of ERalpha mRNA, in the medial preoptic nucleus (POM) and the bed nucleus of the stria terminalis (BSTm), areas implicated in copulatory behavior of adult male quail. Furthermore, embryonic treatment with the selective ERalpha agonist propyl pyrazol triol (PPT) had no effect on the male copulatory behavior. These results suggest that ERbeta may be important for the effects of estrogens on brain differentiation.

  • 5. Cardoso, Joao C. R.
    et al.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Comparative evolution of peptide hormone-binding GPCRs: A route to understanding functional complexity2014In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 209, no SI, p. 1-2Article in journal (Other academic)
  • 6.
    Cardoso, João C R
    et al.
    University of Algarve, Portugal.
    Félix, Rute C
    University of Algarve, Portugal.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    New insights into the evolution of vertebrate CRH (corticotropin-releasing hormone) and invertebrate DH44 (diuretic hormone 44) receptors in metazoans2014In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 209, no SI, p. 162-170Article in journal (Refereed)
    Abstract [en]

    The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 receptors (DH44R) are structurally and functionally related members of the G protein-coupled receptors (GPCR) of the secretin-like receptor superfamily. We show here that they derive from a bilaterian predecessor. In protostomes, the receptor became DH44R that has been identified and functionally characterised in several arthropods but the gene seems to be absent from nematode genomes. Duplicate DH44R genes (DH44 R1 and DH44R2) have been described in some arthropods resulting from lineage-specific duplications. Recently, CRHR-DH44R-like receptors have been identified in the genomes of some lophotrochozoans (molluscs, which have a lineage-specific gene duplication, and annelids) as well as representatives of early diverging deuterostomes. Vertebrates have previously been reported to have two CRHR receptors that were named CRHR1 and CRHR2. To resolve their origin we have analysed recently assembled genomes from representatives of early vertebrate divergencies including elephant shark, spotted gar and coelacanth. We show here by analysis of synteny conservation that the two CRHR genes arose from a common ancestral gene in the early vertebrate tetraploidizations (2R) approximately 500 million years ago. Subsequently, the teleost-specific tetraploidization (3R) resulted in a duplicate of CRHR1 that has been lost in some teleost lineages. These results help distinguish orthology and paralogy relationships and will allow studies of functional conservation and changes during evolution of the individual members of the receptor family and their multiple native peptide agonists.

  • 7.
    Hallgren, Stefan L E
    et al.
    Södertörns Högskola.
    Linderoth, Maria
    Stockholms Universitet.
    Olsén, K Håkan
    Södertörns Högskola.
    Inhibition of cytochrome p450 brain aromatase reduces two male specific sexual behaviours in the male Endler guppy (Poecilia reticulata).2006In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 147, no 3, p. 323-8Article in journal (Refereed)
    Abstract [en]

    In mammalian and avian vertebrate groups, androgens act as controlling agents on male aggression and courtship behaviour by their conversion to oestrogens by cytochrome P450 aromatase in well-defined brain regions. Despite the fact that bony fishes have exceptionally high brain aromatase activity, little is known about it's possible regulatory effects on the reproductive behaviours of teleosts. In this study, Endler guppy males (Poecilia reticulata) were subjected to 26-29 days of 24-h exposure to two different concentrations (15 and 100 microg/L) of the aromatase inhibitor fadrozole in the water. Compared with the control males, two of three courtship activities in males exposed to the higher concentration were reduced when they were paired with receptive stimulus females. Reduction in brain aromatase activity was confirmed in both exposed groups with the use of the tritiated water assay.

  • 8.
    Hallgren, Stefan
    et al.
    Södertörn University, School of Life Sciences.
    Linderoth, Maria
    Olsén, K Håkan
    Södertörn University, School of Life Sciences.
    Inhibition of cytochrome p450 brain aromatase reduces two male specific sexual behaviours in the male Endler guppy (Poecilia reticulata)2006In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 147, no 3, p. 323-328Article in journal (Refereed)
    Abstract [en]

    In mammalian and avian vertebrate groups, androgens act as controlling agents on male aggression and courtship behaviour by their conversion to oestrogens by cytochrome P450 aromatase in well-defined brain regions. Despite the fact that bony fishes have exceptionally high brain aromatase activity, little is known about it's possible regulatory effects on the reproductive behaviours of teleosts. In this study, Endler guppy males (Poecilia reticulata) were subjected to 26-29 days of 24-h exposure to two different concentrations (15 and 100 pg/L) of the aromatase inhibitor fadrozole in the water. Compared with the control males, two of three courtship activities in males exposed to the higher concentration were reduced when they were paired with receptive stimulus females. Reduction in brain aromatase activity was confirmed in both exposed groups with the use of the tritiated water assay.

  • 9.
    Henriksen, Rie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology. University of Groningen, Netherlands .
    Rettenbacher, Sophie
    University of Vet Med, Austria .
    Groothuis, Ton G G.
    University of Groningen, Netherlands .
    Maternal corticosterone elevation during egg formation in chickens (Gallus gallus domesticus) influences offspring traits, partly via prenatal undernutrition2013In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 191, p. 83-91Article in journal (Refereed)
    Abstract [en]

    The relationship between maternal stress during pregnancy in humans and the subsequent physical and mental health disorders in their children has inspired a wide array of studies on animal models. Almost all of these studies have used mammalian species, but more recently oviparous species in which the embryo develops outside the mothers body have received more attention. These new models facilitate disentangling of the underlying mechanism due to the accessibility of the prenatal environment, the egg. Studies in birds have found that maternal stress during egg formation induces phenotypic alterations in the offspring that hatch from these eggs. However, different offspring traits have been measured in different studies and potential underlying mechanisms are barely addressed. In this study we experimentally manipulated maternal corticosterone levels in laying hens. We found that mothers with experimentally elevated plasma corticosterone levels produced offspring that are smaller at hatching, less competitive, less fearful, have lower immunocompetence and higher plasma testosterone levels, as well as an alteration of visually guided behavioural lateralization. Earlier we have showed that eggs produced by these corticosterone treated mothers were lighter and contained lower concentrations of testosterone and progesterone in the yolk. While yolk hormones showed no correlation with any offspring traits, egg mass correlated positively with offsprings body mass from hatching until 10 days of age and hatching mass correlated positively with the offsprings ability to compete for food, indicating that prenatal under nutrition might mediate some effects of maternal stress.

  • 10.
    Ingberg, Edvin
    et al.
    Linköping University, Linköping, Sweden.
    Theodorsson, A.
    Linköping University, Linköping, Sweden.
    Theodorsson, E.
    Linköping University, Linköping, Sweden.
    Ström, Jakob O.
    Linköping University, Linköping, Sweden.
    Methods for long-term 17β-estradiol administration to mice2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 188-193Article in journal (Refereed)
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within--except on one occasion--the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

  • 11.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Methods for long-term 17β-estradiol administration to mice2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 188-193Article in journal (Refereed)
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within – except on one occasion – the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

  • 12.
    Jansson, Erika
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Mattsson, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Goldstone, Jared
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Sex-dependent expression of anti-Müllerian hormone (amh) and amh receptor 2 during sex organ differentiation and characterization of the Müllerian duct development in Xenopus tropicalis2016In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 229, p. 132-144Article in journal (Refereed)
    Abstract [en]

    Amphibian gonadal differentiation involves the action of sex steroids. Recent research indicates that the anti-Müllerian hormone (AMH) is involved in testicular development in some lower vertebrate species. For amphibians there is a lack of data on ontogenetic expression of the AMH receptor AMHR2/amhr2 and of progesterone receptors (PGRS/pgrs). Here we expand the knowledge on amphibian sex differentiation by characterizing ontogenetic mRNA levels of amh, amhr2, intracellular and membrane pgrs (ipgr and mpgr beta) and cytochrome P450 19a1 (cyp19a1) (ovarian marker) in the urogenital complex of the model species Xenopus (Silurana) tropicalis. Furthermore, we characterized the ontogenetic development of the Müllerian ducts (precursors of the female reproductive tract) histologically. The developmental period investigated spanned from beginning of gonadal differentiation, Nieuwkoop and Faber (NF) stage 51, to 4weeks post-metamorphosis. The Müllerian ducts were first observed at NF 64 in both sexes. Male-enhanced amh mRNA levels from NF 53/54 to 6days post-metamorphosis and female-enhanced cyp19a1 levels from NF 53 to 4weeks post-metamorphosis were noted. The sexually dimorphic mRNA level profile was more distinct for amh than for cyp19a1. The pgrs mRNA levels increased over the studied period and showed no sex differences. At later developmental stages, the amhr2 mRNA level was increased in putative females compared with males. Our findings suggest that AMH has a role in gonadal differentiation in X. tropicalis. We propose relative gonadal amh mRNA level as a testicular marker during early gonadal development in amphibians.

  • 13. Kalliokoski, Otto
    et al.
    Hau, Jann
    Jacobsen, Kirsten R.
    Schumacher-Petersen, Camilla
    Abelson, Klas S. P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Distribution and time course of corticosterone excretion in faeces and urine of female mice with varying systemic concentrations2010In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 168, no 3, p. 450-454Article in journal (Refereed)
    Abstract [en]

    Quantification of corticosterone metabolites excreted in faeces and urine is increasingly being used for assessment of preceding corticosterone concentrations in the circulation. This is a promising approach to non-invasive stress assessment in laboratory rodents. It is however unknown whether the proportions of corticosterone metabolites excreted in faeces and urine may differ, depending on the concentration of corticosterone in blood. This uncertainty undermines the applicability of urinary and faecal corticosterone metabolite measurements as biomarkers for stress. Therefore, the terminal distribution and time course of corticosterone excretion, after intravenous injection of varying corticosterone concentrations, was investigated in female mice. Female BALB/c mice excreted 60% of all corticosterone in the urine with an approximate delay of 5 h from tail vein administration. The remaining 40% were excreted in faeces, with an approximate delay of 9 h from administration. The faecal/urinary excretion ratio, as well as time course of excretion, remained unaltered by administration of various doses of corticosterone covering the entire physiological range of serum corticosterone. Although currently untested for other strains of mice and species of animals, these findings add credence to the utility of faecal and urinary corticosterone as non-invasive biomarkers for physiological stress.

