The necroptosis-mediated imbalance of mitochondrial dynamics is involved in DEHP-induced toxicity to immature testes via the PGAM5-DRP1 interaction

作者全名："Zhou, Xiazhu; Hong, Yifan; Chen, Jing; Yu, Yihang; Wang, Siyuan; Wei, Yuexin; Long, Chunlan; Shen, Lianju; Wu, Shengde; Wei, Guanghui"

作者地址："[Zhou, Xiazhu; Hong, Yifan; Chen, Jing; Yu, Yihang; Wang, Siyuan; Wei, Yuexin; Wu, Shengde; Wei, Guanghui] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Urol, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China; [Zhou, Xiazhu; Hong, Yifan; Chen, Jing; Wang, Siyuan; Wei, Yuexin; Long, Chunlan; Shen, Lianju; Wu, Shengde; Wei, Guanghui] Chongqing Med Univ, Chongqing Key Lab Struct Birth Defect & Reconstruc, Chongqing Key Lab Children Urogenital Dev & Tissue, Childrens Hosp, Chongqing 400014, Peoples R China"

通信作者："Wu, SD (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Urol, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China."

来源：ENVIRONMENTAL POLLUTION

ESI学科分类：ENVIRONMENT/ECOLOGY

WOS号：WOS:001198076100001

JCR分区：Q1

影响因子：8.9

年份：2024

卷号：346

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：DEHP; Testicular injury; Necroptosis; Mitochondrial dynamics; PGAM5-DRP1 interaction

摘要："Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that has been shown to impair male reproduction, but the potential mechanism underlying testicular injury caused by DEHP remains unclear. In vivo, rats were gavaged consecutively from postnatal day (PND) 21 to PND 31 with 0, 250, or 500 mg/kg DEHP for 10 days, and impaired mitochondria and increased necroptosis were observed in immature testes. In vitro, the GC -1 and GC -2 cell lines were exposed to monoethylhexyl phthalate (MEHP) at 100, 200 and 400 mu M for 24 h, and this exposure induced oxidative stress damage, necroptosis and mitochondrial injury. Necroptosis and mitochondrial fission were inhibited by the reactive oxygen species (ROS) inhibitor acetylcysteine, and the imbalanced mitochondrial dynamics were rescued by the RIPK1 inhibitor necrostatin-1. Colocalization and co-IP analyses confirmed an interaction between dynamin-related protein 1 (DRP1) and phosphoglycerate mutase 5 (PGAM5), indicating that PGAM5 dephosphorylates DRP1 at serine 637 to induce mitochondrial fragmentation and thereby induces germ cell damage. Drug prediction with Connectivity Map (cMap) identified sulforaphane as a therapeutic drug. In summary, our findings indicate that DEHP triggers necroptosis and mitochondrial injury via a ROS storm in immature testes and that the PGAM5-DRP1 interaction is involved in this process."

基金机构：National Natural Science Foundation of China [82071632]; Chongqing Natural Science Foundation Innovation and Development Joint Fund Project [CSTB2022NSCQ-LZX0019]; Joint Medical Research Project of Chongqing Science and Technology Bureau and Health Commission [2022ZDXM033]; Postgraduate Research Innovation Project of Chongqing Medical University [CYS22355]; Ministry of Education Key Lab- oratory of Child Development and Disorders; [YBRP-202114]

基金资助正文："This work was supported by the National Natural Science Foundation of China (Grant number 82071632) , the Chongqing Natural Science Foundation Innovation and Development Joint Fund Project (No. CSTB2022NSCQ-LZX0019) , the Joint Medical Research Project of Chongqing Science and Technology Bureau and Health Commission (No. 2022ZDXM033) , the Postgraduate Research Innovation Project of Chongqing Medical University (Grant number CYS22355) , and the Youth Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders (Grant number YBRP-202114) ."