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

• Published in: Journal of hazardous materials 2022-02, Vol.424 (Pt A), p.127268-127268, Article 127268
• Main Authors: Zhu, Hua-Long, Dai, Li-Min, Xiong, Yong-Wei, Shi, Xue-Ting, Liu, Wei-Bo, Fu, Yi-Ting, Zhou, Guo-Xiang, Zhang, Shuang, Gao, Lan, Zhang, Cheng, Zhao, Ling-Li, Xu, Xiao-Feng, Huang, Yi-chao, Xu, De-Xiang, Wang, Hua
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cadmium; Cadmium - toxicity; Case-Control Studies; Female; Fetal Growth Retardation - chemically induced; MCL-1; Mice; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Parkin; Placenta; Placentae; Pregnancy; Ubiquitin-Protein Ligases - genetics
• ISSN: 0304-3894; 1873-3336
• DOI: 10.1016/j.jhazmat.2021.127268

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. [Display omitted] •Parkin mitochondrial translocation and apoptosis occur in SGA placentae.•Cadmium promotes placental apoptosis via MCL-1 degradation.•Cadmium causes MCL-1 degradation by Parkin mitochondrial translocation.•Cadmium promotes Parkin mitochondrial translocation via mtROS release.