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

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.