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  • 1. Ali, Imran
    et al.
    Damdimopoulou, Pauliina
    Stenius, Ulla
    Adamsson, Annika
    Mäkelä, Sari I
    Åkesson, Agneta
    Berglund, Marika
    Håkansson, Helen
    Halldin, Krister
    Cadmium-induced effects on cellular signaling pathways in the liver of transgenic estrogen reporter mice.2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 127, no 1, p. 66-75Article in journal (Refereed)
    Abstract [en]

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

  • 2. Ali, Imran
    et al.
    Damdimopoulou, Pauliina
    Stenius, Ulla
    Halldin, Krister
    Cadmium at nanomolar concentrations activates Raf-MEK-ERK1/2 MAPKs signaling via EGFR in human cancer cell lines.2015In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 231Article in journal (Refereed)
    Abstract [en]

    Cadmium (Cd) is an environmental contaminant classified as carcinogenic to humans by the International Agency for Research on Cancer, supported by data from occupational exposure. Environmentally relevant dietary exposure to Cd has recently been associated with osteoporosis and cancers of the prostate, endometrium, and breast in the general population. The low exposure effects have been proposed to result from endocrine modulative properties of Cd, which mimic the physiological actions of estrogen and androgen. However, the mechanism of action of Cd is an unanswered question. We have shown previously, using mouse models, that canonical estrogen receptor signaling is not involved in estrogen mimicry effects of Cd. Instead, low-level Cd exposure stimulated the mitogen-activated protein kinases (MAPKs) ERK1/2 in these mice. Here we investigate further the ERK1/2 MAPK signaling activation by Cd in vitro by using nanomolar concentrations of cadmium chloride (CdCl2) in three different human carcinoma cell lines: HepG2, MCF-7, and ECC-1. The findings also were confirmed in previously collected mouse tissue samples. We show that 10(-8)M levels of CdCl2 activate ERK1/2 (Tyr 204) and the p53 specific ubiquitin ligase Mdm2 (Ser 166) via Raf and MEK by acting through the epidermal growth factor receptor (EGFR). Furthermore, our results suggest that the CdCl2-induced activation of ERK1/2 and Mdm2 may interfere with the p53 response to genotoxic compounds in cancer cell lines. Our data collectively suggest that nanomolar levels of CdCl2 activate Raf-MEK-ERK1/2 via EGFR. We hypothesize that this signaling cascade may be involved in observed low exposure effects of Cd in certain human populations.

  • 3. Ali, Imran
    et al.
    Engström, Annette
    Vahter, Marie
    Skerfving, Staffan
    Lundh, Thomas
    Lidfeldt, Jonas
    Samsioe, Göran
    Halldin, Krister
    Akesson, Agneta
    Associations between cadmium exposure and circulating levels of sex hormones in postmenopausal women2014In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 134, p. 265-269Article in journal (Refereed)
    Abstract [en]

    Recent epidemiological as well as in vivo and in vitro studies collectively suggest that the metalloestrogen cadmium (Cd) could be a potential risk factor for hormone-related cancers in particularly breast cancer. Assessment of the association between Cd exposure and levels of endogenous sex hormones is of pivotal importance, as increased levels of such have been associated with a higher risk of breast cancer in postmenopausal women. The present study investigated the perceived relationship (multivariable-adjusted linear regression analyses) between Cd exposure [blood Cd (B-Cd) and urinary Cd (U-Cd)], and serum levels of androstenedione, testosterone, estradiol, and sex-hormone binding globulin (SHBG), in 438 postmenopausal Swedish women without hormone replacement therapy (HRT). A significant positive association between B-Cd (median 3.4nmol/L) and serum testosterone levels, as well as a significant inverse association between B-Cd and serum estradiol levels and with the estradiol/testosterone ratio were encountered. However, U-Cd (median 0.69nmol/mmol creatinine) was inversely associated with serum estradiol levels only. Our data may suggest that Cd interferes with the levels of testosterone and estradiol in postmenopausal women, which might have implications for breast cancer risk.

