Gestational exposure to environmental cadmium induces placental apoptosis and fetal growth restriction via Parkin-modulated MCL-1 degradation
| Autor: | Cheng Zhang, Xiao-Feng Xu, Yichao Huang, Yong-Wei Xiong, Lan Gao, Hua-Long Zhu, Shuang Zhang, Ling-Li Zhao, De-Xiang Xu, Yi-Ting Fu, Li-Min Dai, Hua Wang, Guo-Xiang Zhou, Wei-Bo Liu, Xue-Ting Shi |
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| Rok vydání: | 2021 |
| Předmět: |
Environmental Engineering
Health Toxicology and Mutagenesis Placenta Ubiquitin-Protein Ligases Apoptosis Matrix metalloproteinase Parkin Melatonin chemistry.chemical_compound Mice In vivo Pregnancy MG132 medicine Environmental Chemistry Animals Waste Management and Disposal Fetal Growth Retardation Pollution In vitro nervous system diseases Cell biology chemistry Proteasome Case-Control Studies Myeloid Cell Leukemia Sequence 1 Protein Female medicine.drug Cadmium |
| Zdroj: | Journal of hazardous materials. 424 |
| ISSN: | 1873-3336 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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