  • 14.
    Karlsson, Anna-Carin
    et al.
    Linkoping Univ, AVIAN Behav Physiol & Genom Grp, IFM Biol, SE-58183 Linkoping, Sweden..
    Fallahshahroudi, Amir
    Linkoping Univ, AVIAN Behav Physiol & Genom Grp, IFM Biol, SE-58183 Linkoping, Sweden..
    Johnsen, Hanna
    Linkoping Univ, AVIAN Behav Physiol & Genom Grp, IFM Biol, SE-58183 Linkoping, Sweden..
    Hagenblad, Jenny
    Linkoping Univ, AVIAN Behav Physiol & Genom Grp, IFM Biol, SE-58183 Linkoping, Sweden..
    Wright, Dominic
    Linkoping Univ, AVIAN Behav Physiol & Genom Grp, IFM Biol, SE-58183 Linkoping, Sweden..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Per
    Linkoping Univ, AVIAN Behav Physiol & Genom Grp, IFM Biol, SE-58183 Linkoping, Sweden..
    A domestication related mutation in the thyroid stimulating hormone receptor gene (TSHR) modulates photoperiodic response and reproduction in chickens2016In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 228, p. 69-78Article in journal (Refereed)
    Abstract [en]

    The thyroid stimulating hormone receptor gene (TSHR) has been suggested to be a "domestication locus" in the chicken. A strong selective sweep over TSHR in domestic breeds together with significant effects of a mutation in the gene on several domestication related traits, indicate that the gene has been important for chicken domestication. TSHR plays a key role in the signal transduction of seasonal reproduction, which is characteristically less strict in domestic animals. We used birds from an advanced intercross line between ancestral Red Junglefowl (RJF) and domesticated White Leghorn (WL) to investigate effects of the mutation on reproductive traits as well as on TSHB, TSHR, DIO2 and DIO3 gene expression during altered day length (photoperiod). We bred chickens homozygous for either the mutation (d/d) or wild type allele (w/w), allowing assessment of the effect of genotype at this locus while also controlling for background variation in the rest of the genome. TSHR gene expression in brain was significantly lower in both did females and males and did females showed a faster onset of egg laying at sexual maturity than wow. Furthermore, did males showed a reduced testicular size response to decreased day length, and lower levels of TSHB and DIO3 expression. Additionally, purebred White Leghorn females kept under natural short day length in Sweden during December had active ovaries and lower levels of TSHR and DIO3 expression compared to Red Junglefowl females kept under similar conditions. Our study indicates that the TSHR mutation affects photoperiodic response in chicken by reducing dependence of seasonal reproduction, a typical domestication feature, and may therefore have been important for chicken domestication.

  • 15.
    Karlsson, Anna-Carin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Fallahsharoudi, Amir
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Johnsen, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Hagenblad, Jenny
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Wright, Dominic
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Andersson, Leif
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    A domestication related mutation in the thyroid stimulating hormonereceptor gene (TSHR) modulates photoperiodic response andreproduction in chickens2016In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 228, p. 69-78Article in journal (Refereed)
    Abstract [en]

    The thyroid stimulating hormone receptor gene (TSHR) has been suggested to be a ‘‘domestication locus”in the chicken. A strong selective sweep over TSHR in domestic breeds together with significant effects ofa mutation in the gene on several domestication related traits, indicate that the gene has been importantfor chicken domestication. TSHR plays a key role in the signal transduction of seasonal reproduction,which is characteristically less strict in domestic animals. We used birds from an advanced intercross linebetween ancestral Red Junglefowl (RJF) and domesticated White Leghorn (WL) to investigate effects ofthe mutation on reproductive traits as well as on TSHB, TSHR, DIO2 and DIO3 gene expression duringaltered day length (photoperiod). We bred chickens homozygous for either the mutation (d/d) or wildtype allele (w/w), allowing assessment of the effect of genotype at this locus while also controlling forbackground variation in the rest of the genome. TSHR gene expression in brain was significantly lowerin both d/d females and males and d/d females showed a faster onset of egg laying at sexual maturity thanw/w. Furthermore, d/d males showed a reduced testicular size response to decreased day length, andlower levels of TSHB and DIO3 expression. Additionally, purebred White Leghorn females kept under naturalshort day length in Sweden during December had active ovaries and lower levels of TSHR and DIO3expression compared to Red Junglefowl females kept under similar conditions. Our study indicates thatthe TSHR mutation affects photoperiodic response in chicken by reducing dependence of seasonal reproduction,a typical domestication feature, and may therefore have been important for chickendomestication.

  • 16. Kobayashi, Yuki
    et al.
    Chiba, Hiroaki
    Yamanome, Takeshi
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Takahashi, Akiyoshi
    Melanocortin receptor subtypes in interrenal cells and corticotropic activity of α-melanocyte-stimulating hormones in barfin flounder, Verasper moseri2011In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 170, no 3, p. 558-568Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to characterize the pituitary-interrenal axis in barfin flounder, a flatfish. Adrenocorticotropic hormone (ACTH) and melanocortin 2 receptor (MC2R) have been shown to be indispensable substances in pituitary and interrenal cells for cortisol release, respectively. We previously identified ACTH in the pars distalis of the barfin flounder pituitary gland, and detected transcripts of Mc1r, Mc4r, and Mc5r in the head kidney wherein interrenal cells are located. We have now demonstrated the presence of MC2R, which is a specific receptor for ACTH, in interrenal cells by molecular cloning of Mc2r cDNA and in situ hybridization, and confirmation of the in vitro cortisol-releasing activity of ACTH. These results show the presence of a classical pituitary-interrenal axis in this fish. We also evaluated the role of α-melanocyte-stimulating hormone (α-MSH) and its related peptides. In situ hybridization was used to demonstrate the expression of Mc5r in interrenal cells; both desacetyl-α-MSH and diacetyl-α-MSH showed in vitro cortisol-releasing activities, while the activity of α-MSH was negligible. These findings indicate the presence of an additional pituitary-interrenal axis consisting of α-MSH-like peptides secreted from the neurointermediate lobe of the pituitary and MC5R in the interrenal cells. The cortisol-releasing activity of desacetyl-α-MSH and diacetyl-α-MSH, compared with the low activity of α-MSH, suggest a unique and specific functional role of these forms of MSH peptides. The interrenal co-expression of two subtypes of Mcrs may play a role in this specialization.

  • 17. Kobayashi, Yuki
    et al.
    Tsuchiya, Keisuke
    Yamanome, Takeshi
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kawauchi, Hiroshi
    Takahashi, Akiyoshi
    Food deprivation increases the expression of melanocortin-4 receptor in the liver of barfin flounder, Verasper moseri2008In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 155, no 2, p. 280-287Article in journal (Refereed)
    Abstract [en]

    The melanocortin (MC) system is composed of melanocyte-stimulating hormone, adrenocorticotropic hormone and their receptors. The MC system has a role in both pigmentation and the regulation of energy homeostasis, in which MC4R, one of the five MC receptors, has a key role. Interestingly, the barfin flounder (Pleuronectiformes) reared with a black background shows retarded growth compared to white background-reared fish, which could be associated with the MC system because of its dual role in regulating pigmentation and energy status. Here, we cloned MC4R and assessed the effects of feeding status on its expression in barfin flounder. Barfin flounder MC4R. was composed of 325 amino acids and showed the highest sequence identity to MC4R of fugu (85%), followed by rainbow trout (82%), zebrafish (79%), goldfish (78%), dogfish (71%), chickens (67%), humans (67%) and mice (65%). Among 18 different tissues examined, the predominant expression of MC4R was observed in the brain, liver, testis and ovary as detected with reverse transcription PCR. Food deprivation resulted in a 4-fold increase in the number of MC4R transcripts in the liver, whereas no change was observed in the brain between fasted fish and fed controls. These results suggest that the NIC system including MC4R is associated with energy homeostasis in barfin flounder and that peripheral tissues could play a role in this regulation.

  • 18. Kobayashi, Yuki
    et al.
    Tsuchiya, Keisuke
    Yamanome, Takeshi
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Takahashi, Akiyoshi
    Differential expressions of melanocortin receptor subtypes in melanophores and xanthophores of barfin flounder2010In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 168, no 1, p. 133-142Article in journal (Refereed)
    Abstract [en]

    alpha-Melanocyte-stimulating hormone (alpha-MSH) is a member of the melanocortin (MC) family, and the MC receptor (MCR) is a member of the G protein-coupled receptor (GPCR) superfamily. We previously found that in barfin flounder, a flatfish, alpha-MSH with an acetyl group at the N-terminus stimulated pigment dispersion in xanthophores; however, this effect was not observed in melanophores. Therefore, the present study was undertaken to find which MCR subtypes are expressed in these pigment cells in order to elucidate how acetylation regulates activities of alpha-MSH-related peptides. Here, we also report the cloning of Mc1r and Mc5r from barfin flounder. Three types of cells-melanophores, xanthophores, and nonchromatophoric dermal cells-were isolated from the skin samples collected from the dorsal fin. These cells were then tested for the expression of Mc1r and Mc5r as well as Mc2r and Mc4r that we had previously cloned. Mc1r and Mc5r transcripts were detected in melanophores, and a sole Mc5r transcript was detected in xanthophores. We had previously found that the efficiency of alpha-MSH was higher than that of desacetyl-alpha-MSH for pigment dispersion in xanthophores. Acetylated MSH peptide may have increased binding affinity to MC5R, whereas alpha-MSH lacks melanin-dispersing activity. Increasing evidences indicate that many GPCRs form heterodimers, and this may affect the affinity of the ligand for the corresponding GPCR. Taken together, the expression of two different Mcr subtypes in melanophores may suggest that a heterodimer consisting of MC1R and MC5R may have a low binding affinity toward alpha-MSH. The present results clarify the types of MCRs that are expressed in melanophores and xanthophores of barfin flounder; furthermore, the results provide important clues about the functional regulation of alpha-MSH-related peptides.

