2. Academic Validation
  3. Melatonin alleviates deoxynivalenol-induced apoptosis of human granulosa cells by reducing mutually accentuated FOXO1 and ER stress‡

Melatonin alleviates deoxynivalenol-induced apoptosis of human granulosa cells by reducing mutually accentuated FOXO1 and ER stress‡

  • Biol Reprod. 2021 Aug 3;105(2):554-566. doi: 10.1093/biolre/ioab084.
Rufeng Xue 1 2 3,  Shuhang Li 4 5,  Huijuan Zou 1 2 3,  Dongmei Ji 1 6 7,  Mingrong Lv 1 2 3,  Ping Zhou 1 6 7,  Zhaolian Wei 1 6 7,  Zhiguo Zhang 1 2 3,  Yunxia Cao 1 2 3
Affiliations

Affiliations

  • 1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 2 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China.
  • 3 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China.
  • 4 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.
  • 5 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.
  • 6 Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China.
  • 7 Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China.
PMID: 33907797 DOI: 10.1093/biolre/ioab084
Abstract

Deoxynivalenol (DON) is one of the most prevalent Fusarium mycotoxins, which cause detrimental effects on human and animal reproductive systems by inducing oxidative stress. Increasing evidence has suggested the potential roles of melatonin in protecting granulosa cells from oxidative injury, but the underlying mechanisms remain largely elusive. Here, we demonstrated that suppression of FOXO1 and endoplasmic reticulum (ER) stress was engaged in melatonin-mediated protection against oxidative damage in human granulosa cells upon DON exposure in vitro. DON induced excess Reactive Oxygen Species accumulation, cells viability loss, reduced estradiol-17β, and progesterone production in human granulosa cells, whereas melatonin ameliorated these phenotypes. Next, we found that the protective effect of melatonin against Apoptosis was via reducing ER stress because the inhibition of ER stress displayed similar protective effects during DON treatment. Moreover, melatonin provided no additional protection when ER stress was inhibited. We further found that FOXO1 is a pivotal downstream effector of melatonin and ER stress in regulating DON-induced Apoptosis in human granulosa cells. Blocking of FOXO1 reduced DON-induced cells death and FOXO1 activation could be suppressed by melatonin or ER stress inhibitor. However, melatonin failed to further restore cells viability in the presence of FOXO1 inhibitor. Collectively, our results reveal a new mechanism of melatonin in protecting against DON-induced Apoptosis and dysfunction by suppressing ER stress and FOXO1 in human granulosa cells.

Keywords

ER stress; FOXO1; ROS; deoxynivalenol; human granulosa cells; melatonin.

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