Embryonic Dibutyl Phthalate Exposure Disrupts Sertoli Cell Glycolipid Metabolism to Drive Premature Spermatogenesis in PND 22 Male Offspring: A Role for the AMPK/Autophagy Axis.

Dibutyl phthalate (DBP), a widely used plasticizer, is frequently added to various plastic products. Being a prevalent environmental endocrine disruptor, DBP interacts non-covalently with plastic matrices, which promotes its release into surrounding environments and subsequent risks to human health. Our previous studies demonstrated that embryonic exposure to DBP induces precocious spermatogenesis in male offspring, though the underlying mechanisms remain unclear. In this study, we established an in vivo model of embryonic DBP exposure at varying doses and found that low-to-medium doses of DBP (0.5, 5, and 50mg/kg/day) enhanced glycolipid metabolism in testis, leading to the premature initiation of spermatogenesis in postnatal day 22 (PND 22) male offspring. Using an in vitro Sertoli cell (SC)- spermatogenic cell co-culture system, we further observed that monobutyl phthalate (MBP, the active metabolite of DBP) promoted the premature development of spermatogenic cells. Mechanistically, MBP enhanced fatty acid β-oxidation (FAO) in SCs, thereby increasing glycolysis and promoting premature spermatogenic cell maturation. Further investigations revealed that MBP exposure activated the AMPK-autophagy signaling pathway in SCs, resulting in elevated FAO. This study is the first to elucidate the molecular mechanism of DBP-induced precocious spermatogenesis from a metabolic perspective, providing critical insights into the environmental etiology of such disorders and highlighting its significance in safeguarding reproductive health in adolescent males.