Abstract
The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU- and β-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPA-mediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus.
Highlights
Bisphenol A (BPA),3 a synthetic xenoestrogen and neurotoxicant, is one of the most widely used chemical components among the human population worldwide
We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs)
These results suggest that chronic exposure of BPA during gestational, lactational, and adulthood periods reduces autophagy, resulting in increased oxidative stress and apoptosis in the hippocampus
Summary
Bisphenol A (BPA),3 a synthetic xenoestrogen and neurotoxicant, is one of the most widely used chemical components among the human population worldwide. Drp-1 Is Involved in the Regulation of BPA-induced Mitochondrial Fragmentation, Apoptosis, and Decrease in Hippocampal NSC Neuronal Differentiation—The mitochondrial dysfunction impairs mitochondrial dynamics, thereby disrupting the fusion-fission equilibrium inside the cells [14, 15, 23]. Quantification of number of BrdU/-III tubulin co-labeled cells suggests that Drp-1 inhibition significantly increased neuronal differentiation in BPA-treated NSC cultures.
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