| 1. |
- Ali, Imran, et al.
(author)
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Associations between cadmium exposure and circulating levels of sex hormones in postmenopausal women.
- 2014
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In: Environmental Research. - : Elsevier BV. - 1096-0953 .- 0013-9351. ; 134, s. 265-269
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Journal article (peer-reviewed)abstract
- 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.
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| 2. |
- Ali, Imran, et al.
(author)
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Cadmium-induced effects on cellular signaling pathways in the liver of transgenic estrogen reporter mice.
- 2012
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In: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 127:1, s. 66-75
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Journal article (peer-reviewed)abstract
- 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.
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| 3. |
- Ali, Imran, et al.
(author)
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Estrogen-like effects of cadmium in vivo do not appear to be mediated via the classical estrogen receptor transcriptional pathway.
- 2010
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In: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 118:10, s. 1389-94
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Journal article (peer-reviewed)abstract
- 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.
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| 4. |
- Bogdanska, Jasna, et al.
(author)
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Tissue distribution of (35)S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose
- 2011
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In: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 284:1-3, s. 54-62
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Journal article (peer-reviewed)abstract
- 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 (35)S-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.
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| 5. |
- Borg, D., et al.
(author)
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Tissue distribution of S-35-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure
- 2010
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In: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 30:4, s. 558-565
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Journal article (peer-reviewed)abstract
- Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to S-35-PFOS (12 5 mg/kg) we determined the distribution in dams fetuses (GD18 and GD20) and pups (postnatal day 1 PND1) employing whole-body autoradiography and liquid scintillation counting In dams levels were highest in liver and lungs After placental transfer S-35-PFOS was present on GD18 at 2-3 times higher levels in lungs liver and kidneys than in maternal blood In PND1 pups levels in lungs were significantly higher than in GD18 fetuses A heterogeneous distribution of S-35-PFOS was observed in brains of fetuses and pups with levels higher than in maternal brain This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.
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| 6. |
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| 7. |
- Nordén, Marcus, 1982-
(author)
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Comparative avian developmental toxicity of PFAAs
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Perfluoroalkyl acids (PFAAs) are persistent organic pollutants that can commonly be found in environmental matrixes and wildlife from all over the globe. The PFAAs have been used in applications such as water and dirt repelling treatments for textiles, oil-resistant paper coatings and fire-fighting foams. Four studies were designed to evaluate the occurrence of PFAAs in Swedish populations of birds, the developmental toxicity of different PFAAs and species sensitivity differences as well as possible modes of action for the toxicity. The studied species were domestic chicken, and the wild species great cormorant and herring gull. Cormorant and gull eggs were collected from bird colonies in Lake Vänern, Sweden. Chemical analyses were performed on some of the eggs to determine the occurrence of 15 PFAAs in the eggs. The other eggs and eggs of domestic chicken were incubated and injected with solutions of the PFAAs PFOS, PFOA, PFBS and PFUnDA. The eggs were candled every 1-3 days to determine viability. High levels of PFAAs, mainly PFOS followed by PFUnDA, were found in the herring gull and great cormorant eggs. PFOS was found at concentrations up to 1163 ng/g and 771 ng/g in cormorant and herring gull, respectively. In the toxicity tests, chicken was found to be more sensitive than the wild species and cormorant was in general the least sensitive species. PFOA was found to be the most toxic of the chemicals followed by PFOS, PFBS and PFUnDA in decreasing order. Comparing these results with the levels of these chemicals found in the eggs of herring gull and great cormorant, PFOS is the chemical of most concern. Although PFOA had the highest toxicity, the levels found in the eggs were very low. In an additional study, the hepatic β-oxidation in developing chicken embryos after in ovo exposure to PFOS was studied with a tritium release assay. PFOS was found to increase the β-oxidation of palmitic acid at PFOS concentrations 3-7 times lower than the average egg levels in cormorant and herring gull. Therefore the occurrence of effects on the fatty acid metabolism cannot be ruled out. The doses of effect on embryo survival in the toxicity and the levels found in the herring gulls and cormorants gives a small margin of safety for the wild populations. Continued environmental monitoring and further studies on the toxicity of PFAAs that occur at high environmental concentrations is important.
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| 8. |
- Nordén, Marcus, et al.
(author)
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Gene expression analysis of chicken during development subsequent to PFOS and PFOA exposure
- 2010
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In: In Vivo. - : International Institute of Anticancer Research. - 0258-851X .- 1791-7549. ; 24:3, s. 358-358
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Journal article (peer-reviewed)abstract
- Perfluorinated compounds have been manufactured for over50 years and have a wide range of applications due to theirsurfactant properties. They have been used as fabricprotectors to repel water and dirt, fire-fighting foams, nonstickcoatings, insecticides and all weather clothing. PFCsare widespread in the environment and are found globally inwildlife. Among the most abundant are perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA). Thelevels in common guillemot eggs from the Baltic Sea areamong the highest found in the Scandinavian environment.Previous studies show effects on embryo survival of chickenat levels close to levels found in the Baltic guillemot. Toinvestigate the possible mechanisms of action, microarraygene expression analysis was conducted. Chicken eggs wereincubated at 37.5 degrees and 60% relative humidity. PFOSor PFOA was administered to eggs on day 4 of incubationby injection into the air cell of the egg. 1 μl injectionsolution per gram egg was used. The injection solutionscontained PFOS or PFOA dissolved at differentconcentrations in sterile water with 5% or 2.5% dimethylsulfoxide respectively. The doses were 10 and 3 mg/kg forPFOS and 1.6 and 0.5 mg/kg for PFOA. The vehiclesolutions were used as control treatment. At day 19 theembryos were sacrificed and the liver was extracted. Four livers per dose and each vehicle control were used. RNA wasextracted from the livers using Qiagen RNeasy Mini Kit.cDNA was synthesized from mRNA and used for microarrayanalysis on Agilent two-color chicken microarrays.
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| 9. |
- Roos, Robert, et al.
(author)
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Hepatic effects of a highly purified 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in male and female rats.
- 2011
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In: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 284:1-3, s. 42-53
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Journal article (peer-reviewed)abstract
- 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.
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| 10. |
- Viluksela, Matti, et al.
(author)
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Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.
- 2014
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e104639-
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Journal article (peer-reviewed)abstract
- 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.
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