  • 4. Ali, Imran
    et al.
    Hurmerinta, Teija
    Nurmi, Tarja
    Berglund, Marika
    Rüegg, Joelle
    Poutanen, Matti
    Halldin, Krister
    Mäkelä, Sari
    Damdimopoulou, Pauliina
    From pure compounds to complex exposure: Effects of dietary cadmium and lignans on estrogen, epidermal growth factor receptor, and mitogen activated protein kinase signaling in vivo.2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 253Article in journal (Refereed)
    Abstract [en]

    Exposure to environmental endocrine active compounds correlates with altered susceptibility to disease in human populations. Chemical risk assessment is single compound based, although exposure often takes place as heterogeneous mixtures of man-made and natural substances within complex matrices like diet. Here we studied whether the effects of cadmium and enterolactone on endocrine endpoints in dietary exposure can be predicted based on pure compound effects. Ovariectomized estrogen reporter ERE-luciferase (ERE-luc) mice were maintained on diets that intrinsically contain increasing concentrations of cadmium and enterolactone precursors for three and 21 days. The activation of the ERE-luc, epidermal growth factor receptor (EGFR), mitogen activated protein kinase (MAPK)-ERK1/2, and classical estrogen responses were measured. Interactions between the diets and endogenous hormone were evaluated by challenging the animals with 17β-estradiol. Compared to animals on basal purified diet, mice consuming experimental diets were exposed to significantly higher levels of cadmium and enterolactone, yet the exposure remained comparable to typical human dietary intake. Surprisingly, we could not detect effects on endpoints regulated by pure enterolactone, such as ERE-luc activation. However, cadmium accumulation in the liver was accompanied with activation of EGFR and MAPK-ERK1/2 in line with our earlier CdCl2 studies. Further, attenuation of 17β-estradiol-induced ERE-luc response in liver by experimental diets was observed. Our findings indicate that the exposure context can have substantial effects on the activity of endocrine active compounds in vivo. Thus, whenever possible, a context that mimics human exposure should be tested along with pure compounds.

  • 5. Ali, Imran
    et al.
    Penttinen-Damdimopoulou, Pauliina E
    Mäkelä, Sari I
    Berglund, Marika
    Stenius, Ulla
    Akesson, Agneta
    Håkansson, Helen
    Halldin, Krister
    Institutet för miljömedicin, Karolinska Institutet.
    Estrogen-like effects of cadmium in vivo do not appear to be mediated via the classical estrogen receptor transcriptional pathway.2010In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 118, no 10, p. 1389-94Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cadmium (Cd), a ubiquitous food contaminant, has been proposed to be an endocrine disruptor by inducing estrogenic responses in vivo. Several in vitro studies suggested that these effects are mediated via estrogen receptors (ERs).

    OBJECTIVE: We performed this study to clarify whether Cd-induced effects in vivo are mediated via classical ER signaling through estrogen responsive element (ERE)-regulated genes or if other signaling pathways are involved.

    METHODS: We investigated the estrogenic effects of cadmium chloride (CdCl2) exposure in vivo by applying the Organisation for Economic Co-operation and Development (OECD) rodent uterotrophic bioassay to transgenic ERE-luciferase reporter mice. Immature female mice were injected subcutaneously with CdCl2 (5, 50, or 500 µg/kg body weight) or with 17α-ethinylestradiol (EE2) on 3 consecutive days. We examined uterine weight and histology, vaginal opening, body and organ weights, Cd tissue retention, activation of mitogen-activated protein kinase (MAPK) pathways, and ERE-dependent luciferase expression.

    RESULTS: CdCl2 increased the height of the uterine luminal epithelium in a dose-dependent manner without increasing the uterine wet weight, altering the timing of vaginal opening, or affecting the luciferase activity in reproductive or nonreproductive organs. However, we observed changes in the phosphorylation of mouse double minute 2 oncoprotein (Mdm2) and extracellular signal-regulated kinase (Erk1/2) in the liver after CdCl2 exposure. As we expected, EE2 advanced vaginal opening and increased uterine epithelial height, uterine wet weight, and luciferase activity in various tissues.

    CONCLUSION: Our data suggest that Cd exposure induces a limited spectrum of estrogenic responses in vivo and that, in certain targets, effects of Cd might not be mediated via classical ER signaling through ERE-regulated genes.