  • 19.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Vanden Broeck, Jozef
    Peptide hormone and receptor evolution2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 153, no 1-3, p. 147-Article in journal (Refereed)
    Abstract [en]

    An important and fascinating theme that unifies both invertebrate and vertebrate endocrinologists is that of the evolution of peptide precursor and receptor genes. Peptide signalling plays a crucial role in processes that control decisive physiological events in organisms as divergent as yeast and mammals. The majority of small neuronal/endocrine peptides exert their functions via an interaction with heptahelical membrane receptors belonging to the G protein-coupled receptor superfamily, a large and diverse signal transducing protein category which has very ancient evolutionary roots. Most of the larger peptides and growth factors function via other well-conserved receptor classes that contain only a single transmembrane segment. The symposium on peptide hormone and receptor evolution brought together scientists studying peptide–receptor evolution in widely divergent metazoans.

    Two State-of-the-Art lectures gave overviews of current knowledge of peptide and receptor gene evolution. The sequencing and annotation of entire animal genomes constitutes a very exciting development that have already revolutionized the general views on metazoan macroevolution. The resulting burst of molecular data represents an impressive boost of novel opportunities for comparative and functional genomics research. Several vertebrate peptide and receptor families were described by Dan Larhammar to have multiplied in the 1–2 basal vertebrate tetraploidizations and in a third tetraploidization in ray-finned fishes before the radiation of teleosts. Families proposed to have multiplied in these events include NPY, tachykinins, opioid peptides, as well as the receptors for these three peptide families. The dynamics of coevolutionary change were discussed by Jozef Vanden Broeck based on several examples of peptide–receptor partners that show conservation across the protostomian–deuterostomian barrier. These examples include peptides belonging to the NPY, tachykinin, glycoprotein hormone and insulin-related peptide families, and their respective receptors.

    Additional examples of coevolution between peptides and their corresponding receptors in insects (the mosquito Aedes aegypti) and chelicerates (the tick Boophilus microplus) were presented by Ron Nachman. His detailed analysis of peptide receptor pharmacology has led to the production and selection of peptidomimetic compounds which specifically activate a particular receptor, while showing enhanced resistance against peptidases. This type of work may ultimately lead to the creation of novel, environmentally safe pest agents for insect management. In two other presentations, the evolution of two quite complex vertebrate peptide receptor systems were discussed. The five divergent and presumably ancient melanocortin receptors found in mammals have only three orthologues in the two sharks investigated so far (Angela Baron). Both the ά-MSH receptor MC1 and the ACTH receptor MC2 still remain to be identified or may have been lost or become widely divergent. The evolution of the large VIP/PACAP/secretin family (Florbela Vieira) involves duplicate PACAP genes in teleost fishes, whereas only a single VIP gene seems to exist. The PACAP gene and its chromosomal environment is more strongly conserved than the VIP gene. Invertebrates only have a single member most closely resembling PACAP.

    The concluding discussion largely revolved around the proposed tetraploidizations in early vertebrate evolution. While some hesitation still lingers, there is nevertheless no alternative explanation that can account better than the chromosome duplication (and tetraploidization) scenario for the extensive chromosome similarities and the high number of gene duplications that arose before gnathostomatous radiation. Additional gene duplications in early vertebrates were mentioned leading to the somatostatin 2-urotensin II gene pair and the somatostain 1-urotensin II-related peptide gene pair (Hervé Tostivint). Also the possible orthology relationships between peptides described in invertebrates, particularly insects, and vertebrates were discussed. Undoubtedly, definitive orthology relationships of neuropeptide precursor genes between protostomes and deuterostomes are often difficult to determine from sequence comparisons only, and will hopefully be aided by information on chromosome locations and gene neighbours.

  • 20.
    Larsson, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larson, Earl T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Cloning and sequence analysis of the neuropeptide Y receptors Y5 and Y6 in the coelacanth Latimeria chalumnae2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 150, no 2, p. 337-342Article in journal (Refereed)
    Abstract [en]

    Two coelacanth species, Latimeria chalumnae and Latimeria menadoensis, the recently discovered second species, have a key evolutionary position at the divergence of bony fishes and tetrapods. Together with lungfishes, they are the only living species separating the species-rich tetrapods from the other major group of vertebrates, the ray-finned fishes. The coelacanth is therefore of great importance for comparisons of gene families that differ between these two groups, such as the neuropeptide Y (NPY) receptor family. In this work we have sequenced the full-length genes for two NPY receptors in Latimeria chalumnae. Phylogenetic analysis indicated that the two sequences are orthologs of the mammalian Y5 and Y6 receptors. The Y5 gene has been implicated in appetite stimulation in mammals but is absent from teleost fishes. The presence of the Y5 receptor in Latimeria together with phylogenetic analysis shows that Y5 existed before the separation of bony fishes and tetrapods. The Latimeria receptor has about 62 % identity to tetrapod Y5 sequences and contains the extended third intracellular loop with several highly conserved motifs that may be involved in signal transduction. The Latimeria Y6 receptor has about 60% identity to tetrapod Y6 sequences. The functional role of Y6 is unclear as the gene is seemingly functional in some mammals but is non-functional in others. The Y6 receptor is also missing in teleost fishes. Our results confirm an early vertebrate origin for all NPY receptor subtypes presently found in mammals followed by differential gene loss in the different classes of vertebrates.

  • 21. Lofgren, Magnus
    et al.
    Johansson, Maja
    Stromberg, Jessica
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Backstrom, Torbjorn
    The influence of social subordinate housing on the withdrawal effects from progesterone and estradiol in male rats2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 177, no 1, p. 62-69Article in journal (Refereed)
    Abstract [en]

    Chronic stress and its concomitant neurobiological consequences are, in all probability, provocateurs of mental disease in humans. To gain some insight into the provocative effects of stress on hormonally dependent conditions, we developed a rat model that combines social subordinate housing (SSH) with withdrawal from combined progesterone (P) and estradiol (E) treatment (PEVVD). At the start of the experiment, male Wistar rats were housed in triads consisting of one younger rat (35 days old) and two older rats (55 days old), with the intent of producing subordination stress in the younger animals. Triads containing three 35-day-old rats were used as age controls. Subordination stress was assessed with the elevated plus maze (EPM) and by corticosterone (CORT) analysis. Social rank within the triads was determined using a food competition test (FCT) and a tube test (TT). The younger rats (subordinate) and the dominant rats were assigned to 10 days of treatment with 5 mg/kg P combined with 10 mu g/kg E, or placebo (vehicle). Twenty-four hours after the last injection, the subordinate and dominant animals were tested in an open-field test (OFT) and a social challenge test (SCT). The SCT consisted of a 10-min exposure to three unfamiliar rats. SSH increased baseline CORT levels and reduced EPM open-arm time and post-EPM CORT levels compared to age-control rats. Only in the subordinate animals did PEWD increase locomotor activity and digging behavior, and reduce wrestling and pinning behavior. The behavioral results indicate an interaction between the effects of the lasting social subordinate stress and PEWD.

  • 22. Löfgren, Magnus
    et al.
    Johansson, Maja
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, Jessica
    Meyerson, Bengt
    Bäckstrom, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    The influence of social subordinate housing on the withdrawal effects from progesterone and estradiol in male rats2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 177, no 1, p. 62-69Article in journal (Refereed)
    Abstract [en]

    Chronic stress and its concomitant neurobiological consequences are, in all probability, provocateurs of mental disease in humans. To gain some insight into the provocative effects of stress on hormonally dependent conditions, we developed a rat model that combines social subordinate housing (SSH) with withdrawal from combined progesterone (P) and estradiol (E) treatment (PEVVD). At the start of the experiment, male Wistar rats were housed in triads consisting of one younger rat (35 days old) and two older rats (55 days old), with the intent of producing subordination stress in the younger animals. Triads containing three 35-day-old rats were used as age controls. Subordination stress was assessed with the elevated plus maze (EPM) and by corticosterone (CORT) analysis. Social rank within the triads was determined using a food competition test (FCT) and a tube test (TT). The younger rats (subordinate) and the dominant rats were assigned to 10 days of treatment with 5 mg/kg P combined with 10 mu g/kg E, or placebo (vehicle). Twenty-four hours after the last injection, the subordinate and dominant animals were tested in an open-field test (OFT) and a social challenge test (SCT). The SCT consisted of a 10-min exposure to three unfamiliar rats. SSH increased baseline CORT levels and reduced EPM open-arm time and post-EPM CORT levels compared to age-control rats. Only in the subordinate animals did PEWD increase locomotor activity and digging behavior, and reduce wrestling and pinning behavior. The behavioral results indicate an interaction between the effects of the lasting social subordinate stress and PEWD. (C) 2012 Elsevier Inc. All rights reserved.

  • 23.
    Mattsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Mura, Elena
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Panzica, GianCarlo
    Halldin, Krister
    Selective activation of estrogen receptor alpha in Japanese quail embryos affects reproductive organ differentiation but not the male sexual behavior or the parvocellular vasotocin system2008In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 159, no 2-3, p. 150-157Article in journal (Refereed)
    Abstract [en]

    Estradiol is crucial for normal female differentiation in birds. Developmental effects of estrogen are believed to be mediated by slow genomic actions through the nuclear estrogen receptors alpha (ERα) and/or beta (ERβ). Consequently, exogenous compounds that interfere with the ERs may disrupt sexual differentiation of the reproductive organs and of the brain areas controlling sexual behaviors. The present study was conducted to elucidate the role of ERα in xenoestrogen-induced disruption of sexual differentiation in the Japanese quail (Coturnix japonica). Embryonic treatment with the synthetic estrogen, ethinylestradiol (EE2), and with the ERα-selective agonist, propyl pyrazole triol (PPT), induced oviductal malformations in females and retention of oviducts in males. Both EE2 and PPT caused weight asymmetry between left and right testes and reduced the cloacal gland area in males. EE2 significantly reduced the copulatory behavior in males whereas PPT had no effect on this behavior. The sexually dimorphic parvocellular vasotocin-immunoreactive (VT-ir) system in the medial preoptic nucleus (POM), the lateral septum (SL) and the medial part of the nucleus of the stria terminalis (BSTm), was not affected by EE2 or PPT. Our results suggest that xenoestrogen-induced effects on reproductive organ differentiation are mediated by ERα, whereas demasculinization of male copulatory behavior and the VT-ir system appears not to be induced by activation of ERα alone.

