title: Bisphenol-A Mediated Inhibition of Hippocampal Neurogenesis Attenuated by Curcumin via Canonical Wnt Pathway.
abstract: Bisphenol A (BPA) is an environmental xenoestrogenic endocrine disruptor, utilized for production of consumer products, and exerts adverse effects on the developing nervous system. Recently, we found that BPA impairs the finely tuned dynamic processes of neurogenesis (generation of new neurons) in the hippocampus of the developing rat brain. Curcumin is a natural polyphenolic compound, which provides neuroprotection against various environmental neurotoxicants and in the cellular and animal models of neurodegenerative disorders. Here, we have assessed the neuroprotective efficacy of curcumin against BPA-mediated reduced neurogenesis and the underlying cellular and molecular mechanism(s). Both in vitro and in vivo studies showed that curcumin protects against BPA-induced hippocampal neurotoxicity. Curcumin protects against BPA-mediated reduced neural stem cells (NSC) proliferation and neuronal differentiation and enhanced neurodegeneration. Curcumin also enhances the expression/levels of neurogenic and the Wnt pathway genes/proteins, which were reduced due to BPA exposure in the hippocampus. Curcumin-mediated neuroprotection against BPA-induced neurotoxicity involved activation of the Wnt/β-catenin signaling pathway, which was confirmed by the use of Wnt specific activators (LiCl and GSK-3β siRNA) and inhibitor (Dkk-1). BPA-mediated increased β-catenin phosphorylation, decreased GSK-3β levels, and β-catenin nuclear translocation were significantly reversed by curcumin, leading to enhanced neurogenesis. Curcumin-induced protective effects on neurogenesis were blocked by Dkk-1 in NSC culture treated with BPA. Curcumin-mediated enhanced neurogenesis was correlated well with improved learning and memory in BPA-treated rats. Overall, our results conclude that curcumin provides neuroprotection against BPA-mediated impaired neurogenesis via activation of the Wnt/β-catenin signaling pathway.
authors.affiliation: Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow, 226001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: Shashi Kant
authors.initials: SK
authors.lastname: Tiwari
authors.affiliation: Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow, 226001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Food, Drugs and Chemical Toxicology Group, CSIR-IITR, 80 MG Marg, Lucknow, 226001, India.
authors.forename: Anurag
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow, 226001, India. rajnish@iitr.res.in.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. rajnish@iitr.res.in.
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D005260:Female; D055785:Gene Knockdown Techniques; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008568:Memory / Q000187:drug effects; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D000066829:Neuroprotection / Q000187:drug effects; D010636:Phenols / Q000633:toxicity*; D017208:Rats, Wistar; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D003474:Curcumin; D000071679:Glycogen Synthase Kinase 3 beta; D010636:Phenols; D051176:beta Catenin; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Bisphenol A (BPA); Curcumin; Hippocampus; Neural stem cells (NSC); Neurogenesis; Neuroprotection; Neurotoxicity; Wnt/β-catenin signaling pathway