  • 6.
    Axelsson, Jeanette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Co-administration of PCB and methoxychlor to male quail embryos alters their adult sexual behavior2004In: Uppsala Journal of Medical Sciences: Abstracts for The 22nd Conference of European Comparative Endocrinologists, 2004, p. 13-Conference paper (Other academic)
  • 7.
    Axelsson, Jeanette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Expression of Estrogen Receptor -alpha and -beta mRNA in Embryonic Quail Brain2003In: Trabajos del Instituto Cajal, 2003, p. 278-Conference paper (Other academic)
  • 8.
    Axelsson, Jeanette
    et al.
    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.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Expression of estrogen receptor-alpha and -beta mRNA in the brain of Japanese quail embryos2007In: Developmental Neurobiology, ISSN 1932-8451, Vol. 67, no 13, p. 1742-1750Article in journal (Refereed)
    Abstract [en]

    The present study was conducted to investigate the mRNA expression of the two estrogen receptor (ER) subtypes ERα and ERβ in the brain of Japanese quail embryos. We found expression of both ERα and ERβ mRNA in homogenate of whole head from 6-day-old embryos, and in brain homogenate from 9- and 12-day-old embryos using real-time PCR. In 9- and 12-day-old embryos the ERα expression was higher in females than in males. We used in situ hybridization to examine the localization of the ERs in sections from male and female brains on day 9 and day 17 of incubation. On day 9, ERβ mRNA was detected in the developing medial preoptic nucleus (POM), in the medial part of the bed nucleus of the striae terminalis (BSTm), and in the tuberal region of the hypothalamus. ERα signal could not be detected in the POM, the BSTm or the tuberal region in 9-day-old embryos. In 17-day-old embryos, ERβ was highly expressed in the preoptic area, the nucleus Taeniae of the Amygdala (TnA) and the BSTm. Expression of ERα mRNA was detected in parts of the preoptic area and in the telencephalic TnA. No ERα expression was found in the BSTm, an area known to be sexually dimorphic in adults. The high embryonic expression of ERβ in brain areas linked to sexual behavior indicates that ERβ plays a role in sexual differentiation of the Japanese quail brain.

  • 9.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunstrom, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Methods for studying xenoestrogenic effects in birds1998In: TOXICOLOGY LETTERS, ISSN 0378-4274, Vol. 103, p. 671-676Article in journal (Other academic)
    Abstract [en]

    The embryonated bird egg provides a simple whole organism test system that allows examination of xenoestrogenic effects at different levels of biological organisation. Test compounds are injected into the yolk, the albumen or the air chamber at defined st

  • 10.
    Berg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Effects of bisphenol A and tetrabromobisphenol A on sex organ development in quail and chicken embryos2001In: ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY, ISSN 0730-7268, Vol. 20, no 12, p. 2836-2840Article in journal (Refereed)
    Abstract [en]

    The plastic monomere bisphenol A (BPA) and the flame retardant tetrabromobisphenol A (TBBPA) were examined for estrogen-like developmental effects on the reproductive organs in avian embryos. The synthetic estrogen diethylstilbestrol (DES) was used as a p

  • 11. Bogdanska, Jasna
    et al.
    Borg, Daniel
    Sundström, Maria
    Bergström, Ulrika
    Halldin, Krister
    Abedi-Valugerdi, Manuchehr
    Bergman, Ake
    Nelson, Buck
    Depierre, Joseph
    Nobel, Stefan
    Tissue distribution of ³⁵S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose.2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, no 1-3, p. 54-62Article in journal (Refereed)
    Abstract [en]

    The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of ³⁵S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.

  • 12. Bogdanska, Jasna
    et al.
    Borg, Daniel
    Sundström, Maria
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Halldin, Krister
    Abedi-Valugerdi, Manuchehr
    Bergman, Åke
    Nelson, Buck
    DePierre, Joseph
    Nobel, Stefan
    Tissue distribution of S-35-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, no 1-3, p. 54-62Article in journal (Refereed)
    Abstract [en]

    The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of S-35-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.

