Journal
JOURNAL OF HAZARDOUS MATERIALS
Volume 424, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jhazmat.2021.127268
Keywords
Cadmium; Placentae; Apoptosis; Parkin; MCL-1
Categories
Funding
- National Key Research and Develop-ment Program of China [2020YFA0803900]
- National Natural Science Foundation of China [81973079, 81473016, 81930093]
- Anhui Provincial Natural Science Foundation [2008085J38]
- Academic Fund-ing Project for Top Talents in Colleges and Universities [gxbjZD2020059]
- Young Scholars of Wan Jiang in Anhui Province, Anhui Provincial Academic and Technical Leader Reserve Candidate Research Founding [2020H208]
- Scientific Research Promotion Plan of Anhui Medical University [2020xkjT005]
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Cadmium induces placental apoptosis and FGR via mtROS-mediated Parkin-modulated degradation of MCL-1.
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, miti-gated 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 an-tioxidants, obviously rescued Cd-caused mitochondrial membrane potential (MMP) decrease, Parkin mito-chondrial 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.
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