ORIGINAL ABSTRACT

The escalating global incidence of male infertility is closely linked to environmental endocrine disruptors, particularly pesticides. Glyphosate (GLY) is a widely used pesticide with endocrine-disrupting activity and has been recognized to pose substantial public health risks. However, its impact on male reproductive health and the underlying mechanisms remains poorly defined. Thus, the present study established a 24-week mouse model of chronic GLY exposure to investigate its effects on spermatogenesis systematically. Pathological analysis revealed that GLY exposure damaged seminiferous tubules and induced sperm acrosomal defects. These defects originated from GLY-induced disruption of the Golgi apparatus, which impaired the accumulation and fusion of proacrosomal vesicles on spermatid nuclei. Integrated network toxicology and transcriptomics showed that autophagy is a critical mediator of GLY-induced Golgi damage and suppression of vesicle biosynthesis. Further analysis demonstrated that GLY triggered Golgi fragmentation and reduced proacrosomal vesicles via activating Golgiphagy. Importantly, knockdown of Golgi phosphoprotein 3 (GOLPH3), a novel Golgiphagy receptor, markedly attenuated GLY-induced Golgiphagy and restored the Golgi structure. Taken together, chronic GLY exposure compromises acrosome biogenesis during spermatogenesis by activating GOLPH3-mediated Golgiphagy, thereby impairing sperm quality. These findings provide a feasible therapeutic strategy to counteract the reproductive health threats posed by GLY and analogous environmental pollutants.