Abstract
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.
Highlights
The effects of xenoestrogen bisphenol-A on autophagy, and association with oxidative stress and apoptosis are still elusive
Effects of BPA on Cell Viability and Neurodegeneration in the Hippocampus—We assessed the effects of BPA at various concentrations (25, 50, 100, 200, and 400 M) on the viability of hippocampal neural stem cells (NSC)-derived neurons by trypan blue and propidium iodide (PI) uptake through flow cytometry (Fig. 1, A and B)
These results suggest that BPA caused apoptosis and enhanced neuronal degeneration in the hippocampus
Summary
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. Autophagy and apoptosis work in a coordinated manner to regulate cell survival and death (24 –26) Several conditions, such as starvation, toxicant exposure, and mechanical injury, result in the generation of ROS and concomitant accumulation of damaged mitochondria and misfolded proteins inside the cells. We studied the effects of BPA exposure on autophagy in vitro hippocampal neural stem cells (NSC)-derived neurons and in the hippocampus region (crucial region for learning and memory regulation) of the rat brain. We elucidated the molecular mechanism(s) underlying the AMPK pathway activation and mTOR down-regulation in response to BPA exposure. The decline in ATP levels after BPA exposure activates AMPK to preserve the cellular energy pool by inhibiting the anabolic processes while turning on the catabolic pathways. Our studies delineate that autophagy acts as a transient cellular protective response against BPAinduced neurotoxicity
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