Technical pentabromodiphenyl ether and hexabromocyclododecane as activators of the pregnane-X-receptor (PXR)

Fery, Yvonne; Buschauer, Inga; Salzig, Christian; Lang, Patrick; Schrenk, Dieter

doi:10.1016/j.tox.2009.07.009

Cited by 39 publications

(25 citation statements)

References 57 publications

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“…BDE-209 showed only weak induction potencies (Pacyniak et al, 2007). In another study, a PentaBDE mixture was also significantly more potent inducer of CAR/PXR-dependent CYP3A4 enzyme in human HepG2 cells and luciferase activity in a reporter assay, compared to only weak induction in both rat hepatocytes and luciferase-transfected rat hepatoma H4IIE cells (Fery et al, 2009). These findings suggest higher sensitivity and toxicological importance of activation of PXR in humans than in rodents.…”

Section: Activation Of Car and Pxr Receptorsmentioning

confidence: 95%

“…PBDEs have been reported, similar to non-dioxin-like PCBs, as inducer of CAR-and PXR-mediated gene expression in vitro (Pacyniak et al, 2007;Wahl et al, 2008;Fery et al, 2009) as well as in vivo (Sanders et al, 2005;Fery et al, 2009;Szabo et al, 2009). BDE-47, -99 and -209 induced PXRdependent gene expression in mice.…”

Section: Activation Of Car and Pxr Receptorsmentioning

confidence: 95%

“…6-OH-BDE-47 effectively suppressed expression of other steroidogenic genes such as CYP11B and StAR in the H295R cells at the concentration 0.025 μM (Song et al, 2009). PBDEs could modulate also metabolism (inactivation) of steroid as well as thyroid hormones via induction of CAR/PXR-mediated gene expression of biotransformation enzymes including CYP and transferase enzymes (Pacyniak et al, 2007;Fery et al, 2009;Suvorov and Takser, 2010). On the other hand, IC 50 s for inhibition of estradiol sulfatation (the effect leading to higher natural estrogen concentrations) were 0.8 and 1.4 µM for BDE-47 and 6-OH-BDE-47, respectively (Hamers et al, 2006).…”

Section: Estrogenicity/antiestrogenicity Of Pbdesmentioning

confidence: 99%

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Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

2011

EFS2

197

147

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EFSA was asked by the European Commission to deliver a scientific opinion on polybrominated diphenyl ethers (PBDEs) in food. PBDEs are additive flame retardants which are applied in plastics, textiles, electronic castings and circuitry. PBDEs are ubiquitously present in the environment and likewise in biota and in food and feed. Data from the analysis of 19 PBDE congeners in 3,971 food samples were provided to EFSA by 11 European countries. Eight congeners were considered by the Panel on Contaminants in the Food Chain (CONTAM Panel) to be of primary interest: . The highest dietary exposure is to . Toxicity studies were carried out with technical PBDE mixtures or individual congeners. Main targets were the liver, thyroid hormone homeostasis and the reproductive and nervous system. PBDEs cause DNA damage through the induction of reactive oxygen species. The Panel identified effects on neurodevelopment as the critical endpoint, and derived benchmark doses (BMDs) and their corresponding lower 95 % confidence limit for a benchmark response of 10 %, BMDL 10 s, for a number of PBDE congeners: BDE-47, 309 μg/kg b.w.; BDE-99, 12 μg/kg b.w.; BDE-153, 83 μg/kg b.w.; BDE-209, 1,700 μg/kg b.w. Due to the limitations and uncertainties in the current database, the Panel concluded that it was inappropriate to use these BMDLs to establish health based guidance values, and instead used a margin of exposure (MOE) approach for the health risk assessment. Since elimination characteristics of PBDE congeners in animals and humans differ considerably, the Panel used the body burden as starting point for the MOE approach. The CONTAM Panel concluded that for BDE-47, -153 and -209 current dietary exposure in the EU does not raise a health concern. For BDE-99 there is a potential health concern with respect to current dietary exposure. 4 The term "intra-species" has been replaced by "inter-species" in the Summary and in Chapter 9.1. The chemical stability of the PBDE congeners varies with the individual structure. In general PBDE congeners with up to three bromine substituents and those with nine or ten bromine substituents are more sensitive to abiotic transformations. PBDE congeners with four to eight bromine substituents show the highest stability. PBDE congeners are particularly susceptible to photolysis, reductive debromination and radical reactions whereas they are less susceptible to oxidation and hydrolysis. In general, PBDE congeners are persistent and bioaccumulative with the exception of BDE-209 bioaccumulative properties of which seem to be species dependent. BDE-209 undergoes debromination reactions both in the abiotic environment and in biota, leading to formation of PBDE congeners containing seven to nine bromine atoms. © European Food SafetyBased on the composition of the technical PBDE mixtures, occurrence in the environment and in food, the Panel on Contaminants in the Food Chain (CONTAM Panel) considered the following eight PBDE congeners to be of primary interest: which are relevant for dietary PBDE exposur...

