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.

中文翻译：

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m6A RNA 甲基化通过靶向双酚 A 诱导的 Leydig 细胞功能障碍中的 Map1lc3b 调节自噬


双酚 A （BPA） 暴露会影响睾丸睾丸间质细胞 （LC），可能导致男性不育。研究表明，RNA 对环境暴露的表观遗传反应可能会影响 LCs 功能和睾酮产生，但 N6-甲基腺苷 （m6A） RNA 甲基化在介导 BPA 暴露中的作用及其调节机制仍不清楚。在这里，我们使用体内和体外模型证明 BPA 暴露显着降低了睾酮生物合成并上调了 LCs 中的 m6A 修饰。发现 m6A“写入器”METTL3 和“擦除器”ALKBH5 在 BPA 暴露期间参与调节 LCs m6A 水平，突出了它们的核心作用。操纵这些因子以降低 m6A 甲基化水平表明有可能减轻 BPA 诱导的 LC 损伤。此外，转录组学和 MeRIP 测序数据的综合分析表明，BPA 诱导的 m6A 水平上调特异性靶向自噬的关键调节因子 Map1lc3b mRNA，从而对自噬过程产生抑制作用。总之，我们的研究结果表明，靶向 m6A RNA 甲基化可能是减轻 BPA 诱导的生殖毒性的潜在治疗方法，为男性生殖健康的表观遗传调控提供了新的见解。