Role of ferroptosis mediated by abnormal membrane structure in DEHP-induced reproductive injury

Di-(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer, has been demonstrated to possess reproductive toxicity; however, the precise mechanisms underlying this effect have yet to be fully elucidated. This study aimed to investigate the potential mechanisms by which prepubertal DEHP exposure impairs testicular development and to provide possible therapeutic targets. We exposed BALB/c male mice from postnatal days 22–35 to different doses of DEHP (0, 250, and 500 mg/kg/day) and utilized lipid metabolomics and other methods to elucidate the reproductive damage caused by DEHP from a multidimensional tissue-cell-molecule perspective. Our findings indicate that DEHP exposure induces ferroptosis in testicular tissue by remodeling membrane lipid structure, in which the imbalance of phospholipid-polyunsaturated fatty acids (PL-PUFA) and phospholipid-monounsaturated fatty acids (PL-MUFA) playing a crucial role. DEHP exposure altered the expression of ACSL4 and MBOAT2 via HIPPO and androgen receptor pathways, thereby impacting PL-PUFA/PL-MUFA synthesis. In conclusion, this study highlights a link between DEHP-induced reproductive damage and lipid metabolism reprogramming, suggesting new targets for preventing DEHP-induced reproductive toxicity.