  • 24.
    Mattsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Olsson, Jan A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Activation of estrogen receptor alpha disrupts differentiation of the reproductive organs in chicken embryos2011In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 172, no 2, p. 251-259Article in journal (Refereed)
    Abstract [en]

    Gonadal estrogen plays an important role in the differentiation of a female phenotype in birds. Exogenous compounds that interfere with estrogen signaling, for instance by binding to the estrogen receptors alpha and beta (ER alpha and ER beta), are therefore potential disruptors of sexual differentiation in birds. The ER alpha agonist propyl-pyrazole-triol (PPT), the ER alpha antagonist methyl piperidino pyrazole (MPP) and the ER beta agonist diarylproprionitrile (DPN) were used in the present study to explore the roles of the ERs in normal and disrupted sex differentiation in the chicken embryo. Activation of ER alpha by PPT caused disturbed differentiation of the reproductive organs in both sexes. In male embryos, PPT caused left-side ovotestis formation and retention of the Mullerian ducts. In female embryos, PPT caused retention of the right Mullerian duct (which normally regresses) and malformation of both Mullerian ducts. PPT also induced hepatic expression of mRNA for the estrogen-regulated egg yolk protein apoVLDL II. Notably, none of these effects were observed following treatment with DPN. ER alpha-inactivation by MPP counteracted the action of PPT but had little effect by its own. Our results indicate that ER alpha plays an important role in sex differentiation of the reproductive tract in female chicken embryos and show that ERa can mediate xenoestrogen-induced disturbances of sex differentiation.

  • 25.
    Nässel, Dick R.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Liu, Yiting
    Stockholm University, Faculty of Science, Department of Zoology.
    Luo, Jiangnan
    Stockholm University, Faculty of Science, Department of Zoology.
    Insulin/IGF signaling and its regulation in Drosophila2015In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 221, p. 255-266Article in journal (Refereed)
    Abstract [en]

    Taking advantage of Drosophila as a genetically tractable experimental animal much progress has been made in our understanding of how the insulin/IGF signaling (IS) pathway regulates development, growth, metabolism, stress responses and lifespan. The role of IIS in regulation of neuronal activity and behavior has also become apparent from experiments in Drosophila. This review briefly summarizes these functional roles of IIS, and also how the insulin producing cells (IPCs) are regulated in the fly. Furthermore, we discuss functional aspects of the spatio-temporal production of eight different insulin-like peptides (DILP1-8) that are thought to act on one known receptor (dInR) in Drosophila.

  • 26.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evolution of the growth hormone, prolactin, prolactin 2 and somatolactin family2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 264, p. 94-112Article in journal (Refereed)
    Abstract [en]

    Growth hormone (GH), prolactin (PRL), prolactin 2 (PRL2) and somatolactin (SL) belong to the same hormone family and have a wide repertoire of effects including development, osmoregulation, metabolism and stimulation of growth. Both the hormone and the receptor family have been proposed to have expanded by gene duplications in early vertebrate evolution. A key question is how hormone-receptor preferences have arisen among the duplicates. The first step to address this is to determine the time window for these duplications. Specifically, we aimed to see if duplications resulted from the two basal vertebrate tetraploidizations (1R and 2R). GH family genes from a broad range of vertebrate genomes were investigated using a combination of sequence-based phylogenetic analyses and comparisons of synteny. We conclude that the PRL and PRL2 genes arose from a common ancestor in 1R/2R, as shown by neighboring gene families. No other gene duplicates were preserved from these tetraploidization events. The ancestral genes that would give rise to GH and PRL/PRL2 arose from an earlier duplication; most likely a local gene duplication as they are syntenic in several species. Likewise, some evidence suggests that SL arose from a local duplication of an ancestral GH/SL gene in the same time window, explaining the lack of similarity in chromosomal neighbors to GH, PRL or PRL2. Thus, the basic triplet of ancestral GH, PRL/ PRL2 and SL genes appear to be unexpectedly ancient. Following 1R/2R, only SL was duplicated in the teleost-specific tetraploidization 3R, resulting in SLa and SLb. These time windows contrast with our recent report that the corresponding receptor genes GHR and PRLR arose through a local duplication in jawed vertebrates and that both receptor genes duplicated further in 3R, which reveals a surprising asynchrony in hormone and receptor gene duplications.

  • 27.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Evolution of the receptors for growth hormone, prolactin, erythropoietin and thrombopoietin in relation to the vertebrate tetraploidizations2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 257, p. 143-160Article in journal (Refereed)
    Abstract [en]

    The receptors for the pituitary hormones growth hormone (GH), prolactin (PRL) and somatolactin (SL), and the hematopoietic hormones erythropoietin (EPO) and thrombopoietin (TPO), comprise a structurally related family in the superfamily of cytokine class-I receptors. GH, PRL and SL receptors have a wide variety of effects in development, osmoregulation, metabolism and stimulation of growth, while EPO and TPO receptors guide the production and differentiation of erythrocytes and thrombocytes, respectively. The evolution of the receptors for GH, PRL and SL has been partially investigated by previous reports suggesting different time points for the hormone and receptor gene duplications. This raises questions about how hormone-receptor partnerships have emerged and evolved. Therefore, we have investigated in detail the expansion of this receptor family, especially in relation to the basal vertebrate (1R, 2R) and teleost (3R) tetraploidizations. Receptor family genes were identified in a broad range of vertebrate genomes and investigated using a combination of sequence-based phylogenetic analyses and comparative genomic analyses of synteny. We found that 1R most likely generated EPOR/TPOR and GHR/PRLR ancestors; following this, 2R resulted in EPOR and TPOR genes. No GHR/PRLR duplicate seems to have survived after 2R. Instead the single GHR/PRLR underwent a local duplication sometime after 2R, generating separate syntenic genes for GHR and PRLR. Subsequently, 3R duplicated the gene pair in teleosts, resulting in two GHR and two PRLR genes, but no EPOR or TPOR duplicates. These analyses help illuminate the evolution of the regulatory mechanisms for somatic growth, metabolism, osmoregulation and hematopoiesis in vertebrates.

  • 28.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lewicka, Michalina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The oxytocin/vasopressin receptor family has at least five members in the gnathostome lineage, inclucing two distinct V2 subtypes2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 135-143Article in journal (Refereed)
    Abstract [en]

    The vertebrate oxytocin and vasopressin receptors form a family of G-protein-coupled receptors (GPCRs) that mediate a large variety of functions, including social behavior and the regulation of blood pressure, water balance and reproduction. In mammals four family members have been identified, three of which respond to vasopressin (VP) named V1A, V1B and V2, and one of which is activated by oxytocin (OT), called the OT receptor. Four receptors have been identified in chicken as well, but these have received different names. Until recently only V1-type receptors have been described in several species of teleost fishes. We have identified family members in several gnathostome genomes and performed phylogenetic analyses to classify OT/VP-receptors across species and determine orthology relationships. Our phylogenetic tree identifies five distinct ancestral gnathostome receptor subtypes in the OT/VP receptor family: V1A, V1B, V2A, V2B and OT receptors. The existence of distinct V2A and V2B receptors has not been previously recognized. We have found these two subtypes in all examined teleost genomes as well as in available frog and lizard genomes and conclude that the V2A-type is orthologous to mammalian V2 receptors whereas the V2B-type is orthologous to avian V2 receptors. Some teleost fishes have acquired additional and more recent gene duplicates with up to eight receptor family members. Thus, this analysis reveals an unprecedented complexity in the gnathostome repertoire of OT/VP receptors, opening interesting research avenues regarding functions such as regulation of water balance, reproduction and behavior, particularly in reptiles, amphibians, teleost fishes and cartilaginous fishes.

  • 29.
    Olsén, K Håkan
    et al.
    Södertörn University, School of Life Sciences.
    Sawisky, G. R.
    Stacey, N. E.
    Endocrine and milt responses of male crucian carp (Carassius carassius L.) to periovulatory females under field conditions2006In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 149, no 3, p. 294-302Article in journal (Refereed)
    Abstract [en]

    Laboratory studies in domesticated goldfish (Carassius auratus) show that, during the preovulatory luteinizing hormone (LH) surge, females release a complex steroidal pheromone that induces in males a rapid increase of plasma LH, which in turn increases strippable milt (sperm and seminal fluid) prior to ovulation and spawning. The objective of this study was to determine if the same phenomenon occurs in a wild congener, the crucian carp (Carassius carassius), under field conditions where fish are held in natural waters under ambient temperature and photoperiod. During the spawning season in June 2003, crucian carp were trapped in a small pond near Uppsala, Sweden, and held separately by sex in floating net pens. Addition of untreated females to male pens did not change male LH concentrations or milt volume during the 17 h sampling period. In contrast.. addition of females injected with Ovaprim (TM) (to induce an LH surge and ovulation) increased male LH concentrations at all sample times (5, 9, 13, and 17 h) following female addition and increased milt volumes at all but the first (5 h) sample time. Similar increases in male LH and milt that also occurred when untreated females ovulated spontaneously after addition to male pens suggest it is female ovulatory condition, rather than injection of ovaprim per se, that induced male LH and milt responses. Males also increased LH and milt 9 It after addition of females injected with the goldfish pheromonal steroid 4-pregnen-17,20 beta-diol-3-one (17,20 beta P), suggesting that similar responses to ovaprim-injected females were due, at least in part, to release of preovulatory pheromonal steroid(s). The clear and consistent effects of ovulatory females on male LH and milt, and the fact that crucian carp adapted well to confinement.. ovulated spontaneously, and exhibited apparently normal spawning behavior, all suggest that this species can serve as a useful cyprinid model to study reproductive processes in natural conditions.

