Di‐(2‐ethylhexyl) phthalate induces ferroptosis in prepubertal mouse testes via the lipid metabolism pathway

Author:

Wang Xia12,Li Dinggang12,Zheng Xiangqin12,Hong Yifan12,Zhao Jie12,Deng Wei12,Wang Mingxin12,Shen Lianju12,Long Chunlan12,Wei Guanghui12,Wu Shengde12

Affiliation:

1. Department of Urology Children's Hospital of Chongqing Medical University Chongqing China

2. Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics Chongqing China

Abstract

AbstractDi‐(2‐ethylhexyl) phthalate (DEHP), a widely used plasticizer, has been shown to cause reproductive toxicity, but the precise mechanism remains unclear. This study aimed to investigate the possible molecular mechanism of DEHP‐induced testicular damage. In vivo study, we administered different doses of DEHP (0, 250, and 500 mg/kg/day) to male C57BL/6 mice from 22 and 35 days after birth. We found that DEHP exposure induced histopathological alterations in prepubertal testes, and testicular lipidomics indicated notable alterations in lipid metabolism and significant enrichment of ferroptosis. Further tests showed that ferrous iron (Fe2+) and malondialdehyde (MDA) levels significantly increased after DEHP exposure. Western blotting revealed that DEHP exposure reduced glutathione peroxidase 4 (GPX4) expression, and elevated acyl coenzyme A synthetase long‐chain member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) expression. The in vitro results were consistent with the in vivo results. When Leydig cells and Sertoli cells were treated with ferrostatin‐1 and monoethylhexyl phthalate (MEHP), MEHP‐induced increases in Fe2+ and MDA levels, accumulation of lipid reactive oxygen species, downregulation of GPX4, and upregulation of ACSL4 and LPCAT3 were reversed. Collectively, our findings suggested that aberrant lipid metabolism and ferroptosis may be involved in prepubertal DEHP exposure‐induced testicular damage.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Health, Toxicology and Mutagenesis,Management, Monitoring, Policy and Law,Toxicology,General Medicine

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