He Huanshan, Li Xiang, Shen Jianing, Bai Shuying, Li Cong, Shi Huaiping
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
Ecotoxicol Environ Saf. 2022 Sep 15;243:113996. doi: 10.1016/j.ecoenv.2022.113996. Epub 2022 Aug 26.
Bisphenol A (BPA), one of the chemicals with the highest volume of production worldwide, has been demonstrated to cause testicular toxicity via different pathways. However, there is little evidence concerning the mechanism of BPA exposure induced histone modification alterations, especially regarding the effect on the histone H3 lysine 4 (H3K4) epigenetic modification. Our results demonstrated a new epigenetic regulation of BPA exposure on testicular damage using both cell culture and mouse models. With BPA treatment, disordered and shrunken seminiferous tubules and poor sperm quality were observed in vivo, and mouse spermatogonial germ cell proliferation was inhibited in vitro. BPA attenuated PI3K expression inducing phospho-AKT inhibition in vivo and in vitro. DPY30 was the only downregulated subunit in BPA and MEK2206 (AKT inhibitor) treated cells, which contributed to reducing H3K4me3 recruitment at the PIK3CA transcriptional start site (TSS) in BPA treated cells. The toxicity caused by BPA exposure was relieved after the transduction of adenoviruses expressing DPY30 transgenes, which resulted in the stimulation of PI3K/AKT with H3K4me3 enriched at the PI3KCA TSS. DPY30 promoted cell glycolysis via AMPK and proliferation through AKT/P21. DPY30 was mainly located in the round and elongated spermatids for energy accumulation in mature sperm in AD-DPY30-treated mice which showed higher sperm quality. Overall, our results indicated that BPA exposure causes testicular toxicity through a DPY30-mediated H3K4me3 epigenetic modification, which serves to regulate the PI3K/AKT/P21 pathway.
双酚A（BPA）是全球产量最高的化学品之一，已被证明可通过不同途径导致睾丸毒性。然而，关于BPA暴露诱导组蛋白修饰改变的机制，尤其是对组蛋白H3赖氨酸4（H3K4）表观遗传修饰的影响，证据很少。我们的研究结果使用细胞培养和小鼠模型证明了BPA暴露对睾丸损伤的一种新的表观遗传调控。经BPA处理后，在体内观察到生精小管紊乱和萎缩以及精子质量差，并且在体外小鼠精原生殖细胞增殖受到抑制。BPA在体内和体外均减弱PI3K表达，诱导磷酸化AKT抑制。DPY30是在BPA和MEK2206（AKT抑制剂）处理的细胞中唯一下调的亚基，这有助于减少BPA处理细胞中PIK3CA转录起始位点（TSS）处的H3K4me3募集。在转导表达DPY30转基因的腺病毒后，BPA暴露引起的毒性得到缓解，这导致PI3K/AKT受到刺激，且PI3KCA TSS处富集H3K4me3。DPY30通过AMPK促进细胞糖酵解，并通过AKT/P21促进细胞增殖。在AD-DPY30处理的小鼠中，DPY30主要位于圆形和细长形精子细胞中，用于成熟精子的能量积累，这些小鼠的精子质量更高。总体而言，我们的研究结果表明，BPA暴露通过DPY30介导的H3K4me3表观遗传修饰导致睾丸毒性，该修饰用于调节PI3K/AKT/P21途径。