  • 30.
    Porseryd, T.
    et al.
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden.
    Caspillo, N. Reyhanian
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden;Orebro Univ, Sch Sci & Technol, Orebro Life Sci Ctr, SE-70182 Orebro, Sweden.
    Volkova, K.
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden;Orebro Univ, Sch Sci & Technol, Orebro Life Sci Ctr, SE-70182 Orebro, Sweden.
    Elabbas, L.
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden.
    Källman, T.
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dinnetz, P.
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden.
    Olsson, P-E
    Örebro Life Science Center, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    Porsch-Hällstrom, I.
    Södertörn Univ, Sch Nat Sci Technol & Environm Studies, SE-14189 Huddinge, Sweden.
    Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17 alpha-ethinyl estradiol2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 262, p. 44-58Article in journal (Refereed)
    Abstract [en]

    17 alpha-Ethinylestradiol (EE2) is a ubiquitous aquatic contaminant shown to decrease fish fertility at low concentrations, especially in fish exposed during development. The mechanisms of the decreased fertility are not fully understood. In this study, we perform transcriptome analysis by RNA sequencing of testes from zebrafish with previously reported lowered fertility due to exposure to low concentrations of EE2 during development. Fish were exposed to 1.2 and 1.6 ng/L (measured concentration; nominal concentrations 3 and 10 ng/L) of EE2 from fertilization to 80 days of age, followed by 82 days of remediation in clean water. RNA sequencing analysis revealed 249 and 16 genes to be differentially expressed after exposure to 1.2 and 1.6 ng/L, respectively; a larger inter-sample variation was noted in the latter. Expression of 11 genes were altered by both exposures and in the same direction. The coding sequences most affected could be categorized to the putative functions cell signalling, proteolysis, protein metabolic transport and lipid metabolic process. Several homeobox transcription factors involved in development and differentiation showed increased expression in response to EE2 and differential expression of genes related to cell death, differentiation and proliferation was observed. In addition, several genes related to steroid synthesis, testis development and function were differentially expressed. A number of genes associated with spermatogenesis in zebrafish and/or mouse were also found to be differentially expressed. Further, differences in non-coding sequences were observed, among them several differentially expressed miRNA that might contribute to testis gene regulation at post-transcriptional level. This study has generated insights of changes in gene expression that accompany fertility alterations in zebrafish males that persist after developmental exposure to environmental relevant concentrations of EE2 that persist followed by clean water to adulthood. Hopefully, this will generate hypotheses to test in search for mechanistic explanations.

  • 31.
    Porseryd, T.
    et al.
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden.
    Caspillo, N. Reyhanian
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden; Örebro Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Volkova, K.
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden; Örebro Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Elabbas, L.
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden.
    Källman, T.
    National Bioinformatics Infrastructure Sweden, Uppsala University, Uppsala, Sweden; Science for Life Laboratory and Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Dinnetz, P.
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology. Örebro Life Science Center.
    Porsch-Hallstrom, I.
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden.
    Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17 alpha-ethinyl estradiol2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 262, p. 44-58Article in journal (Refereed)
    Abstract [en]

    17 alpha-Ethinylestradiol (EE2) is a ubiquitous aquatic contaminant shown to decrease fish fertility at low concentrations, especially in fish exposed during development. The mechanisms of the decreased fertility are not fully understood. In this study, we perform transcriptome analysis by RNA sequencing of testes from zebrafish with previously reported lowered fertility due to exposure to low concentrations of EE2 during development. Fish were exposed to 1.2 and 1.6 ng/L (measured concentration; nominal concentrations 3 and 10 ng/L) of EE2 from fertilization to 80 days of age, followed by 82 days of remediation in clean water. RNA sequencing analysis revealed 249 and 16 genes to be differentially expressed after exposure to 1.2 and 1.6 ng/L, respectively; a larger inter-sample variation was noted in the latter. Expression of 11 genes were altered by both exposures and in the same direction. The coding sequences most affected could be categorized to the putative functions cell signalling, proteolysis, protein metabolic transport and lipid metabolic process. Several homeobox transcription factors involved in development and differentiation showed increased expression in response to EE2 and differential expression of genes related to cell death, differentiation and proliferation was observed. In addition, several genes related to steroid synthesis, testis development and function were differentially expressed. A number of genes associated with spermatogenesis in zebrafish and/or mouse were also found to be differentially expressed. Further, differences in non-coding sequences were observed, among them several differentially expressed miRNA that might contribute to testis gene regulation at post-transcriptional level. This study has generated insights of changes in gene expression that accompany fertility alterations in zebrafish males that persist after developmental exposure to environmental relevant concentrations of EE2 that persist followed by clean water to adulthood. Hopefully, this will generate hypotheses to test in search for mechanistic explanations.

  • 32.
    Porseryd, Tove
    et al.
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Environmental Science.
    Reyhanian Caspillo, Nasim
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology. Örebro universitet.
    Volkova, Kristina
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology. Örebro universitet.
    Elabbas, Lubna
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology.
    Källman, Thomas
    Uppsala university.
    Dinnétz, Patrik
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Environmental Science.
    Olsson, Per-Erik
    Örebro universitet.
    Porsch Hällström, Inger
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology.
    Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17α-ethinyl estradiol2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 262, p. 44-58Article in journal (Refereed)
    Abstract [en]

    17α-Ethinylestradiol (EE2) is a ubiquitous aquatic contaminant shown to decrease fish fertility at low concentrations, especially in fish exposed during development. The mechanisms of the decreased fertility are not fully understood. In this study, we perform transcriptome analysis by RNA sequencing of testes from zebrafish with previously reported lowered fertility due to exposure to low concentrations of EE2during development. Fish were exposed to 1.2 and 1.6 ng/L (measured concentration; nominal concentrations 3 and 10 ng/L) of EE2 from fertilization to 80 days of age, followed by 82 days of remediation in clean water. RNA sequencing analysis revealed 249 and 16 genes to be differentially expressed after exposure to 1.2 and 1.6 ng/L, respectively; a larger inter-sample variation was noted in the latter. Expression of 11 genes were altered by both exposures and in the same direction. The coding sequences most affected could be categorized to the putative functions cell signalling, proteolysis, protein metabolic transport and lipid metabolic process. Several homeobox transcription factors involved in development and differentiation showed increased expression in response to EE2 and differential expression of genes related to cell death, differentiation and proliferation was observed. In addition, several genes related to steroid synthesis, testis development and function were differentially expressed. A number of genes associated with spermatogenesis in zebrafish and/or mouse were also found to be differentially expressed. Further, differences in non-coding sequences were observed, among them several differentially expressed miRNA that might contribute to testis gene regulation at post-transcriptional level. This study has generated insights of changes in gene expression that accompany fertility alterations in zebrafish males that persist after developmental exposure to environmental relevant concentrations of EE2 that persist followed by clean water to adulthood. Hopefully, this will generate hypotheses to test in search for mechanistic explanations.

  • 33.
    Pradhan, Ajay
    et al.
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Germ cell depletion in zebrafish leads to incomplete masculinization of the brain2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 265, no SI, p. 15-21Article in journal (Refereed)
    Abstract [en]

    Zebrafish sex differentiation is under the control of multiple genes, but also relies on germ cell number for gonadal development. Morpholino and chemical mediated germ cell depletion leads to sterile male development in zebrafish. In this study we produced sterile males, using a dead end gene morpholino, to determine gonadal-brain interactions. Germ cell depletion following dnd inhibition downregulated the germ cell markers, vasa and ziwi, and later the larvae developed as sterile males. Despite lacking proper testis, the gonadal 11-ketotestosterone (11-KT) and estradiol (E2) levels of sterile males were similar to wild type males. Qualitative analysis of sexual behavior of sterile males demonstrated that they behaved like wild type males. Furthermore, we observed that brain 11-KT and E2 levels in sterile males remained the same as in the wild type males. In female brain, 11-KT was lower in comparison to wild type males and sterile males, while E2 was higher when compared to wild type males. qRT-PCR analysis revealed that the liver transcript profile of sterile adult males was similar to wild type males while the brain transcript profile was similar to wild type females. The results demonstrate that proper testis development may not be a prerequisite for male brain development in zebrafish but that it may be needed to fully masculinize the brain.

  • 34.
    Pradhan, Ajay
    et al.
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Inhibition of retinoic acid synthesis disrupts spermatogenesis and fecundity in zebrafish2015In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 217, p. 81-91Article in journal (Refereed)
    Abstract [en]

    Timing of germ cell entry into meiosis is sexually dimorphic in mammals. However it was recently shown that germ cells initiate meiosis at the same time in male and female zebrafish. Retinoic acid (RA) has been shown to be critical for mammalian spermatogenesis. Inhibition of RA synthesis by WIN 18,446 has been reported to inhibit spermatogenesis in a wide variety of animals including humans and was once used as a contraceptive in humans. In this study we explored the role of RA in zebrafish spermatogenesis. In silico analysis with Internal coordinate mechanics docking software showed that WIN 18,446 can bind to the rat, human and zebrafish Aldh1a2 catalytic domain with equivalent potency. RA exposure resulted in upregulation of the RA metabolizing enzyme genes cyp26a1, cyp26b1 and cyp26c1 in vitro and in vivo. Exposure to WIN 18,446 resulted in down-regulation of Aldh1a2, cyp26a1 and cyp26b1 in vivo. WIN 18,446 was effective in disrupting spermatogenesis and fecundity in zebrafish but the reduction in sperm count and fecundity was only observed when zebrafish were maintained on a strict Artemia nauplii diet which is known to contain low levels of vitamin A. This study shows that RA is involved in spermatogenesis as well as oocyte development in zebrafish. As the zebrafish Aldh1a2 structure and function is similar to the mammalian counterpart, Aldh1a2 inhibitor screening using zebrafish as a model system may be beneficial in the discovery and development of new and safe contraceptives for humans.

