title: Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation.
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.
authors.affiliation: From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and.
authors.forename: Swati
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Yadav
authors.affiliation: From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and.
authors.forename: Shashi Kant
authors.initials: SK
authors.lastname: Tiwari
authors.affiliation: From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and.
authors.forename: Brashket
authors.initials: B
authors.lastname: Seth
authors.affiliation: the Central Instrumentation Facility, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.
authors.forename: Lalit Kumar Singh
authors.initials: LK
authors.lastname: Chauhan
authors.affiliation: From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and.
authors.forename: Puneet
authors.initials: P
authors.lastname: Khare
authors.affiliation: the Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group.
authors.forename: Ratan Singh
authors.initials: RS
authors.lastname: Ray
authors.affiliation: From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and rajnish@iitr.res.in itrcrajnish@gmail.com.
authors.forename: Rajnish Kumar
authors.identifier: 0000-0001-9591-7636
authors.initials: RK
authors.lastname: Chaturvedi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D034281:Dynamins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D010636:Phenols / Q000633:toxicity*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000098826:Bisphenol A Compounds
chemical_list: D000255:Adenosine Triphosphate; D001559:Benzhydryl Compounds; D034281:Dynamins; D010636:Phenols; C519851:Dnm1l protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Mitochondrial dynamics; hippocampus; mitochondria; mitophagy; neural stem cell (NSC); neurodegeneration; neurogenesis; neurotoxicity; neurotoxin; xenobiotic