Endocrine Abstracts

Fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, many of these endocrine disruptors have only a weak affinity for the classical ERs and other mechanisms have been suggested. Bisphenol A, a chemical poluttant, used as monomer to manufacture polycarbonate plastic, released from lining canned food or beverages or from dental sealants, was able to promote human testicular seminoma cell (JKT-1) proliferation in vitro at very low environmental relevant concentrations (10⁻⁹ to 10⁻¹² M), (seminoma cells are supposed to derive from germ stem cells (fetal gonocytes or adult undifferentiated spermatogonia). BPA activated both PKA and PKG pathways and triggered a rapid (15 min) phosphorylation of the transcription factor CREB and the cell cycle regulator Rb. This non genomic activation, did not involve classical ERs since it could not be reversed by ICI182780, an ER antagonist, nor reproduced either by E₂ or by DES a potent synthetic estrogen which triggered instead, a suppressive effect. It was only reproduced by E₂ coupled to BSA, unable to enter the cell. As E₂–BSA, BPA promoted JKT-1 cell proliferation through a G protein coupled receptor (GPCR) involving a Gαs and a Gαi/Gαq subunit as shown by the reversible effect observed by the corresponding inhibitors NF449 and Pertussis toxin. This promoting effect on JKT-1 cells was completely inhibited by G15, a specific antagonist of the G protein coupled estrogen receptor (GPER) (also known as GPR30) and by invalidation of GPER by siRNA and reproduced by G1, a GPER agonist.

This GPRE-mediated non genomic action represents a new basis for evaluating BPA, which could at low doses and with a high affinity for this GPER, interfere, when crossing the placenta, with the developmental programming of fetal germ cell proliferation and/or differentiation.