Nanoplastics (NPs) exposure could disrupt the synthesis of steroid hormones, thereby posing a potential threat to male reproductive health. However, the existing comprehension of the molecular mechanisms participating in this process remains limited, and the reversibility of NPs-triggered male reproductive toxicity is poorly understood. This investigation focused on the impact of histone modification on testosterone production in mice under long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs). The results showed 500 nm and 100 nm PS-NPs could accumulate in mouse testis, with a subsequent significant decrease following a period of self-recovery. The testosterone levels significantly increased after exposure to 500 nm and 100 nm PS-NPs, and the protein levels of CYP11A1, CYP17A1, and 17β-HSD were upregulated. Furthermore, PS-NPs exposure decreased the levels of multiple histone modifications (H3K9me1/2, H3K4me2/3, and H3K4/9ac) while increased H3K9me3 in mouse testis. Histone H3K9 methylation is linked with gene inhibition, whereas H3K4 methylation and H3K4/9 acetylation contribute to gene activation. ChIP analysis further confirmed that H3K9me2 was markedly decreased in the promoter regions of Cyp11a1 and Hsd17b. Additionally, H3K9me2 demethylase Jhdm2a was significantly increased. These findings suggested that low-level PS-NPs inhibited H3K9me2 through upregulating Jhdm2a, thereby activating key steroidogenic proteins CYP11A1 and 17β-HSD, ultimately promoting testosterone synthesis in mouse testis. Importantly, the changes in testosterone, steroidogenic proteins and histone modifications were effectively reversed upon the cessation of exposure to 500 nm and 100 nm PS-NPs. Collectively, these discoveries offer fresh perspectives on the epigenetic mechanisms underlying male reproductive endocrine disruption caused by PS-NPs, and contribute to assessing the human health hazards associated with exposure to environmental NPs.

中文翻译：

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聚苯乙烯纳米塑料诱导的小鼠睾酮生物合成破坏的可逆性：组蛋白修饰的作用


纳米塑料 （NPs） 暴露可能会破坏类固醇激素的合成，从而对男性生殖健康构成潜在威胁。然而，对参与这一过程的分子机制的现有理解仍然有限，并且对 NPs 触发的男性生殖毒性的可逆性知之甚少。该研究的重点是组蛋白修饰对长期暴露于环境相关剂量的聚苯乙烯纳米塑料 （PS-NPs） 小鼠睾酮产生的影响。结果显示 500 nm 和 100 nm PS-NPs 可以在小鼠睾丸中积累，随后在一段时间的自我恢复后显着减少。暴露于 500 nm 和 100 nm PS-NPs 后睾酮水平显著升高，CYP11A1、CYP17A1 和 17β-HSD 蛋白水平上调。此外，PS-NPs 暴露降低了小鼠睾丸中多种组蛋白修饰 （H3K9me1/2 、 H3K4me2/3 和 H3K4/9ac） 的水平，同时增加了 H3K9me3 的水平。组蛋白 H3K9 甲基化与基因抑制有关，而 H3K4 甲基化和 H3K4/9 乙酰化有助于基因激活。ChIP 分析进一步证实，H3K9me2 在 Cyp11a1 和 Hsd17b 的启动子区显著降低。此外，H3K9me2 去甲基化酶 Jhdm2a 显著增加。这些发现表明，低水平 PS-NPs 通过上调 Jhdm2a 抑制 H3K9me2，从而激活关键的类固醇生成蛋白 CYP11A1 和 17β-HSD，最终促进小鼠睾丸中的睾酮合成。重要的是，在停止暴露于 500 nm 和 100 nm PS-NPs 后，睾酮、类固醇生成蛋白和组蛋白修饰的变化被有效逆转。 总的来说，这些发现为 PS-NPs 引起的男性生殖内分泌干扰的表观遗传机制提供了新的视角，并有助于评估与暴露于环境 NPs 相关的人类健康危害。