Relationship between the results of in vitro receptor binding assay to human estrogen receptor α and in vivo uterotrophic assay: Comparative study with 65 selected chemicals

Department of Human Environmental Science, Ochanomizu University, 2-1-1, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
Toxicology in Vitro (Impact Factor: 2.9). 03/2008; 22(1):225-31. DOI: 10.1016/j.tiv.2007.08.004
Source: PubMed


For screening chemicals possessing endocrine disrupting potencies, the uterotrophic assay has been placed in a higher level in the OECD testing framework than the ER binding assay to detect ER-mediated activities. However, there are no studies that can demonstrate a clear relationship between these assays. In order to clarify the relationship between the in vitro ER binding and in vivo uterotrophic assays and to determine meaningful binding potency from the ER binding assay, we compared the results from these assays for 65 chemicals spanning a variety of chemicals classes. Under the quantitative comparison between logRBAs (relative binding affinities) and logLEDs (lowest effective doses), the log RBA was well correlated with both logLEDs of estrogenic and anti-estrogenic compounds at r(2)=0.67 (n=28) and 0.79 (n=23), respectively. The RBA of 0.00233% was found to be the lowest ER binding potency to elicit estrogenic or anti-estrogenic activities in the uterotrophic assay, accordingly this value is considered as the detection limit of estrogenic or anti-estrogenic activities in the uterotrophic assay. The usage of this value as cutoff provided the best concordance rate (82%). These findings are useful in a tiered approach for identifying chemicals that have potential to induce ER-mediated effects in vivo.

