Perfluorooctane sulfonate exposure disrupts steroid hormone synthesis in rats via the gut-metabolism-testis axis.

Perfluorooctane sulfonate (PFOS) is an emerging persistent organic pollutant, and environmental exposure to it induces male reproductive toxicity. Given the close relationship between gut microbiota homeostasis and male reproductive function, this study aimed to reveal the impacts of gut microbiota and related metabolism on testicular steroidogenesis in rats following low-level PFOS exposure. The results showed that PFOS exposure significantly elevated progesterone and testosterone levels in rat serum by upregulating the expression of key steroidogenic genes, including steroidogenic acute regulatory protein (StAR). Moreover, PFOS altered the composition of gut microbiota, especially increasing the abundance of Lactobacillus, and disrupted arachidonic acid (AA) metabolism in gut, serum, and testis of rats. Multi-omics analysis revealed a significant correlation between Lactobacillus, AA metabolites, and steroid hormones. We also found that AA oxidative metabolites (5-HpETE, 5-HETE, and 5-oxoETE) were increased, which activated the oxo-eicosanoid receptor (OXE-R) and StAR expressions. Collectively, it is suggested that PFOS exposure increases the abundance of gut Lactobacillus, which enhances AA metabolism in rat testis, thereby activating the OXE-R signaling and stimulating steroid hormone synthesis. These results provide novel insights into the mechanism of PFOS-disrupted steroidogenesis via the gut-metabolism-testis axis, which may be useful for the risk assessment of male reproductive disorder induced by environmental PFOS exposure.