Journal
JOURNAL OF HAZARDOUS MATERIALS
Volume 401, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jhazmat.2020.123438
Keywords
Cadmium; Placental angiogenesis; Fetal growth; General control non-derepressible 2; Mitochondrial stress
Categories
Funding
- National Natural Science Foundation of China [81973079, 81473016, 81930093]
- Anhui Provincial Natural Science Foundation [2008085J38]
- Young Scholars of Wan Jiang in Anhui Province
- Translational Foundation from Anhui Medical University [2017zhyx22]
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Cadmium exposure can negatively affect placental angiogenesis and progesterone levels, potentially impairing fetal growth through a mechanism involving GCN-2-mediated mitochondrial stress.
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 ble 2 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-eIF2 alpha 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.
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