Estrogen-related receptor γ (ERRγ), one of the 48 human nuclear receptors, has a fully active conformation with no ligand. We recently demonstrated that ERRγ binds strongly bisphenol A (BPA), one of the nastiest endocrine disruptors, and thus retaining ERRγ's high basal constitutive activity. A report that BPA accumulates in the human maternal-fetal placental unit has led us to hypothesize that a large amount of ERRγ might exist in the human placenta. Here we report evidence that placenta indeed expresses ERRγ exceptionally strongly. We first ascertained the presence of nine different ERRγ mRNA variants and the resulting three ERRγ protein isoforms. By real-time PCR, we estimated the relative amount of ERRγ mRNA using total RNA extracts from human reproductive tissues. Placenta was found to express ERRγ extremely highly. Among the three ERRγ protein isoforms, placenta exclusively expresses the type-1 isoform, which possesses additional 23-mer amino-acid residues at the N-terminus of the ordinary ERRγ. This N-terminal elongation was found to elevate by approximately 50% the basal constitutive activity of ERRγ, as evidenced in the luciferase reporter gene assay. The present results suggest that BPA accumulates in the placenta by binding to ERRγ.
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