Gestational exposure to environmental cadmium induces placental apoptosis and fetal growth restriction via Parkin-modulated MCL-1 degradation.

Abstract

Heavy metal cadmium (Cd), a classical environmental pollutant, causes placental apoptosis and fetal growth restriction (FGR), whereby the mechanism remains unclear. Here, our human case-control study firstly showed that there was a positive association of Parkin mitochondrial translocation, MCL-1 reduction, placental apoptosis, and all-cause FGR. Subsequently, Cd was administered to establish in vitro and in vivo models of placental apoptosis or FGR. Our models demonstrated that Parkin mitochondrial translocation was observed in Cd-administrated placental trophoblasts. Meaningfully, Parkin siRNA (siR) dramatically mitigated Cd-triggered apoptosis in placental trophoblasts. Mdivi-1 (M-1), an inhibitor for Parkin mitochondrial translocation, mitigated Cd-induced apoptosis in placental trophoblasts, which further ameliorated the effect of attenuated placental sizes in Cd-exposed mice. Furthermore, the interaction of MCL-1 with Parkin or Ub in Cd-stimulated cells was stronger than that in controls. MG132, an inhibitor for proteasome, abolished MCL-1 degradation in Cd-stimulated cells. Importantly, Parkin siR and M-1 memorably abolished the ubiquitin-dependent degradation of MCL-1 in placental trophoblasts. Interestingly, mito-TEMPO and melatonin, two mitochondria-targeted antioxidants, obviously rescued Cd-caused mitochondrial membrane potential (MMP) decrease, Parkin mitochondrial translocation, MCL-1 degradation, and apoptosis in placental trophoblasts. In conclusion, cadmium induces placental apoptosis and FGR via mtROS-mediated Parkin-modulated degradation of MCL-1.

• Authors: Hua-Long Zhu, Li-Min Dai, Yong-Wei Xiong, Xue-Ting Shi, Wei-Bo Liu, Yi-Ting Fu, Guo-Xiang Zhou, Shuang Zhang, Lan Gao, Cheng Zhang, Ling-Li Zhao, Xiao-Feng Xu, Yi-Chao Huang, De-Xiang Xu, Hua Wang
• Journal: Journal of hazardous materials (J Hazard Mater) Vol. 424 Issue Pt A Pg. 127268 (02 15 2022) ISSN: 1873-3336 [Electronic] Netherlands
• PMID: 34583167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Myeloid Cell Leukemia Sequence 1 Protein
• Cadmium
• Ubiquitin-Protein Ligases

Topics

• Animals
• Apoptosis
• Cadmium (toxicity)
• Case-Control Studies
• Female
• Fetal Growth Retardation (chemically induced)
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (genetics)
• Placenta
• Pregnancy
• Ubiquitin-Protein Ligases (genetics)