Abstract

Environmental exposure to microplastics, especially polystyrene microplastics (PS-MPs), poses growing concerns for male reproductive health. In this study, we demonstrate that PS-MPs internalize into Sertoli cells, triggering CEBPB-mediated lysosomal hyperactivation and the degradation of tight junction proteins, thereby impairing the structural integrity of the blood-testis barrier (BTB). Concurrently, PS-MPs accumulate in mature human sperm, damaging mitochondrial ultrastructure and inducing ROS-driven lipid peroxidation and ferroptosis-like injury. These alterations result in reductions in motility, DNA integrity, and early embryonic development following intracytoplasmic sperm injection (ICSI). Crucially, the antioxidant N-acetylcysteine (NAC) rescued sperm functional metrics and restored embryo quality. These findings reveal dual cellular pathways, disruption of both the barrier and sperm mitochondrial integrity, by which environmental PS-MPs impair male fertility. The study highlights NAC as a promising intervention and identifies chloroquine as a potent modulator of lysosome-mediated BTB disruption. The environmental relevance of PS-MPs and their mechanistic impact on human reproductive health underscore the urgent need for strategies to reduce pre-fertilization microplastic exposure.