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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    Regulatory Toxicology and Pharmacology 01/2015; 22(3). DOI:10.1016/j.yrtph.2015.01.002 · 2.03 Impact Factor
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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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    Environmental Health Perspectives 11/2012; 120(11):1613-8. DOI:10.1289/ehp.1104748 · 7.98 Impact Factor
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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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