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.

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

“…previous studies demonstrated that BPA exposure inhibits NSC proliferation and differentiation and also causes neurodegeneration in the hippocampus (1)(2)(3). In the present study, we found increased mitochondrial fission, increased oxidative stress, and apoptosis.…”

“…Hippocampal NSC Culture-Hippocampus-derived NSC culture was carried out following our previous studies (2,3,62). Briefly, pregnant Wistar rats were deeply anesthetized with a mixture of ketamine and xylazine (3:1 ratio) and dissected cautiously to remove the embryos at embryonic day 12.…”

“…Fluorescent images were acquired using an inverted fluorescent microscope. The quantification of proliferating and differentiating cells was carried out following our previously published studies (2,3,62,68). Co-localization of Drp-1 and TOMM20, in terms of % Drp-1 mitochondrial translocation was quantified using ImageJ (National Institutes of Health) employing the JACoP plugin (1, 69).…”

“…Bisphenol A (BPA), 3 a synthetic xenoestrogen and neurotoxicant, is one of the most widely used chemical components among the human population worldwide. The extensive usage of BPA in the manufacturing of plastic packaging materials and its release inside the food because of the alteration in the physiological conditions and consequential health hazards are some issues that need to be addressed.…”

“…Our recent study suggests that the adverse consequences of BPA vary with the duration of its exposure, such as activation of autophagic flux takes place after the transient exposure of BPA in the hippocampus region of the rat brain to ameliorate its neurotoxicity (1). Contrarily, prolonged and chronic exposure of BPA impairs autophagy as well as neurogenesis in the hippocampus, leading to neurodegeneration and cognitive impairments (1)(2)(3). Several studies have reported the association between toxic effects of BPA and pathogenesis of neurodegenerative disorders and other diseases (4 -7).…”