DEHP induces ferroptosis in testes via p38α-lipid ROS circulation and destroys the BTB integrity

Exposure to Di (2-ethylhexyl) phthalate (DEHP) has been associated with toxic effects of the reproductive system. However, the exact mechanism remains to be elucidated. In this study we explored the testicular toxicity induced by DEHP, and the probable molecular mechanism in the process. In vivo, the results demonstrated that DEHP affected testosterone levels and blood-testosterone barrier (BTB) integrity and caused ferroptosis. We further demonstrated that DEHP up-regulated the expression of p38α, p-p38α, p53, p-p53, SAT1, ALOX15. This view has also been confirmed in TM4 cells. After pre-treatment with fer-1 or si-MAPK14, the expression of either p53, p-p53, SAT1 and ALOX15 up-regulated by MEHP was inhibited in vitro. Interestingly, p38α can prevent the accumulation of lipid ROS, and the production of lipid ROS in turn promoted the expression of p38α, thus forming a feedback loop during the ferroptosis. In this process, a vicious cycle consisting of p38α, p53, SAT1, ALOX15, lipid ROS was involved. This study provides new mechanistic insights into DEHP-induced toxicity of the reproductive system.