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

Authors :
Zhu HL
Dai LM
Xiong YW
Shi XT
Liu WB
Fu YT
Zhou GX
Zhang S
Gao L
Zhang C
Zhao LL
Xu XF
Huang YC
Xu DX
Wang H
Source :
Journal of hazardous materials [J Hazard Mater] 2022 Feb 15; Vol. 424 (Pt A), pp. 127268. Date of Electronic Publication: 2021 Sep 20.
Publication Year :
2022

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.<br /> (Copyright © 2021 Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
1873-3336
Volume :
424
Issue :
Pt A
Database :
MEDLINE
Journal :
Journal of hazardous materials
Publication Type :
Academic Journal
Accession number :
34583167
Full Text :
https://doi.org/10.1016/j.jhazmat.2021.127268