Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor γ (ERRγ) with high constitutive activity

Bisphenol A (BPA) has been acknowledged as an estrogenic chemical able to interact with human estrogen receptors (ER). Many lines of evidence reveal that BPA has an impact as an endocrine disruptor even at low doses. However, its binding to ER and hormonal activity is extremely weak, making the intrinsic significance of low dose effects obscure. We thus supposed that BPA might interact with nuclear receptor(s) other than ER. Here we show that BPA strongly binds to human estrogen-related receptor gamma (ERRgamma), an orphan receptor and one of 48 human nuclear receptors. In a binding assay using [3H]4-hydroxytamoxifen (4-OHT) as a tracer, BPA exhibited a definite dose-dependent receptor binding curve with the IC50 value of 13.1 nM. 4-Nonylphenol and diethylstilbestrol were considerably weaker (5-50-fold less than BPA). When examined in the reporter gene assay for ERRgamma using HeLa cells, BPA completely preserved ERRgamma's high constitutive activity. Notably, BPA exhibited a distinct antagonist action to reverse the inverse agonist activity of 4-OHT, retaining high basal activity. ERRgamma is expressed in a tissue-restricted manner, for example very strongly in the mammalian brain during development, and in the adult in the brain, lung and other tissues. It will now be important to evaluate whether BPA's hitherto reported low dose effects may be mediated through ERRgamma.