Di-(2-Ethylhexyl) phthalate causes testicular ferroptosis though deficiency of androgen receptor and disruption of mitochondrial quality control

Di (2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer known to cause testicular toxicity, though its mechanism remains incompletely understood. This study investigated whether DEHP-induced testicular injury involved suppression of Androgen Receptor (AR) expression. In vivo, rats were exposed to DEHP (500 mg/kg) for 60 days, causing damage to the testicles. Further, the expression of AR was decreased, mitochondrial quality control (MQC) was impaired, mitochondrial damage occurred, and ultimately led to Ferroptosis. Specifically, DEHP reduced levels of mitochondrial biogenesis markers (PGC-1α, TFAM, NRF1/2) and fusion markers (MFN1/2, OPA1), while increasing fission markers (DRP1, FIS1) and Mitophagy markers (PINK1, PARKIN). In vitro, to further explore the relationship between AR, MQC, and Ferroptosis, the TM4 cell model overexpressing AR was established and exposed to MEHP (200 μM). The findings demonstrated that AR overexpression effectively alleviated DEHP-induced disruption of MQC, mitochondrial impairment, and Ferroptosis. Together, these findings demonstrated that DEHP impaired the MQC system by inhibiting AR expression, thereby promoting Ferroptosis.

Androgen receptor; DEHP; Ferroptosis; Mitochondrial quality control; Testicular injury.