Bisphenol A promotes testicular seminoma cell proliferation through GPER/GPR30

Abstract

Dear Sir, Testicular germ cell tumors (TGCT) are the most frequent cancer affecting young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown. Epidemiological, clinical and molecular data have suggested that fetal exposure to environmental endocrine disruptors with estrogenic effects could participate in testicular germ cell carcinogenesis by influencing the fate of germ stem cells that share molecular markers with the malignant germ cells. However, no animal model supports this hypothesis, and even estrogen dependency of TGCT has not yet been fully demonstrated. Using the JKT-1 cell line derived from a human testicular seminoma and seminoma tumors, the most frequent TGCTs, we have previously reported that seminoma cells expressed functional aromatase, which is able to convert testosterone into estradiol as well as estrogen receptor beta (ERb) but not ERa. Estradiol 17b (E2) at physiological concentrations was able to suppress in vitro JKT-1 cell proliferation through ERb. However, when E2 was conjugated to bovine serum albumin (E2-BSA), which does not cross the membrane, the effect observed was completely different. E2BSA was able to stimulate JKT-1 cell proliferation by activating the PKA pathway with a rapid (15 min) phosphorylation of the transcription factor cAMP response element binding protein (CREB), through a membrane G-protein-coupled receptor (GPCR). Similar results were obtained with bisphenol A (BPA) at low (pM to nM) concentrations. BPA, a well-recognized estrogenic endocrine disruptor, is used as the monomer to manufacture polycarbonate plastic, and it is released from resin lining of canned foods or beverages or from dental sealants. It is believed to be involved in developmental, reproductive and malignant diseases by mimicking the natural hormone E2 and interfering with