  • 35.
    Rosengren, Malin
    et al.
    Univ Gothenburg, Dept Biol & Environm Sci, POB 463, SE-40531 Gothenburg, Sweden..
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sundell, Kristina
    Univ Gothenburg, Dept Biol & Environm Sci, POB 463, SE-40531 Gothenburg, Sweden..
    The brain-gut axis of fish: Rainbow trout with low and high cortisol response show innate differences in intestinal integrity and brain gene expression2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 257, p. 235-245Article in journal (Refereed)
    Abstract [en]

    In fish, the stress hormone cortisol is released through the action of the hypothalamic pituitary interrenal axis (HPI-axis). The reactivity of this axis differs between individuals and previous studies have linked this to different behavioural characteristics and stress coping styles. In the current study, low and high responding (LR and HR) rainbow trout in terms of cortisol release during stress were identified, using a repeated confinements stress test. The expression of stress related genes in the forebrain and the integrity of the stress sensitive primary barrier of the intestine was examined. The HR trout displayed higher expression levels of mineralocorticoid and serotonergic receptors and serotonergic re-uptake pumps in the telencephalon during both basal and stressed conditions. This confirms that HPI-axis reactivity is linked also to other neuronal behavioural modulators, as both the serotonergic and the corticoid system in the telencephalon are involved in behavioural reactivity and cognitive processes. Involvement of the HPI-axis in the brain-gut-axis was also found. LR trout displayed a lower integrity in the primary barrier of the intestine during basal conditions compared to the HR trout. However, following stress exposure, LR trout showed an unexpected increase in intestinal integrity whereas the HR trout instead suffered a reduction. This could make the LR individuals more susceptible to pathogens during basal conditions where instead HR individuals would be more vulnerable during stressed conditions. We hypothesize that these barrier differences are caused by regulation/effects on tight junction proteins possibly controlled by secondary effects of cortisol on the intestinal immune barrier or differences in parasympathetic reactivity.

  • 36.
    Roufidou, Chrysoula
    et al.
    Stockholm Univ, Dept Zool, S-10691 Stockholm, Sweden..
    Schmitz, Monika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Mayer, Ian
    Norwegian Univ Life Sci, Fac Vet Med & Biosci, Oslo, Norway..
    Sebire, Marion
    Ctr Environm Fisheries & Aquaculture Sci Cefas, Weymouth, Dorset, England..
    Katsiadaki, Ioanna
    Ctr Environm Fisheries & Aquaculture Sci Cefas, Weymouth, Dorset, England..
    Shao, Yi Ta
    Natl Taiwan Ocean Univ, Inst Marine Biol, Keelung, Taiwan..
    Borg, Bertil
    Stockholm Univ, Dept Zool, S-10691 Stockholm, Sweden..
    Hormonal changes over the spawning cycle in the female three-spined stickleback, Gasterosteus aculeatus2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 257, p. 97-105Article in journal (Refereed)
    Abstract [en]

    Female three-spined sticklebacks are batch spawners laying eggs in a nest built by the male. We sampled female sticklebacks at different time points, when they were ready to spawn and 6, 24, 48 and 72 h post-spawning (hps) with a male. Following spawning, almost all females (15 out of 19) had ovulated eggs again at Day 3 post-spawning (72 hps). At sampling, plasma, brain and pituitaries were collected, and the ovary and liver were weighed. Testosterone (T) and estradiol (E2) were measured by radioimmunoassay. Moreover, the mRNA levels of follicle-stimulating hormone (fsh-beta) and luteinizing hormone (lh-beta) in the pituitary, and of the gonadotropin-releasing hormones (GnRHs: gnrh2, gnrh3) and kisspeptin (kiss2) and its G protein-coupled receptor (gpr54) in the brain were measured by real-time qPCR. Ovarian weights peaked in "ready to spawn" females, dropped after spawning, before again progressively increasing from 6 to 72 hps. Plasma T levels showed peaks at 24 and 48 hps and decreased at 72 hps, while E2 levels increased already at 6 hps and remained at high levels up to 48 hps. There was a strong positive correlation between T and E2 levels over the spawning cycle. Pituitary lh-beta mRNA levels showed a peak at 48 hps, while fsh-beta did not change. The neuropeptides and gpr54 did not show any changes. The changes in T and E2 over the stickleback spawning cycle were largely consistent with those found in other multiple-spawning fishes whereas the marked correlation between T and E2 does not support T having other major roles over the cycle than being a precursor for E2.

  • 37.
    Roufidou, Chrysoula
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Schmitz, Monika
    Mayer, Ian
    Sebire, Marion
    Katsiadaki, Ioanna
    Shao, Yi Ta
    Borg, Bertil
    Stockholm University, Faculty of Science, Department of Zoology.
    Hormonal changes over the spawning cycle in the female three-spined stickleback, Gasterosteus aculeatus2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 257, no SI, p. 97-105Article in journal (Refereed)
    Abstract [en]

    Female three-spined sticklebacks are batch spawners laying eggs in a nest built by the male. We sampled female sticklebacks at different time points, when they were ready to spawn and 6, 24, 48 and 72 hours post-spawning (hps) with a male. Following spawning, almost all females (15 out of 19) had ovulated eggs again at Day 3 post-spawning (72hps). At sampling, plasma, brain and pituitaries were collected, and the ovary and liver were weighed. Testosterone (T) and estradiol (E2) were measured by radioimmunoassay. Moreover, the mRNA levels of follicle-stimulating hormone (fsh-β) and luteinizing hormone (lh-β) in the pituitary, and of the gonadotropin-releasing hormones (GnRHs: gnrh2, gnrh3) and kisspeptin (kiss2) and its G protein-coupled receptor (gpr54) in the brain were measured by real-time qPCR. Ovarian weights peaked in “ready to spawn” females, dropped after spawning, before again progressively increasing from 6 to 72hps. Plasma T levels showed peaks at 24 and 48hps and decreased at 72hps, while E2 levels increased already at 6hps and remained at high levels up to 48hps. There was a strong positive correlation between T and E2 levels over the spawning cycle. Pituitary lh-β mRNA levels showed a peak at 48hps, while fsh-β did not change. The neuropeptides and gpr54 did not show any changes. The changes in T and E2 over the stickleback spawning cycle were largely consistent with those found in other multiple-spawning fishes whereas the marked correlation between T and E2 does not support T having other major roles over the cycle than being a precursor for E2.

  • 38. Schjolden, Joachim
    et al.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Larson, Earl T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Melanocortin peptides affect the motivation to feed in rainbow trout (Oncorhynchus mykiss)2009In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 160, no 2, p. 134-138Article in journal (Refereed)
    Abstract [en]

    In this study, we investigated the effects of one melanocortin receptor (MCR) agonist and two antagonists on food intake in juvenile rainbow trout. Baseline food intake was established prior to 1 microl intracerebroventricular injection (ICV) of the non-specific agonist MTII, the MC4R antagonist HS024 and the MC3/4R antagonist SHU9119 at concentrations of 0.3, 1 or 3 nM. Saline-injected fish and untreated fish served as controls. Changes in food intake were observed 1h after the ICV injections. Our results showed that treatment with MTII significantly decreased food intake at 3 nM compared to control, HS024 significantly increased food intake at 3 nM compared to control and saline-treated fish, and SHU9119 significantly increased food intake at 3 nM compared to saline-treated fish. In conclusion, our study provides further evidence, and hence strengthens the hypothesis, that MC4R participates in the control of energy balance in fish in the same manner as in mammals. Our findings that HS024 is more potent than SHU9119 in increasing food intake suggest that the effects of melanocortin on energy balance in rainbow trout are mainly regulated by activation of MC4R. Hence, HS024 seems an excellent tool as a MC4R antagonist in rainbow trout.

  • 39. Shao, Y. T.
    et al.
    Arvidsson, M.
    Trombley, Susanne
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Schulz, R. W.
    Schmitz, Monica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Borg, B.
    Androgen feedback effects on LH and FSH, and photoperiodic control of reproduction in male three-spined sticklebacks, Gasterosteus aculeatus2013In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 182, p. 16-23Article in journal (Refereed)
    Abstract [en]

    Sexual maturation in the stickleback is controlled by photoperiod. The aim of this study was to find out whether changes in feedback effects exerted by sex steroids could mediate the photoperiodic effect, which is regarded to be of an all-or-nothing character. To that end, males were castrated and treated with different doses of testosterone (T) and in one experiment also with the aromatase inhibitor fadrozole (AI) and kept under different photoperiods. In control fish, long day (LD 16:8) stimulated maturation, associated with more hypertrophied kidneys (a secondary sexual character) and higher levels of pituitary lhb and fshb mRNA than under short day conditions (LD 8:16). Under LD 8:16, low doses of T suppressed both lhb and fshb mRNA levels. However, with the use of high doses of T and/or longer photoperiods the inhibitory effects on lhb and fshb mRNA levels became less clear or instead positive effects were observed. Under intermediate photoperiod conditions, the negative feedback effect of a low dose of T on fshb was more prominent with shorter photoperiods, whereas no such shift was observed for lhb mRNA. The inhibitory effect of the low dose of T on lhb mRNA levels under LD 8:16 was abolished by AI, whereas the stimulatory effect of the high dose of T was not. The negative feedback effects were more marked under short days than under long days, whereas positive feedback effects were more marked under long days. The suppression of both fshb and lhb mRNA levels by low androgen levels, especially under short days, may inhibit maturation completely unless a rise of androgens above threshold levels would allow complete maturation.

