m6A RNA methylation modulates autophagy by targeting Map1lc3b in bisphenol A induced Leydig cell dysfunction

Bisphenol A (BPA) exposure can affect testicular Leydig cells (LCs), potentially causing male infertility. Research suggests that RNA epigenetic response to environmental exposure may impact LCs function and testosterone production, but the role of N⁶-methyladenosine (m6A) RNA methylation in mediating BPA exposure and its regulatory mechanisms remain unknown. Here, we demonstrate that BPA exposure significantly reduces testosterone biosynthesis and upregulates m6A modification in LCs using both in vivo and in vitro models. The involvement of the m6A "writer" METTL3 and the "eraser" ALKBH5 in regulating LCs m6A levels during BPA exposure was discovered, highlighting their central role. Manipulating these factors to reduce m6A methylation levels demonstrated potential for alleviating BPA-induced damage to LCs. Furthermore, integrated analysis of transcriptomic and MeRIP sequencing data reveals that the upregulation of m6A levels induced by BPA specifically targets the Map1lc3b mRNA, a pivotal regulator of autophagy, thereby exerting suppressive effects on autophagic processes. In conclusion, our findings suggest that targeting m6A RNA methylation could be a potential therapeutic approach to mitigate BPA-induced reproductive toxicity, offering novel insights into the epigenetic regulation of male reproductive health.