  • 13. Bondesson, Maria
    et al.
    Jönsson, Jill
    Pongratz, Ingemar
    Olea, Nicholas
    Cravedi, Jean-Pierre
    Zalko, Daniel
    Håkansson, Helen
    Halldin, Krister
    Institutet för miljömedicin, Karolinska Institutet.
    Di Lorenzo, Diego
    Behl, Christian
    Manthey, Dieter
    Balaguer, Patrick
    Demeneix, Barbara
    Fini, Jean Baptiste
    Laudet, Vincent
    Gustafsson, Jan-Ake
    A CASCADE of effects of bisphenol A.2009In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 28, no 4, p. 563-7Article in journal (Refereed)
  • 14. Borg, Daniel
    et al.
    Bogdanska, Jasna
    Sundström, Maria
    Nobel, Stefan
    Håkansson, Helen
    Bergman, Åke
    DePierre, Joseph
    Halldin, Krister
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Perinatal tissue distribution of perfluorooctane sulphonate (PFOS) in mice.2009In: Abstracts of the 46th Congress of the European Societies of Toxicology, 2009, p. S147-Conference paper (Refereed)
    Abstract [en]

    Perfluorooctane sulfonate (PFOS) is an industrial chemical that has been used as a surfactant and surface protector for more than fifty years. It has during the last decade emerged as an environmental contaminant due to its widespread presence in humans and wildlife and its persistant, bioaccumulative and toxic properties. PFOS is developmentally toxic and late in utero exposure in rodents affects neonatal survival and growth. Observed symptoms suggest impaired pulmonary function, but the cause of the mortality has not been clarified. The purpose of this study was to determine the perinatal tissue distribution of S35-labelled PFOS in mice using whole-body autoradiography (WBA) combined with liquid scintillation counting (LSC). Pregnant C57Bl/6 mice were dosed orally on gestation day (GD) 16 and sampled on GD18, GD20 and postnatal day (PND) 1 (dams + pups). The results from the WBA and the LSC were unequivocal. In dams, PFOS accumulated primarily in the liver, but also the lungs contained levels higher than the blood. PFOS was readily transferred to the fetus. At GD18 general PFOS levels were higher in the fetus than in the blood of the corresponding dam with accumulation in the liver. At GD20, general PFOS levels remained higher in the fetus than in the dam, with substantial accumulation also in the lung. The accumulation in the lung persisted at PND1. Our results show that the fetus is exposed to higher levels of PFOS than the dam and point towards the lung being the main perinatal target organ of PFOS.

  • 15.
    Borg, Daniel
    et al.
    Karolinska Institutet.
    Bogdanska, Jasna
    Stockholms Universitet.
    Sundström, Maria
    Stockholms Universitet.
    Nobel, Stefan
    Stockholms Universitet.
    Håkansson, Helen
    Karolinska Institutet.
    Bergman, Åke
    Stockholms Universitet.
    Depierre, Jospeh W
    Stockholms Universitet.
    Halldin, Krister
    Karolinska Institutet.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Tissue distribution of (35)S-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 4, p. 558-565Article in journal (Refereed)
    Abstract [en]

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

  • 16.
    Brunström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. 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. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Effects of endocrine modulators on sex differentiation in birds.2003In: Ecotoxicology, ISSN 0963-9292, Vol. 12, no 1-4, p. 287-95Article in journal (Refereed)
  • 17.
    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.

