Reversibility of polystyrene nanoplastics-induced disruption of testosterone biosynthesis in mice: The role of histone modifications

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.