| 1. |
- Gaehrs, Maike, et al.
(författare)
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Role of the nuclear xenobiotic receptors CAR and PXR in induction of cytochromes P450 by non-dioxinlike polychlorinated biphenyls in cultured rat hepatocytes
- 2013
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Ingår i: Toxicology and Applied Pharmacology. - : Academic Press. - 0041-008X .- 1096-0333. ; 272:1, s. 77-85
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Tidskriftsartikel (refereegranskat)abstract
- Polychlorinated biphenyls (PCBs) are among the most ubiquitously detectable 'persistent organic pollutants'. In contrast to 'dioxinlike' (DL) PCBs, less is known about the molecular mode of action of the larger group of the 'non-dioxinlike' (NDL) PCBs. Owing to the life-long exposure of the human population, a carcinogenic, i.e., tumor-promoting potency of NDL-PCBs has to be considered in human risk assessment. A major problem in risk assessment of NDL-PCBs is dioxin-like impurities that can occur in commercially available NDL-PCB standards. In the present study, we analyzed the induction of CYP2B1 and CYP3A1 in primary rat hepatocytes using a number of highly purified NDL-PCBs with various degrees of chlorination and substitution patterns. Induction of these enzymes is mediated by the nuclear xenobiotic receptors CAR (Constitutive androstane receptor) and PXR (Pregnane X receptor). For CYP2B1 induction, concentration-response analysis revealed a very narrow window of EC50 estimates, being in the range of 1-4 mu M for PCBs 28 and 52, and between 0.4 and 1 mu M for PCBs 101, 138, 153 and 180. CYP3A1 induction was less sensitive to NDL-PCBs, the most pronounced induction being achieved at 100 mu M with the higher chlorinated congeners. Using okadaic acid and small interfering RNAs targeting CAR and PXR, we could demonstrate that CAR plays a major role and PXR a minor role in NDL-PCB-driven induction of CYPs, both effects showing no stringent structure-activity relationship. As the only obvious relevant determinant, the degree of chlorination was found to be positively correlated with the inducing potency of the congeners. (C) 2013 Elsevier Inc. All rights reserved.
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| 2. |
- Roos, Robert, et al.
(författare)
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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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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 284:1-3, s. 42-53
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Tidskriftsartikel (refereegranskat)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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| 3. |
- van den Berg, Martin, et al.
(författare)
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Polybrominated Dibenzo-p-Dioxins, Dibenzofurans, and Biphenyls : Inclusion in the Toxicity Equivalency Factor Concept for Dioxin-Like Compounds
- 2013
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Ingår i: Toxicological Sciences. - Oxfors, United Kingdom : Oxford University Press. - 1096-6080 .- 1096-0929. ; 133:2, s. 197-208
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Forskningsöversikt (refereegranskat)abstract
- In 2011 a joint World Health Organization (WHO) and United Nations Environment Programme (UNEP) expert consultation took place, during which the possible inclusion of brominated analogues of the dioxin-like compounds in the WHO Toxicity Equivalency Factor (TEF) scheme were evaluated. The expert panel concluded that polybrominated dibenzo-p-dioxins (PBDDs), dibenzofurans (PBDFs), and some dioxin-like biphenyls (dl-PBBs) may contribute significantly in daily human background exposure to the total dioxin toxic equivalencies (TEQs). These compounds are also commonly found in the aquatic environment. Available data for fish toxicity were evaluated for possible inclusion in the WHO-UNEP TEF scheme (Van den Berg et al., 1998). Because of the limited database it was decided not to derive specific WHO-UNEP TEFs for fish, but for ecotoxicological risk assessment the use of specific relative effect potencies (REPs) from fish embryo assays is recommended. Based on the limited mammalian REP database for these brominated compounds, it was concluded that sufficient differentiation from the present TEF values of the chlorinated analogues (Van den Berg et al., 2005) was not possible. However, the REPs for PBDDs, PBDFs, and non-ortho dl-PBBs in mammals closely follow those of the chlorinated analogues, at least within one order of magnitude. Therefore, the use of similar interim TEF values for brominated and chlorinated congeners for human risk assessment is recommended, pending more detailed information in the future.
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| 4. |
- Viluksela, Matti, et al.
(författare)
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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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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e104639-
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Tidskriftsartikel (refereegranskat)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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