  • 18.
    Halldin, Krister
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Embryonic co-exposure to methoxychlor and Clophen A50 alters sexual behavior in adult male quail2005In: Archives of Toxicology, Vol. 79, no 4, p. 237-42Article in journal (Refereed)
  • 19. Halldin, Krister
    et al.
    Axelsson, Jeanette
    Avd för ekotoxikologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Avd för ekotoxikologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Avd för ekotoxikologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Developmental toxicity in Japanese quail exposed to hydroxylated metabolites pf PCBs in ovo.2005In: Avian and Poultry Biology Reviews, no 16, p. 11-17Article in journal (Refereed)
  • 20. Halldin, Krister
    et al.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Effects of endocrine modulators on sexual differentiation and reproductive function in male Japanese quail.2005In: Brain Res Bull, ISSN 0361-9230, Vol. 65, no 3, p. 211-8Article in journal (Refereed)
  • 21. Halldin, Krister
    et al.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Embryonic co-exposure to methoxychlor and Clophen A50 alters sexual behavior in adult male quail.2005In: Arch Toxicol, ISSN 0340-5761, Vol. 79, no 4, p. 237-42Article in journal (Refereed)
  • 22. Halldin, Krister
    et al.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Localization of Estrogen Receptor -alpha and -beta mRNA in the Brain of Embryonic and Adult Japanese Quail2003In: Trabajos del Instituto Cajal, 2003, p. 279-Conference paper (Other academic)
  • 23. Halldin, Krister
    et al.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Holmgren, Claes
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Localization of estrogen receptor-alpha and -betamRNA in brain areas controlling sexual behavior in Japanese quail.2006In: J Neurobiol, ISSN 0022-3034, Vol. 66, no 2, p. 148-54Article in journal (Refereed)
  • 24. Halldin, Krister
    et al.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Holmgren, Clas
    Brunström, Björn
    Localization of estrogen receptor-alpha and -beta mRNA in brain areas controlling sexual behavior in Japanese quail2006In: Journal of Neurobiology, Vol. 66, no 2, p. 148-54Article in journal (Refereed)
  • 25.
    Halldin, Krister
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Bergman, Åke
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Distribution of bisphenol A and tetrabromobisphenol A in quail eggs, embryos and laying birds and studies on reproduction variables in adults following in ovo exposure2001In: ARCHIVES OF TOXICOLOGY, ISSN 0340-5761, Vol. 75, no 10, p. 597-603Article in journal (Refereed)
    Abstract [en]

    In a previous study, we showed that bisphenol A (BPA) had oestrogen-like effects in bird embryos, causing malformations of the oviducts in Japanese quail (Coturnix japonica) and feminisation of the left testis in chicken (Gallus domesticus). In this study

  • 26.
    Halldin, Krister
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ridderstråle, Yvonne
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Reproductive impairment in Japanese quail (Coturnix japonica) after in ovo exposure to o,p'-DDT.2003In: Arch Toxicol, ISSN 0340-5761, Vol. 77, no 2, p. 116-22Article in journal (Refereed)
  • 27. Hollert, Henner
    et al.
    Durr, Matthias
    Olsman, Helena
    Halldin, Krister
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    van Bavel, Bert
    Brack, Werner
    Tysklind, Mats
    Engwall, Magnus
    Braunbeck, Thomas
    Biological and chemical determination of dioxin-like compounds in sediments by means of a sediment triad approach in the catchment area of the river Neckar.2002In: Ecotoxicology, ISSN 0963-9292, Vol. 11, no 5, p. 323-36Article in journal (Refereed)
  • 28.
    Mattsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Embryonic exposure to an ERalpha-agonist affects reproductive organ development but not copulatory behaviour in Japanese quail2006In: Toxicology Letters 164, Supplement 1, 2006, p. S166-S167Conference paper (Other academic)
  • 29.
    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.

  • 30. Merino, Ruben
    et al.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Avd för ekotoxikologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Heart morphology and liver EROD induction in Japanese quail embryos exposed to TCDD in ovo.2005In: Organohalogen Compounds 67, 2005, p. 2396-2398Conference paper (Refereed)
  • 31. Roos, Robert
    et al.
    Andersson, Patrik L
    Halldin, Krister
    Institutet för miljömedicin, Karolinska Institutet.
    Håkansson, Helen
    Westerholm, Emma
    Hamers, Timo
    Hamscher, Gerd
    Heikkinen, Päivi
    Korkalainen, Merja
    Leslie, Heather A
    Niittynen, Marjo
    Sankari, Satu
    Schmitz, Hans-Joachim
    van der Ven, Leo T M
    Viluksela, Matti
    Schrenk, Dieter
    Hepatic effects of a highly purified 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in male and female rats.2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, no 1-3, p. 42-53Article in journal (Refereed)
    Abstract [en]

