Study on the Induction Mechanism of Low-Dose Bisphenol A

Sheng Zhiguo and Zhu Benzhan from the Research Group of Radical Chemistry and Combined Toxicology, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco‑Environmental Sciences, Chinese Academy of Sciences, have made important progress in exploring the novel mechanism by which low‑dose bisphenol A (BPA) induces spermatogonial cell proliferation.

According to experts, bisphenol A (2,2-(4,4-dihydroxydiphenyl)propane, BPA) is a precursor for the production of polycarbonate, epoxy resin and other materials. It is widely used in the manufacture of fungicides, dyes, beverage containers, tableware, baby bottles and other products, ranking among the world's highest-yield industrial chemicals with an annual output growth rate of 6%–10%. Recent epidemiological studies have shown that BPA and its metabolites are ubiquitously detected in body fluids of the general population. Given that the chemical structure of BPA shares high similarity with estrogen E2, its potential disruptive effects on the reproductive and endocrine systems have attracted widespread attention. The relevant research findings have recently been published in Environmental Health Perspectives.

Numerous in vivo and in vitro studies have indicated that environmentally relevant doses of BPA can promote germ cell proliferation by rapidly activating signaling pathways mediated by membrane G-protein coupled receptors. However, the specific molecular mechanism remains unclear.

The research by Sheng Zhiguo and Zhu Benzhan reveals that environmentally relevant concentrations of BPA (10⁻¹⁰–10⁻⁸ M) induce proliferation of the mouse spermatogonial cell line GC-1 mainly through the PKG and EGFR-ERK signaling pathways. BPA can rapidly (within 15 minutes) activate cell proliferation marker proteins: the transcription factor cAMP response element-binding protein (CREB) and the cell cycle regulatory protein Rb. Notably, although estrogen receptor ER-α is involved in BPA-induced proliferation of GC-1 cells, it is not directly activated by BPA.

Further studies demonstrate that BPA activates ER-α by triggering the EGFR-ERK-c-fos signaling pathway mediated by the membrane-coupled orphan receptor GPR30; activated ER-α in turn positively regulates this signaling cascade, ultimately stimulating the proliferation of GC-1 cells.

This study is the first to confirm that at environmentally relevant low doses, BPA activates the PKG and EGFR/ERK/c-fos signaling pathways via crosstalk between the membrane-coupled receptor GPR30 and the nuclear receptor ER-α, thereby inducing proliferation of mouse spermatogonial GC-1 cells.