Environmental exposure to cadmium impairs fetal growth and placental angiogenesis via GCN-2-mediated mitochondrial stress.

Abstract

Cadmium (Cd), a well-known environmental pollutant, can lead to placental insufficiency and fetal growth restriction. However, the underlying mechanism is unknown. The purpose of our study is to explore the effect of Cd on placental angiogenesis and its mechanism using in vitro and in vivo models. Results found that gestational Cd exposure obviously decreased placental weight and impaired placental vascular development in mice. Correspondingly, Cd exposure evidently downregulated the expression of VEGF-A protein (a key indicator of angiogenesis) and progesterone receptor (PR) in placental trophoblasts. Further experiment showed that lentivirus PR overexpression reversed Cd-caused the reduction of VEGF-A level in human placental trophoblasts. In addition, Cd significantly reduced progesterone level, down-regulated the expression of key progesterone synthase (StAR, CYP11A1), and activated mitochondrial stress response and GCN-2/p-eIF2α signaling in placental trophoblasts. Additional experiment showed that GCN-2 siRNA pretreatment markedly alleviated Cd-activated mitochondrial stress response, restored Cd-downregulated the expression of CYP11A1, reversed Cd-reduced the level of progesterone and VEGF-A in human placental trophoblasts. Finally, our case-control study confirmed that impaired placental angiogenesis and reduced progesterone level occurred in all-cause small for gestational age placenta. Taken together, environmental exposure to Cd impairs fetal growth and placental angiogenesis via GCN-2-mediated mitochondrial stress.

• Authors: Yong-Wei Xiong, Xiao-Feng Xu, Hua-Long Zhu, Xue-Lin Cao, Song-Jia Yi, Xue-Ting Shi, Kai-Heng Zhu, Yuan Nan, Ling-Li Zhao, Chen Zhang, Lan Gao, Yuan-Hua Chen, De-Xiang Xu, Hua Wang
• Journal: Journal of hazardous materials (J Hazard Mater) Vol. 401 Pg. 123438 (01 05 2021) ISSN: 1873-3336 [Electronic] Netherlands
• PMID: 32763717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Vascular Endothelial Growth Factor A
• Cadmium

Topics

• Animals
• Cadmium (toxicity)
• Case-Control Studies
• Environmental Exposure
• Female
• Fetal Development
• Mice
• Placenta
• Pregnancy
• Trophoblasts
• Vascular Endothelial Growth Factor A (genetics)