1. Academic Validation
  2. Gestational cadmium exposure impairs placental angiogenesis via activating GC/GR signaling

Gestational cadmium exposure impairs placental angiogenesis via activating GC/GR signaling

  • Ecotoxicol Environ Saf. 2021 Aug 16;224:112632. doi: 10.1016/j.ecoenv.2021.112632.
Xue-Ting Shi 1 Hua-Long Zhu 1 Xiao-Feng Xu 2 Yong-Wei Xiong 1 Li-Min Dai 1 Guo-Xiang Zhou 1 Wei-Bo Liu 1 Yu-Feng Zhang 1 De-Xiang Xu 1 Hua Wang 3
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • 2 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.
  • 3 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@ahmu.edu.cn.
Abstract

Gestational exposure to environmental Cd caused placental angiogenesis impairment and fetal growth restriction (FGR). However, its mechanism remained unclear. This study was to investigate the effects of Cd exposure during pregnancy on placental angiogenesis and its mechanism. Pregnant mice were exposed to CdCl2 (4.5 mg/kg) on gestational day (GD) 8 with or without melatonin (MT) (5.0 mg/kg), an anti-endoplasmic reticulum stress agent, from GD7 to GD15. Human primary placental trophoblasts and JEG-3 cells were stimulated using CdCl2 (20 μM) after MT (1 mM) preprocessing. We firstly found MT treatment obviously mitigated environmental Cd-induced placental angiogenesis disorder and reduction of the VEGF-A level. Mechanistically, MT reversed environmental Cd-downregulated the protein expression of VEGF-A via inhibiting Glucocorticoid Receptor (GR) activation. Notably, our data showed MT treatment antagonized Cd-activated GC/GR signaling via blocking PERK signaling and thereby upregulated VEGF-A and 11β-HSD2 protein expression. Based upon the population case-control study, the levels of VEGF-A and 11β-HSD2 protein in small-for-gestational-age placentae were significantly reduced when compared to appropriate-for-gestational-age placentae. Overall, environmental Cd exposure during gestation impaired placental angiogenesis via PERK-regulated GC/GR signaling in placental trophoblasts. Our findings will provide a basis for prevention and treatment of placental impairments and fetal growth restriction caused by environment toxicants in future.

Keywords

Cadmium; Fetal growth restriction; Glucocorticoid receptor; Melatonin; Placental angiogenesis.

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