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Section: Activation Of Car and Pxr Receptorsmentioning

confidence: 95%

Section: Activation Of Car and Pxr Receptorsmentioning

confidence: 95%

Section: Estrogenicity/antiestrogenicity Of Pbdesmentioning

confidence: 99%

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Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

2011

EFS2

197

147

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“…The seeding density of PC12 was 3.3 Â 10 4 cells/mL and 2.6 Â 10 4 cells/mL for 3 days and 6 days, respectively. Exposure times were generally within 6 days in the most of previous in vitro studies (Barber et al, 2006;Fery et al, 2009;He et al, 2008a,b;Hu et al, 2007;Peters et al, 2004Peters et al, , 2006Song et al, 2009). So, we chose 3 days and 6 days as exposure time in this study.…”

Section: Exposure Of Cells To Bde-47mentioning

confidence: 99%

“…In general, previous studies of PBDEs in vitro have incorporated micromolar (lM) levels in the culture media, although several reports have used nanomolar (nM) levels (Barber et al, 2006;Cantón et al, 2006;Dingemans et al, 2007Dingemans et al, , 2008Fery et al, 2009;Giordano et al, 2008Giordano et al, , 2009He et al, 2008aHe et al, ,b, 2009Hu et al, 2007;Madia et al, 2004;Mercado-Feliciano and Bigsby, 2008;Peters et al, 2004Peters et al, , 2006Stavenes Andersen et al, 2009;Song et al, 2009;Stapleton et al, 2009;Tagliaferri et al, 2010;Zhang et al, 2007). None of these studies measured the cellular PBDE concentrations but it is assumed that the concentrations used may not be environmentally relevant because they are much higher than the picomolar (pM) or lower levels typically found in environmental water or body fluids (Frederiksen et al, 2009;Gill et al, 2004;Streets et al, 2006;Wu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Determination of environmentally relevant exposure concentrations of polybrominated diphenyl ethers for in vitro toxicological studies

Wei

Zhao

Liu

et al. 2010

Toxicology in Vitro

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a b s t r a c tToxicological studies at environmentally relevant concentrations are essential for understanding ecotoxic and health risks of pollutants such as polybrominated diphenyl ethers (PBDEs). However, no information is available on what exposure levels of PBDEs in vitro studies are environmentally relevant. We exposed MCF-7, HepG2, H295R and PC12 cells to BDE-47, and measured BDE-47 concentrations in the cells after exposure. We also used the percentile method to summarize literature data on environmental exposure levels of biotic tissues to PBDEs. The exposure concentration that resulted in a BDE-47 burden in cells close to the 90th percentile of PBDEs levels in tissues was assigned as the upper limit for the environmentally relevant concentration. Exposure to 1 nM BDE-47 resulted in PBDEs burdens in MCF-7, HepG2 and H295R cells close to the 90th percentile but PBDEs burdens in PC12 cells were higher than the 90th percentile. In consideration of the high exposure levels in PBDE-polluted areas, we concluded that the highest environmentally relevant exposure concentration of PBDEs in culture media should be approximately 10 nM for MCF-7, HepG2 and H295R cells, and <10 nM for PC12 cells. These results provide an approximate reference for setting environmentally relevant exposure concentrations of PBDEs for studies in vitro.

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Interaction study with rats given two flame retardants: polybrominated diphenyl ethers (Bromkal 70‐5 DE) and chlorinated paraffins (Cereclor 70L)

Lundstedt‐Enkel

Karlsson

Darnerud

2010

Journal of Chemometrics

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This study explored possible interaction effects on animal liver microsomal enzymes and thyroid hormones of two flame retardants: Bromkal 70-5 DE, a mixture of polybrominated diphenyl ethers (hereafter called PBDE); and Cereclor 70L, a mixture of chlorinated paraffins (hereafter called CP).Female Sprague-Dawley rats were exposed to these compounds in dose ranges of 1.3-18.7 mg/kg bw/day (PBDE) and 1-55 mg/kg bw/day (CP), by gavage for 14 days. Biological responses were measured on liver somatic index (LSI) and hepatic enzyme activity of (a) ethoxyresorufin-O-deethylase (EROD) (indicating CYP1A1 activity), (b) pentoxyresorufin-O-depentylase (PROD) (indicating CYP2B activity) and (c) the phase II conjugation enzyme uridine diphosphoglucuronosyl transferase (UDP-GT). The levels of total and free thyroxine hormone in rat plasma (TT 4 and FT 4 , respectively) were also measured. In the experimental work, a Doehlert uniform shell design was used in order to select the combination of concentrations of PBDE and CP administered to the rats. Eight different combinations were used, including a control. The measured responses were modelled with multiple linear regression (MLR), giving response surface plots. The results showed strong synergism between the two flame retardants at one particular exposure combination, resulting in increased hepatic microsomal enzyme responses and decreased serum T 4 concentrations. Notably, the exposure combination causing the most marked effects represented intermediate doses of both substances. The mechanisms behind the observed effects are unknown, but may involve induction or inhibition of enzyme systems.

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Technical pentabromodiphenyl ether and hexabromocyclododecane as activators of the pregnane-X-receptor (PXR)

Cited by 39 publications

References 57 publications

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

Determination of environmentally relevant exposure concentrations of polybrominated diphenyl ethers for in vitro toxicological studies

Interaction study with rats given two flame retardants: polybrominated diphenyl ethers (Bromkal 70‐5 DE) and chlorinated paraffins (Cereclor 70L)

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