  • 40.
    Shao, Yi Ta
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Arvidsson, Mia
    Stockholm University, Faculty of Science, Department of Zoology.
    Trombley, Susanne
    Schulz, Rudiger W.
    Schmitz, Monika
    Borg, Bertil
    Stockholm University, Faculty of Science, Department of Zoology.
    Androgen feedback effects on LH and FSH, and photoperiodic control of reproduction in male three-spined sticklebacks, Gasterosteus aculeatus2013In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 182, p. 16-23Article in journal (Refereed)
    Abstract [en]

    Sexual maturation in the stickleback is controlled by photoperiod. The aim of this study was to find out whether changes in feedback effects exerted by sex steroids could mediate the photoperiodic effect, which is regarded to be of an all-or-nothing character. To that end, males were castrated and treated with different doses of testosterone (T) and in one experiment also with the aromatase inhibitor fadrozole (AI) and kept under different photoperiods. In control fish, long day (LD 16:8) stimulated maturation, associated with more hypertrophied kidneys (a secondary sexual character) and higher levels of pituitary lhb and fshb mRNA than under short day conditions (LD 8:16). Under LD 8:16, low doses of T suppressed both lhb and fshb mRNA levels. However, with the use of high doses of T and/or longer photoperiods the inhibitory effects on lhb and fshb mRNA levels became less clear or instead positive effects were observed. Under intermediate photoperiod conditions, the negative feedback effect of a low dose of T on fshb was more prominent with shorter photoperiods, whereas no such shift was observed for lhb mRNA. The inhibitory effect of the low dose of T on lhb mRNA levels under LD 8:16 was abolished by AI, whereas the stimulatory effect of the high dose of T was not. The negative feedback effects were more marked under short days than under long days, whereas positive feedback effects were more marked under long days. The suppression of both fshb and lhb mRNA levels by low androgen levels, especially under short days, may inhibit maturation completely unless a rise of androgens above threshold levels would allow complete maturation.

  • 41.
    Sundh, Henrik
    et al.
    Fish Endocrinology Laboratory, Department of Zoology, Göteborg University, Box 463, SE-405 30 Göteborg, Sweden.
    Larsson, Dennis
    Högskolan i Skövde, Institutionen för vård och natur.
    Sundell, Kristina
    Fish Endocrinology Laboratory, Department of Zoology, Göteborg University, Box 463, SE-405 30 Göteborg, Sweden.
    Environmental salinity regulates the in vitro production of [3H]-1,25-dihydroxyvitamin D3 and [3H]-24,25 dihydroxyvitamin D3 in rainbow trout (Oncorhynchus mykiss)2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 152, no 2-3, p. 252-258Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that specific binding of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) to enterocyte basolateral membranes (BLM), as well as circulating concentrations, is affected in response to changes in environmental salinity. It is not known if the production of 1,25(OH)2D3 and 24,25(OH)2D3 is affected by environmental salinity. The aim of the present study was to measure the in vitro production of [3H]-1,25(OH)2D3 and [3H]-24,25(OH)2D3 in fresh water (FW) and after 1, 2, 3, and 7 days after transfer to seawater (SW). Pooled sub-cellular fractions (mitochondria and microsomes) from liver or kidney was incubated with [3H]-25(OH)D3 and the produced metabolites were separated using HPLC. Hepatic production of [3H]-1,25(OH)2D3 was decreased after 24 h in SW. This was followed by an up-regulation after 48 h and a second, slower decrease in production rate which leveled out after 7 days in SW. The production rate in SW was lower than the original rate in FW-adapted fish. For hepatic [3H]-24,25(OH)2D3 production the pattern was reversed. Renal production of [3H]-24,25(OH)2D3 increased significantly during the period of SW acclimation. These results suggest that environmental salinity regulates the production rate of the two antagonizing calcium regulatory hormones; 1,25(OH)2D3 and 24,25(OH)2D3. This gives further evidence to the hypothesis that there is a physiological regulation and a differentiated importance of 1,25(OH)2D3 and 24,25(OH)2D3 in relation to environmental calcium concentrations.

  • 42.
    Sundh, Henrik
    et al.
    Fish Endocrinology Laboratory, Department of Zoology, Göteborg University, Box 463, SE-405 30 Göteborg, Sweden.
    Larsson, Dennis
    University of Skövde, School of Life Sciences.
    Sundell, Kristina
    Fish Endocrinology Laboratory, Department of Zoology, Göteborg University, Box 463, SE-405 30 Göteborg, Sweden.
    Environmental salinity regulates the in vitro production of [3H]-1,25-dihydroxyvitamin D3 and [3H]-24,25 dihydroxyvitamin D3 in rainbow trout (Oncorhynchus mykiss)2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 152, no 2-3, p. 252-258Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that specific binding of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) to enterocyte basolateral membranes (BLM), as well as circulating concentrations, is affected in response to changes in environmental salinity. It is not known if the production of 1,25(OH)2D3 and 24,25(OH)2D3 is affected by environmental salinity. The aim of the present study was to measure the in vitro production of [3H]-1,25(OH)2D3 and [3H]-24,25(OH)2D3 in fresh water (FW) and after 1, 2, 3, and 7 days after transfer to seawater (SW). Pooled sub-cellular fractions (mitochondria and microsomes) from liver or kidney was incubated with [3H]-25(OH)D3 and the produced metabolites were separated using HPLC. Hepatic production of [3H]-1,25(OH)2D3 was decreased after 24 h in SW. This was followed by an up-regulation after 48 h and a second, slower decrease in production rate which leveled out after 7 days in SW. The production rate in SW was lower than the original rate in FW-adapted fish. For hepatic [3H]-24,25(OH)2D3 production the pattern was reversed. Renal production of [3H]-24,25(OH)2D3 increased significantly during the period of SW acclimation. These results suggest that environmental salinity regulates the production rate of the two antagonizing calcium regulatory hormones; 1,25(OH)2D3 and 24,25(OH)2D3. This gives further evidence to the hypothesis that there is a physiological regulation and a differentiated importance of 1,25(OH)2D3 and 24,25(OH)2D3 in relation to environmental calcium concentrations.

  • 43.
    Sundström, Görel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Brenner, Sydney
    Venkatesh, Byrappa
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evolution of the neuropeptide Y family: new genes by chromosome duplications in early vertebrates and in teleost fishes2008In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 155, no 3, p. 705-716Article in journal (Refereed)
    Abstract [en]

    Despite sequence information from many vertebrates the evolution of the neuropeptide Y (NPY) family of peptides has been difficult to resolve, particularly among ray-finned fishes. We have used chromosomal location and sequence analyses to identify orthologs and gene duplicates in teleost fish genomes. Our analyses support origin of NPY and peptide YY (PYY) from a common ancestor in early vertebrate evolution through a chromosome duplication. We report here that the teleost tetraploidization generated duplicates of both NPY and PYY and that all four genes are still present in the two sequenced pufferfish genomes Tetraodon nigroviridis and Takifugu rubripes as well as three-spined stickleback, Gasterosteus aculeatus. The zebrafish Danio rerio NPYb gene has probably been lost whereas medaka, Oryzias latipes seems to lack PYYb. Some of the previously published PYY sequences were misidentified and actually constitute NPYb. Our analyses confirm that the peptide previously named PY in some fish species is a duplicate of the PYY gene and hence should be called PYYb. The NPYa and NPYb genes in Takifugu rubripes are predominantly expressed in brain, as detected by RT-PCR, whereas PYYa and PYYb are expressed in several organs including brain, intestine and gonads. Thus, also the resemblance in expression pattern supports the fish gene duplication scenario. Our study shows that when sequence comparisons give ambiguous results, chromosomal location can serve as a useful criterion to identify orthologs. This strategy may help to resolve relationships in several families of short peptides.

  • 44.
    Sundström, Görel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larsson, Tomas A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Heldin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Conlon, JM
    Dept of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University .
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Denver, RJ
    Department of Molecular, Cellular and Developmental Biology, The University of Michigan, 3065C Kraus Building, Ann Arbor, MI 48109-1048, USA.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Characterization of the neuropeptide Y system in the frog Silurana tropicalis (Pipidae): three peptides and six receptor subtypes2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 177, no 3, p. 322-331Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y and its related peptides PYY and PP (pancreatic polypeptide) are involved in feeding behavior, regulation of the pituitary and the gastrointestinal tract, and numerous other functions. The peptides act on a family of G-protein coupled receptors with 4-7 members in jawed vertebrates. We describe here the NPY system of the Western clawed frog Silurana (Xenopus) tropicalis. Three peptides, NPY, PYY and PP, were identified together with six receptors, namely subtypes Y1, Y2, Y4, Y5, Y7 and Y8. Thus, this frog has all but one of the ancestral seven gnathostome NPY-family receptors, in contrast to mammals which have lost 2-3 of the receptors. Expression levels of mRNA for the peptide and receptor genes were analyzed in a panel of 19 frog tissues using reverse transcriptase quantitative PCR. The peptide mRNAs had broad distribution with highest expression in skin, blood and small intestine. NPY mRNA was present in the three brain regions investigated, but PYY and PP mRNAs were not detectable in any of these. All receptor mRNAs had similar expression profiles with high expression in skin, blood, muscle and heart. Three of the receptors, Y5, Y7 and Y8, could be functionally expressed in HEK-293 cells and characterized with binding studies using the three frog peptides. PYY had the highest affinity for all three receptors (K(i) 0.042-0.34 nM). Also NPY and PP bound to the Y8 receptor with high affinity (0.14 and 0.50 nM). The low affinity of NPY for the Y5 receptor (100-fold lower than PYY) differs from mammals and chicken. This may suggest a less important role of NPY on Y5 in appetite stimulation in the frog compared with amniotes. In conclusion, our characterization of the NPY system in S. tropicalis with its six receptors demonstrates not only greater complexity than in mammals but also some interesting differences in ligand-receptor preferences.

