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Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts.
Zhu, Hua-Long; Shi, Xue-Ting; Xu, Xiao-Feng; Zhou, Guo-Xiang; Xiong, Yong-Wei; Yi, Song-Jia; Liu, Wei-Bo; Dai, Li-Min; Cao, Xue-Lin; Xu, De-Xiang; Wang, Hua.
Afiliação
  • Zhu HL; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Shi XT; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Xu XF; Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui, China.
  • Zhou GX; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Xiong YW; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Yi SJ; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Liu WB; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Dai LM; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Cao XL; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • Xu DX; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. Electronic address: xudex@126.com.
  • Wang H; Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. Electronic address: wanghuadev@126.com.
Redox Biol ; 40: 101854, 2021 04.
Article em En | MEDLINE | ID: mdl-33454563
ABSTRACT
Gestational exposure to environmental stress induces fetal growth restriction (FGR), and thereby increasing the risk of infant death and chronic noncommunicable diseases in adults. However, the mechanism by which environmental stress induces FGR remains unclear. Based on case-control study, we found that the reduced level of melatonin (MT), a major secretory product from the pineal gland, was observed in placentae of FGR. This work was to investigate the protective effect of MT on environmental stress-caused FGR and its mechanisms. We used cadmium (Cd) as an environmental stressor to stimulate pregnant mice and thereby establishing a FGR model. The data showed that maternal Cd exposure lowered the P4 concentration in maternal sera, placentae and amniotic fluid, and caused FGR. Correspondingly, the expression of CYP11A1, a critical P4 synthase, was markedly downregulated in Cd-treated placentae. Simultaneously, Cd triggered BNIP3-dependent mitophagy in placental trophoblasts, as determined by the degradation of mitochondrial proteins, including HSP60 and COX IV, and the accumulation of puncta representing co-localization of TOM20 with LC3B or BNIP3 with LC3B. Based on our case-control study, we also found that activated BNIP3-dependent mitophagy and P4 synthesis inhibition occurred in SGA placentae. Most importantly, BNIP3 siRNA reversed Cd-induced P4 synthesis suppression in human placental trophoblasts. It is noteworthy that MT alleviated Cd-caused P4 synthesis suppression and FGR via antagonizing BNIP3-dependent mitophagy in placental trophoblasts. Further results confirmed that MT attenuated Cd-triggered BNIP3-dependent mitophagy via blocking GCN2/ATF4 signaling. Amusingly, Cd triggered oxidative stress and then activating GCN2/ATF4 signaling in placental trophoblasts. As expected, MT obviously suppressed Cd-caused reactive oxygen species (ROS) release. In the present study, we propose a neoteric mechanism by which MT protects against environmental stress-impaired P4 synthesis and fetal growth via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts. As above, MT is a potential therapeutic agent antagonizing environmental stress-induced developmental toxicity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trofoblastos / Melatonina Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Animals / Female / Humans / Pregnancy Idioma: En Revista: Redox Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trofoblastos / Melatonina Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Animals / Female / Humans / Pregnancy Idioma: En Revista: Redox Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China