Low doses of bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor.
BACKGROUND
Fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, many of these xenoestrogens have only a weak affinity for the classical estrogen receptors (ERs,) which is 1,000-fold less potent than the affinity of 17beta-estradiol (E(2)). Thus, several mechanisms have been suggested to explain how they could affect male germ cell proliferation at low environmental relevant concentrations.


OBJECTIVE
In this study we aimed to explore the possible promoting effect of bisphenol A (BPA) on human testicular seminoma cells. BPA is a well-recognized estrogenic endocrine disruptor used as a monomer to manufacture poly carbonate plastic and released from resin-lined food or beverage cans or from dental sealants.


RESULTS
BPA at very low concentrations (10(-9) to 10(-12) M) similar to those found in human fluids stimulated JKT-1 cell proliferation in vitro. BPA activated both cAMP-dependent protein kinase and cGMP-dependent protein kinase pathways and triggered a rapid (15 min) phosphorylation of the transcription factor cAMP response-element-binding protein (CREB) and the cell cycle regulator retinoblastoma protein (Rb). This nongenomic activation did not involve classical ERs because it could not be reversed by ICI 182780 (an ER antagonist) or reproduced either by E(2) or by diethylstilbestrol (a potent synthetic estrogen), which instead triggered a suppressive effect. This activation was reproduced only by E(2) coupled to bovine serum albumin (BSA), which is unable to enter the cell. As with E(2)-BSA, BPA promoted JKT-1 cell proliferation through a G-protein-coupled nonclassical membrane ER (GPCR) involving a Galpha(s) and a Galpha(i)/Galpha(q) subunit, as shown by the reversible effect observed by the corresponding inhibitors NF449 and pertussis toxin.


CONCLUSIONS
This GPCR-mediated nongenomic action represents--in addition to the classical ER-mediated effect--a new basis for evaluating xenoestrogens such as BPA that, at low doses and with a high affinity for this GPCR, could interfere with the developmental programming of fetal germ cell proliferation and/or differentiation when they cross the placenta.
Bouskine
Adil
A
Institut National de la recherché Médicale (INSERM) U895, Team 5-Environment and Reproduction: Genomic and Nongenomic Mechanisms, University of Nice-Sophia-Antipolis, Faculty of Medicine, Nice, France.
Nebout
Marielle
M
Brücker-Davis
Françoise
F
Benahmed
Mohamed
M
Fenichel
Patrick
P
D000328:Adult; D000395:Air Pollutants, Occupational / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D008297:Male; D037342:Pertussis Toxin / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D018239:Seminoma / Q000473:pathology*; D000098826:Bisphenol A Compounds
D000395:Air Pollutants, Occupational; D001557:Benzenesulfonates; D001559:Benzhydryl Compounds; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D004958:Estradiol; D004965:Estrogen Antagonists; D000077267:Fulvestrant; D037342:Pertussis Toxin; D010636:Phenols; D043562:Receptors, G-Protein-Coupled; D016160:Retinoblastoma Protein; C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); C006780:bisphenol A; D000098826:Bisphenol A Compounds