Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways

• Published in: The Journal of biological chemistry Vol. 290; no. 34; pp. 21163 - 21184
• Main Authors: Agarwal, Swati, Tiwari, Shashi Kant, Seth, Brashket, Yadav, Anuradha, Singh, Anshuman, Mudawal, Anubha, Chauhan, Lalit Kumar Singh, Gupta, Shailendra Kumar, Choubey, Vinay, Tripathi, Anurag, Kumar, Amit, Ray, Ratan Singh, Shukla, Shubha, Parmar, Devendra, Chaturvedi, Rajnish Kumar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.08.2015; American Society for Biochemistry and Molecular Biology
• Subjects: AMP-Activated Protein Kinase Kinases; Androstadienes - pharmacology; Animals; Animals, Newborn; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; Autophagy - genetics; Beclin-1; Benzhydryl Compounds - antagonists & inhibitors; Benzhydryl Compounds - toxicity; Environmental Pollutants - antagonists & inhibitors; Environmental Pollutants - toxicity; Gene Expression Regulation; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Humans; Macrolides - pharmacology; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; neural stem cell (NSC); Neurobiology; neurodegeneration; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Oxidative Stress; Phenols - antagonists & inhibitors; Phenols - toxicity; Primary Cell Culture; Protein Kinases - genetics; Protein Kinases - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Sequestosome-1 Protein; Signal Transduction; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; toxicology; Wortmannin; xenobiotic; toxicology; neurodegeneration; hippocampus; xenobiotic; neural stem cell (NSC)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.648998

The human health hazards related to persisting use of bisphenol-A (BPA) are well documented. BPA-induced neurotoxicity occurs with the generation of oxidative stress, neurodegeneration, and cognitive dysfunctions. However, the cellular and molecular mechanism(s) of the effects of BPA on autophagy and association with oxidative stress and apoptosis are still elusive. We observed that BPA exposure during the early postnatal period enhanced the expression and the levels of autophagy genes/proteins. BPA treatment in the presence of bafilomycin A1 increased the levels of LC3-II and SQSTM1 and also potentiated GFP-LC3 puncta index in GFP-LC3-transfected hippocampal neural stem cell-derived neurons. BPA-induced generation of reactive oxygen species and apoptosis were mitigated by a pharmacological activator of autophagy (rapamycin). Pharmacological (wortmannin and bafilomycin A1) and genetic (beclin siRNA) inhibition of autophagy aggravated BPA neurotoxicity. Activation of autophagy against BPA resulted in intracellular energy sensor AMP kinase (AMPK) activation, increased phosphorylation of raptor and acetyl-CoA carboxylase, and decreased phosphorylation of ULK1 (Ser-757), and silencing of AMPK exacerbated BPA neurotoxicity. Conversely, BPA exposure down-regulated the mammalian target of rapamycin (mTOR) pathway by phosphorylation of raptor as a transient cell's compensatory mechanism to preserve cellular energy pool. Moreover, silencing of mTOR enhanced autophagy, which further alleviated BPA-induced reactive oxygen species generation and apoptosis. BPA-mediated neurotoxicity also resulted in mitochondrial loss, bioenergetic deficits, and increased PARKIN mitochondrial translocation, suggesting enhanced mitophagy. These results suggest implication of autophagy against BPA-mediated neurodegeneration through involvement of AMPK and mTOR pathways. Hence, autophagy, which arbitrates cell survival and demise during stress conditions, requires further assessment to be established as a biomarker of xenoestrogen exposure. Background: The effects of xenoestrogen bisphenol-A on autophagy, and association with oxidative stress and apoptosis are still elusive. Results: Transient activation of autophagy protects against bisphenol-A-induced neurodegeneration via AMPK activation and mTOR down-regulation. Conclusion: Autophagy induction against bisphenol-A is an early cell's tolerance response. Significance: Autophagy provides an imperative biological marker for evaluation of neurotoxicity by xenoestrogen.