    PCB 180 (2,2',3,4,4',5,5'-heptachlorobiphenyl) is a persistent and accumulating polychlorinated biphenyl abundantly present in food and the environment. In this study, we used highly purified PCB 180 (dioxinlike impurities: 2.7 ng TEQ(WHO)/g PCB 180) in a 28-day toxicity study in young adult Sprague-Dawley rats. Male and female rats were given total doses of 3, 10, 30, 100, 300, 1000 or 1700 mg/kg b.w. PCB 180 by gavage. Increased liver weights were observed at ≥ 300 mg/kg b.w. in males and females. No increases in serum ALT or ALP activities were found. A significant increase in liver pentoxyresorufin O-dealkylase (PROD) activity was found in males at ≥ 10 mg/kg b.w. and in females at ≥ 30 mg/kg b.w. In both genders, a significant induction of hepatic 7-ethoxyresorufin O-deethylase (EROD) activity was also observed in males at ≥ 10 mg/kg b.w. and in females at ≥ 300 mg/kg b.w. Western blotting showed that mainly cytochromes P450 (CYPs) 2B1/2 and 3A1 were induced while slight effects were seen on CYP1A1, CYP1A2 and CYP1B1. However, no induction of CYP1A1, 1A2 and 1B1 was found on the mRNA level, except for a slight effect in females at 1000 mg/kg b.w. Furthermore, hepatic UDP-glucuronosyltransferases (UGTs) 1A1 and 1A6 were markedly induced in males and slightly induced in females. The hepatic concentrations of apolar retinoids were decreased in males at ≥ 30 mg/kg b.w. and in females at ≥ 300 mg/kg b.w. Taken together our findings show that pure PCB 180 leads to hepatic changes in a dose range which did not cause CYP1A1 induction but causes centrilobular liver hypertrophy, affects drug-metabolizing enzymes involved in the metabolism of exogenous and endogenous substrates and leads to changes in liver retinoid levels. A benchmark dose (BMD) approach is presented in order to model lowest effective dose levels for these effects. Comparison of PCB 180 liver level related to BMDL₅ for hepatic hypertrophy in rats with human data on 'total' hepatic PCB levels in individuals without history of specific exposure suggests a relatively small margin of tissue burden in the range of 37-fold. Our results show that the highly pure non dioxin-like PCB 180 exerted strong effects different to dioxin-like compounds and that the low TEQ contamination allowed a characterization of the PCB as non-dioxinlike.

  • 32.
    Scholz, Birger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Mattsson, Anna
    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.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Sex-dependent gene expression in early brain development of chicken embryos2006In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 7, p. 12-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms.

    RESULTS:

    Using cDNA microarrays and real-time PCR we found gene expression differences between the male and female embryonic brain (or whole head) that may be independent of morphological differentiation of the gonads. Genes located on the sex chromosomes (ZZ in males and ZW in females) were common among the differentially expressed genes, several of which (WPKCI-8, HINT, MHM non-coding RNA) have previously been implicated in avian sex determination. A majority of the identified genes were more highly expressed in males. Three of these genes (CDK7, CCNH and BTF2-P44) encode subunits of the transcription factor IIH complex, indicating a role for this complex in neuronal differentiation.

    CONCLUSION:

    In conclusion, this study provides novel insights into sexually dimorphic gene expression in the embryonic chicken brain and its possible involvement in sex differentiation of the nervous system in birds.

  • 33.
    Scholz, Birger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Söderlund, Robert
    Kultima, Kim
    Mattsson, Anna
    Halldin, Krister
    Stigson, Michael
    Brunström, Björn
    Dencker, Lennart
    Comparative sex-specific and estradiol related gene expression in embryonic Japanese quail and chicken brainManuscript (Other academic)
  • 34. Viluksela, Matti
    et al.
    Heikkinen, Päivi
    van der Ven, Leo T M
    Rendel, Filip
    Roos, Robert
    Esteban, Javier
    Korkalainen, Merja
    Lensu, Sanna
    Miettinen, Hanna M
    Savolainen, Kari
    Sankari, Satu
    Lilienthal, Hellmuth
    Adamsson, Annika
    Toppari, Jorma
    Herlin, Maria
    Finnilä, Mikko
    Tuukkanen, Juha
    Leslie, Heather A
    Hamers, Timo
    Hamscher, Gerd
    Al-Anati, Lauy
    Stenius, Ulla
    Dervola, Kine-Susann
    Bogen, Inger-Lise
    Fonnum, Frode
    Andersson, Patrik L
    Schrenk, Dieter
    Halldin, Krister
    Håkansson, Helen
    Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.2014In: PloS one, ISSN 1932-6203, Vol. 9, no 8, p. e104639-Article in journal (Refereed)
    Abstract [en]

    PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.

1 - 34 of 34
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