2. Academic Validation
  3. Melatonin attenuates di-(2-ethylhexyl) phthalate-induced apoptosis of human granulosa cells by inhibiting mitochondrial fission

Melatonin attenuates di-(2-ethylhexyl) phthalate-induced apoptosis of human granulosa cells by inhibiting mitochondrial fission

  • Reprod Toxicol. 2022 Oct;113:18-29. doi: 10.1016/j.reprotox.2022.08.004.
Rufeng Xue 1,  Shuhang Li 2,  Zhaolian Wei 3,  Zhiguo Zhang 4,  Yunxia Cao 5
Affiliations

Affiliations

  • 1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China. Electronic address: xrufeng@mail.ustc.edu.cn.
  • 2 Department of Oncology of The First Affiliated Hospital, the CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China; Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China.
  • 4 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China. Electronic address: zzg_100@163.com.
  • 5 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China. Electronic address: caoyunxia5972@ahmu.edu.cn.
PMID: 35952901 DOI: 10.1016/j.reprotox.2022.08.004
Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is one of the most used plasticizers which have contaminated environment widely, and its extensive use causes female reproductive injury. Melatonin has a substantial protective effect against female reproductive toxicity. This study was undertaken to investigate the influence of melatonin on DEHP-induced damage of human granulosa cells (GCs) in vitro and explore the potential mechanisms. Here, we found that melatonin treatment alleviated DEHP-induced human GCs Apoptosis and improved mitochondrial function via inhibiting dynamin-related protein 1 (Drp1) mediated mitochondrial fission. Melatonin inhibited the expression, activation and oligomerization of Drp1, which decreased translocation of Drp1 to mitochondria in DEHP-exposed human GCs. Inhibition of mitochondrial fission reduced intracellular Reactive Oxygen Species (ROS) production, sustained mitochondrial membrane potential and decreased cytochrome c release. Further research showed that AMPK-PGC-1α signal pathway was involved in the inhibition of melatonin on Drp1 expression and activation. Melatonin treatment promoted AMPK activation suppressed by DEHP, and activated AMPK recovered the balance of Drp1 phosphorylation at Ser616 and Ser637 sites and enhanced PGC-1α expression. Moreover, PGC-1α could prevent mitochondrial fission by decreasing Drp1 expression directly via binding to its promoter. In contrast, blocking of AMPK or PGC-1α with specific inhibitor negated the protective effects of melatonin on mitochondrial homeostasis and GCs Apoptosis. In summary, our results indicated the protective effects of melatonin on improving mitochondrial function and attenuating cells injury in DEHP-exposed human GCs. Melatonin treatment may be a promising therapeutic approach against DEHP-induced reproductive disorder.

Keywords

AMPK-PGC-1α signal; Di-(2-ethylhexyl) phthalate; Human granulosa cells; Melatonin; Mitochondrial fission.

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