  • 45. Takahashi, Akiyoshi
    et al.
    Kosugi, Takayoshi
    Kobayashi, Yuki
    Yamanome, Takeshi
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kawauchi, Hiroshi
    The melanin-concentrating hormone receptor 2 (MCH-R2) mediates the effect of MCH to control body color for background adaptation in the barfin flounder2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 151, no 2, p. 210-219Article in journal (Refereed)
    Abstract [en]

    Melanin-concentrating hormone (MCH) is a neuropeptide generated in neurons originating in the hypothalamus, from which axons project to the entire brain and neurohypophysis in fish. MCH has both central and peripheral roles such as food intake and body color change. Here we cloned two MCH receptors (MCH-R) from the barfin flounder, Verasper moseri, Pleuronectiformes. The phylogenetic analysis shows that these are orthologues to the mammalian MCH-R1 and MCH-R2 showing 49 and 30% amino acid sequence identity to the corresponding human receptors while they have 31% amino acid sequence identify between them. Essential amino acid residues for ligand binding, signal transduction and receptor conformation, which have been shown in mammalian MCH-R, are well conserved in the flounder MCH-Rs. MCH-R1 has one intron in the extracellular N-terminal region and MCH-R2 has one intron in the DRY motif, which is a homologous position to one of the five introns of human MCH-R2. Orthologues of MCH-R1 and MCH-R2 may have appeared by gene duplication of the ancestry of MCH-Rs having at least two introns, and then MCH-R1 and MCH-R2 inherited different introns in flounder strains. We also determined their tissue distribution and functional role in rearing condition. Reverse transcription PCR revealed that the expression of MCH-R1 is confined to the brain of the barfin flounder, while transcripts of MCH-R2 were detected in the brain, pituitary, eyeball, gill, atrium, ventricle, head kidney, body kidney, spleen, intestine, inclinator, skeletal muscle testis, ovary, eyed-side skin, and non-eyed-side skin. The expression of MCH-R2 in eyed-side skin was higher in fish reared in a black tank (121 days) than in a white tank while the expression levels of MCH in the brain were significantly greater in the group reared with the white background suggesting down-regulation of this receptor gene with increased levels of MCH. The results suggest that the MCH-R2 mediates the effect of MCH to control body color for background adaptation in the eyed-side skin of the barfin flounder.

  • 46.
    Thomas, Peter
    et al.
    Marine Science Institute, The University of Texas at Austin, Port Aransas TX, USA.
    Converse, Aubrey
    Marine Science Institute, The University of Texas at Austin, Port Aransas TX, USA.
    Berg, Håkan A.
    Örebro University, School of Science and Technology.
    ZIP9, a novel membrane androgen receptor and zinc transporter protein2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 257, p. 130-136Article in journal (Refereed)
    Abstract [en]

    Rapid, androgen actions initiated at the cell surface have been reported in a variety of vertebrate cells, including several macrophage and prostate cancer cell lines that lack the nuclear androgen receptor. However, until recently the identity of the novel membrane androgen receptor (mAR) mediating these nonclassical androgen actions remained unknown. In 2014, a novel mAR unrelated to nuclear androgen receptors was identified in Atlantic croaker ovaries as the zinc transporter protein, ZIP9. ZIP9 is one of the 14 members of the ZIP (ZRT-and Irt-like Protein, SLC39A) family that regulates zinc homeostasis by transporting zinc across cell and organelle membranes into the cytoplasm. Zinc is a micronutrient critical for the maintenance of physiological and cellular processes, such as development, growth, protein assembly and activity, signaling, and apoptosis. Both croaker ZIP9 and human ZIP9 proteins have the binding characteristics of high affinity, specific mARs, and are coupled to G proteins. Testosterone induces apoptosis through ZIP9 in croaker granulosa cells and in human breast and prostate cancer cells by a unique mechanism involving increases in both second messengers and intracellular free zinc concentrations. ZIP9 also mediates testosterone regulation of tight junction formation in Sertoli cells and nonclassical testosterone signaling in spermatogenic cells. ZIP9 acts through several signal transduction pathways, a stimulatory G protein (Gs) in granulosa cells, an inhibitory one (Gi) in cancer cells, and a Gq11 one (Gnα11) in spermatogenic cells. ZIP9 has a very broad tissue distribution and is predicted to mediate numerous and diverse nonclassical androgen actions in vertebrates.

  • 47. Tipsmark, Christian
    et al.
    Jörgensen, C
    Brande-Lavridsen, Nanna
    Engelund, M
    Olesen, J.H.
    Madsen, S
    Effects of cortisol, growth hormone and prolactin on gill claudin expression in Atlantic salmon2009In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 163, p. 270-277Article in journal (Refereed)
    Abstract [en]

    We recently showed that a series of tight junction proteins of the claudin family are regulated in the gill of salmon during salinity acclimation. The aim of the present study was to investigate the role of cortisol, growth hormone (GH) and prolactin (PRL) on regulation of expression of these isoforms. Experiments on primary cultures of gill tissue showed that cortisol stimulates claudin 10e, 27a and 30 mRNA levels while no significant effects were observed on claudin 28a and 28b. The associated receptor signalling pathway was examined using glucocorticoid and mineralocorticoid receptor antagonists RU486 and spironolactone, respectively. The observed in vitro responses were blocked by RU486, suggesting the involvement of a glucocorticoid type receptor. Injections of FW salmon with cortisol increased the expression of claudin 10e, 27a, and 30 but did not affect claudin 28a and 28b significantly. While GH had no effect on its own, the combination of GH and cortisol reduced claudin 28b levels. Injection of SW salmon with PRL selectively increased the expression of claudin 28a but had no effect on the other examined isoforms. The data shows that FW- (27a and 30) and SW-induced (10e) claudins are all stimulated by cortisol while the major osmoregulatory hormones GH and PRL had no effect on these salinity sensitive isoforms. This suggests that other hormones and/or osmotic conditions interact with cortisol to determine claudin composition in the gill.

  • 48. Trombley, S.
    et al.
    Rocha, A.
    Björnsson, B. Th.
    Borg, Bertil
    Stockholm University, Faculty of Science, Department of Zoology.
    Schmitz, M.
    Effects of androgens on the leptin system in immature male Atlantic salmon parr2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 257, p. 122-129Article in journal (Refereed)
    Abstract [en]

    Leptin modulates all levels of the reproductive endocrine axis in mammals, and in turn, both leptin and the leptin receptor are regulated by sex steroids. The aim of this study was to investigate if sex steroids regulate the leptin system also in fish. Immature one-year old male Atlantic salmon parr were implanted with Silclear capsules that were either empty or filled with 11-ketoandrostenedione (11 KA) or testosterone (T) and the effects of 35-days treatment were investigated on measures of maturation, gene expression of leptin (lepa1, lepa2), leptin receptor (lepra1) and circulating plasma leptin. Both 11-KA and T stimulated the reproductive axis by increasing testes weight and up-regulated pituitary lh-beta mRNA levels and for T also fsh-beta. T up-regulated transcription levels of lepa1 and lepra1 in the pituitary, while 11-KA had no effect. Leptin receptor expression in the testis was unaltered by either androgen. T up-regulated lepa1 mRNA levels significantly also in the liver, but had no effect on lepa2, and 11 KA did not affect hepatic gene expression of either lepa1 or lepa2. Plasma leptin levels did not differ significantly between treatments. The results indicate that androgens regulate gene expression of leptin and the leptin receptor in different tissues in fish and that the effects of leptin might be tissue specific considering plasma levels remained unaltered. Overall, the results suggest a role for leptin in fish reproduction, where sex steroids are able to regulate components of the leptin system differentially in liver and important tissues of the reproductive axis.

  • 49.
    Trombley, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Maugars, Gersende
    Muséum National d’Histoire Naturelle, Paris Cedex 05, France.
    Kling, Peter
    Göteborg universitet.
    Björnsson, Björn Thrandur
    Göteborg universitet.
    Schmitz, Monika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Effects of long-term restricted feeding on plasma leptin, hepatic leptin expression and leptin receptor expression in juvenile Atlantic salmon (Salmo salar L.)2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 92-99Article in journal (Refereed)
    Abstract [en]

    Leptin is a pleiotropic hormone and plays a key role in body weight regulation, energy homeostasis and lipid store utilization in mammals. In this study, we investigated the effect of feed-restriction on leptin genes (lepa1 and lepa2), leptin receptor (lepr) gene expression and plasma leptin levels in juvenile Atlantic salmon parr. Feed restriction was performed from late April to mid-June, in order to gain insight into the role of the leptin system in energy balance regulation and adiposity in juvenile salmon. A significant increase in lepa1 expression as well as higher levels of plasma leptin was found in feed-restricted fish in June compared to fully fed controls, while lepa2 gene expression decreased in both groups during the treatment period. Lepa2 was, however significantly higher in the feed-restricted group in June. Leptin receptor expression was up regulated during the period of enhanced growth and lipid deposition in the fully fed control, indicating a seasonal effect on the receptor expression in the brain. Both lepa1 and lepa2 genes very mainly expressed in the liver in juvenile salmon, while lepr was expressed in the brain but showed also considerable expression in various peripheral tissues. The study provides evidence that the leptin system is sensitive to the metabolic status of the fish as both season and restricted feeding affect lepa1 and lepa2 gene expression in the liver and brain leptin receptor expression, however, for lepa1 expression and leptin plasma level in an opposite way as that observed in the mammalian system.

  • 50.
    Trombley, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Mustafa, Arshi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Schmitz, Monika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Regulation of the seasonal leptin and leptin receptor expression profile during early sexual maturation and feed restriction in male Atlantic salmon, Salmo salar L., parr2014In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 204, p. 60-70Article in journal (Refereed)
    Abstract [en]

    In mammals, leptin acts as an adiposity signal and is a crucial link between nutritional status and the reproductive axis. So far the link between leptin and energy balance during sexual maturation in teleosts has been poorly investigated. In this study, seasonal gene expression changes in two leptin genes (lepa1 andlepa2) and the leptin receptor were investigated during early sexual maturation in male Atlantic salmon parr under fully fed (control) and feed restricted conditions from April through September. Both Atlantic salmonlepa1 and lepa2 in the liver and lepr in the brain were significantly down-regulated in non-maturing control males in early spring, coinciding with the start of the growth and fat accumulation. In maturing control males, hepatic leptin expression increased during mid-spermatogenesis and lepa1 and lepa2 mRNA levels were up-regulated by 7.7 and 49 times respectively during final maturation. For the first time in a fish species, a significant up-regulation of lepr expression was observed in the testis throughout mid to late spermatogenesis. Feed restriction decreased the incidence of sexual maturation by 53% and highly up-regulated both leptin genes in the liver and the leptin receptor in the pituitary. This study shows that hepaticlepa1 and lepa2 expression and lepr expression in the testis is affected by early sexual maturation in male Atlantic salmon parr. Fast growth and high fat stores are associated with low leptin levels while feed restriction has a stimulatory effect on hepatic leptin and leptin receptor gene expression in the pituitary, suggesting a role for leptin other than that as an adiposity signal.

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