Perinatal exposure to polystyrene microplastics induces multigenerational impairment of male reproduction via disrupted steroidogenesis and proteostasis

• Maternal PS-MPs exposure impairs testicular development in F1 and F2 offspring. • F2 males show compensatory StAR/SRSF1 upregulation vs. stressed F1. • Multigenerational toxicity mechanisms: DNA damage and disrupted steroidogenesis. • Severity of reproductive injury is attenuated in F2 generation. • Study reveals a potential adaptive response to ancestral PS-MPs exposure. Microplastics (MPs) are pervasive environmental contaminants that pose potential health risks through multiple exposure routes. Although their toxic effects have attracted increasing concern, their multigenerational impacts remain poorly understood. This study investigated the reproductive effects of maternal exposure to polystyrene microplastics (PS-MPs) during gestation and lactation, on male offspring across two generations (F1 and F2) of Sprague-Dawley rats. Results demonstrated that maternal PS-MP exposure induced significant reproductive toxicity in both F1 and F2 male offspring, manifesting as impaired testicular development with reduced sperm count, and accompanied by increased oxidative stress and DNA damage, as indicated by elevated levels of ROS, 8-OHdG, and γ-H2AX. In the F1 generation, we observed suppressed testosterone synthesis and endoplasmic reticulum (ER) stress, characterized by decreased levels of testosterone and steroidogenic acute regulatory protein (StAR), along with increased GRP78. Interestingly, the F2 generation exhibited a distinct adaptive response, characterized by the upregulation of StAR and Serine arginine-rich splicing factor 1 (SRSF1), suggesting that modulation of steroidogenesis and RNA splicing may partially counteract the reproductive impairment induced by ancestral exposure. In conclusion, gestational and lactational exposure to PS-MPs induces multigenerational reproductive toxicity in male offspring. However, compensatory mechanisms appear to attenuate these effects in the F2 generation. These findings provide crucial experimental evidence for the comprehensive assessment of multigenerational reproductive risks from microplastic exposure.