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    • "Additionally, BPF has been shown to exhibit in vitro androgenic and anti-androgenic effects (Cabaton et al., 2009; Kitamura et al., 2005; Stroheker et al., 2004). BPF was shown to have estrogenic and anti-estrogenic activity in some in vivo studies with female rats (Akahori et al., 2008). For D-8 there is only limited evidence of endocrine activity. "
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    ABSTRACT: Alternatives to bisphenol A (BPA) are more and more used in thermal paper receipts.To get an overview of the situation in Switzerland, 124 thermal paper receipts were collected and analyzed. Whereas BPA was detected in most samples (n=100), some alternatives, namely Bisphenol S (BPS) , Pergafast(®) 201 and D-8 have been found in respectively 4, 11 and 9 samples. As no or few data on their endocrine activity are available, these chemicals and bisphenol F (BPF) were tested in vitro using the H295R steroidogenesis assay. 17β-estradiol production was induced by BPA and BPF, whereas free testosterone production was inhibited by BPA and BPS. Both non-bisphenol substances did not show significant effects. The binding affinity to 16 proteins and the toxicological potential (TP) were further calculated in silico using VirtualToxLab(TM). TP values lay between 0.269 and 0.476 and the main target was the estrogen receptor β (84.4 nM to 1.33 μM). A substitution of BPA by BPF and BPS should be thus considered with caution, since they exhibit almost a similar endocrine activity as BPA. D-8 and Pergafast(®) 201 could be alternatives to replace BPA, however further analyses are needed to better characterize their effects on the hormonal system. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Regulatory Toxicology and Pharmacology
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    • "Several compounds to which the general U.S. population is regularly exposed have been implicated as affecting endocrine function or development. For example, certain benzophenones, dichlorophenols, parabens, and the compound triclosan have been shown to disrupt estrogen receptor signaling in animal and in vitro models either by binding directly to the receptor itself or through modulation of downstream signaling processes (Akahori et al. 2008; Craig et al. 2011; Kawaguchi et al 2009; Shaw and deCatanzaro 2009; Stoker et al. 2010; Vo et al. 2010; Yamasaki et al. 2005). Conversely, compounds such as phthalates and bisphenol A have been shown in human and animal studies to disrupt androgen-dependent processes (Howdeshell et al. 2008; Miao et al 2011; Svechnikov et al. 2010), with bisphenol A implicated in both anti-androgenic and estrogenic responses (Chao et al. 2012). "
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    ABSTRACT: Background: The observed age of menarche has fallen, which may have important adverse social and health consequences. Increased exposure to endocrine-disrupting compounds (EDCs) has been associated with adverse reproductive outcomes. Objective: Our objective was to assess the relationship between EDC exposure and the age of menarche in adolescent girls. Methods: We used data from female participants 12–16 years of age who had completed the reproductive health questionnaire and laboratory examination for the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey (NHANES) for years 2003–2008 (2005–2008 for analyses of phthalates and parabens). Exposures were assessed based on creatinine-corrected natural log urine concentrations of selected environmental chemicals and metabolites found in at least 75% of samples in our study sample. We used Cox proportional hazards analysis in SAS 9.2 survey procedures to estimate associations after accounting for censored data among participants who had not reached menarche. We evaluated body mass index (BMI; kilograms per meter squared), family income-to-poverty ratio, race/ethnicity, mother’s smoking status during pregnancy, and birth weight as potential confounders. Results: The weighted mean age of menarche was 12.0 years of age. Among 440 girls with both reproductive health and laboratory data, after accounting for BMI and race/ethnicity, we found that 2,5-dichlorophenol (2,5-DCP) and summed environmental phenols (2,5-DCP and 2,4-DCP) were inversely associated with age of menarche [hazard ratios of 1.10; 95% confidence interval (CI): 1.01, 1.19 and 1.09; 95% CI: 1.01, 1.19, respectively]. Other exposures (total parabens, bisphenol A, triclosan, benzophenone-3, total phthalates, and 2,4-DCP) were not significantly associated with age of menarche. Conclusions: Our findings suggest an association between 2,5-DCP, a potential EDC, and earlier age of menarche in the general U.S. population.
    Preview · Article · Nov 2012 · Environmental Health Perspectives
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    • "Tetrabromo-bisphenol A (TBBPA) is used primarily as a flame retardant in epoxy resin circuit boards, electronic enclosures, paper, plastic, and textiles (NTP, 2002; Olsen et al., 2003) and bisphenol AF (BPAF) is used in fluoroelastomers, polyamides, polyesters, polycarbonate copolymers , and other specialty polymers (Akahori et al., 2008; NTP, 2008; Perez et al., 1998). BPA and BPAF have been shown to induce estrogen-dependent responses in vivo and in vitro via binding to estrogen receptor (ER) ERa and ERb (Akahori et al., 2008; Bay et al., 2004; Wetherill et al., 2007; Yamasaki et al., 2003), whereas studies on the estrogenicity of TBBPA in vitro are inconsistent. Both BPAF and TBBPA have been nominated for toxicological characterization by the NTP, National Institute of Environmental Health Sciences (NTP, 2002, 2008). "
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    ABSTRACT: Exposure to xenoestrogens occurs against a backdrop to physiological levels of endogenous estrogens. Endogenous estrogen levels vary from low levels in early childhood to high levels during pregnancy and in young women. However, few studies have addressed how xenoestrogens interact with endogenous estrogens. The current study was designed to characterize the individual dose-response curves of estradiol-17beta (E(2)), bisphenol A (BPA), tetrabromo-bisphenol A (TBBPA), and bisphenol AF (BPAF, 4,4'-hexafluoroisopropylidene diphenol) on estrogen-dependent luciferase expression in T47D-KBluc cells and to determine how binary (8 x 8 factorial) and ternary (4 x 4 x 4 factorial) mixtures of an endogenous estrogen (E(2)) interact with BPA and/or BPAF. Log EC(50) and hillslope values with SEs, respectively, for individual compounds were as follows: E(2), -12.10M +/- 0.06071, 0.7702 +/- 0.1739; BPA, -6.679M +/- 0.08505, 1.194 +/- 0.2137; and BPAF, -7.648M +/- 0.05527, 1.273 +/- 0.1739. TBBPA was not evaluated in mixture studies because of its minimally estrogenic response at 3 x10(-5)M and elicited cytotoxicity at higher concentrations. Both the binary mixtures of E(2) with BPA and BPAF and the ternary mixture of E(2), BPA, and BPAF behaved in an additive manner. For binary mixtures, as E(2) concentration increased, higher concentrations of BPA and BPAF were necessary to induce a significant increase in the estrogenic response. Understanding the behavior of mixture interactions of xenoestrogens, like BPA and BPAF, with endogenous estrogens will allow a better assessment of the potential risk associated with exposure to these chemicals, individually or as mixtures.
    Full-text · Article · May 2010 · Toxicological Sciences
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