Endocrine Abstracts

Introduction: Testicular germ cell tumours are the most frequent cancer of young men. Epidemiological and clinical data have suggested that fetal or perinatal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, EEDs (like bisphenol A (BPA) are often weak ligands for classical nuclear estrogen receptors.

Using a human seminoma cell line (JKT-1), devoid of ERα, we previously reported that low doses of estradiol (E₂; 10⁻⁹ M) inhibited cell proliferation through classical ERβ. At the opposite, BPA, at the same concentration, could induce cell proliferation through a non classical membrane G-protein coupled estrogen receptor (GPER/GPR30).

Methods: We carried JKT-1 cell proliferation assays with various doses of E₂ and BPA, with or without selective agonists and antagonists of ERβ (ZU, ICI) and GPER (G1, G15), in order to determine the affinity of BPA for ERβ and GPER.

Results: Using selective agonists and antagonists, we confirmed in our model that E₂ had a greater affinity for ERβ than for GPER, with a maximal effect at the concentration of 10⁻⁹ M. At the opposite, BPA exhibited a greater affinity for GPER than for ERβ, with a maximal effect at the concentration of 10-9M. The response of JKT-1 seminoma cells to E₂ (from 10-5 to 10-12 M) followed a U-shaped nonmonotonic dose response (NMDR) curve. Interestingly, they responded to BPA in the opposite direction, following an inverted U-shaped NMDR curve, which could be totally shifted from top to bottom in case of coexposition to BPA and E₂.

Conclusion: In our model, BPA promotes seminoma cell proliferation at low doses (environmentally relevant) because it exhibits a greater affinity for GPER than for ERβ, explaining the inverted U-shaped NMDR curve observed.