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

• Published in: Ecotoxicology and environmental safety 2021-11, Vol.224, p.112632, Article 112632
• Main Authors: Shi, Xue-Ting, Zhu, Hua-Long, Xu, Xiao-Feng, Xiong, Yong-Wei, Dai, Li-Min, Zhou, Guo-Xiang, Liu, Wei-Bo, Zhang, Yu-Feng, Xu, De-Xiang, Wang, Hua
• Format: Article
• Language: English
• Subjects: Cadmium; Fetal growth restriction; Glucocorticoid receptor; Melatonin; Placental angiogenesis
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2021.112632

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. [Display omitted] •Cd impairs placental angiogenesis via downregulating VEGF-A.•Cd reduces placental VEGF-A via PERK-dependent GR activation.•MT alleviates Cd-impaired VEGF-A dependent placental angiogenesis.•MT reverses Cd-activated GR signaling by blocking PERK signaling.