Abstract
Bisphenol A (BPA) is an environmental contaminant widely suspected to be a neurological toxicant. Epidemiological studies have demonstrated close links between BPA exposure, pathogenetic brain degeneration, and altered neurobehaviors, considering BPA a risk factor for cognitive dysfunction. However, the mechanisms of BPA resulting in neurodegeneration remain unclear. Herein, cultured N2a neurons were subjected to BPA treatment, and neurotoxicity was assessed using neuronal viability and differentiation assays. Signaling cascades related to cellular self-degradation were also evaluated. BPA decreased cell viability and axon outgrowth (e.g., by down-regulating MAP2 and GAP43), thus confirming its role as a neurotoxicant. BPA induced neurotoxicity by down-regulating Bcl-2 and initiating apoptosis and autophagy flux inhibition (featured by nuclear translocation of apoptosis-inducing factor (AIF), light chain 3B (LC3B) aggregation, and p62 accumulation). Both heme oxygenase (HO)-1 and AMP-activated protein kinase (AMPK) up-regulated/activated by BPA mediated the molecular signalings involved in apoptosis and autophagy. HO-1 inhibition or AIF silencing effectively reduced BPA-induced neuronal death. Although BPA elicited intracellular oxygen free radical production, ROS scavenger NAC exerted no effect against BPA insults. These results suggest that BPA induces N2a neurotoxicity characterized by AIF-dependent apoptosis and p62-related autophagy defects via HO-1 up-regulation and AMPK activation, thereby resulting in neuronal degeneration.
Highlights
Bisphenol A (BPA) is a common endocrine-disrupting chemical widely used in the manufacture of polycarbonate plastics and epoxy resins, and people inevitably come into contact with it in daily life [1,2,3,4]
Our results suggest that heme oxygenase (HO)-1 selectively induced by BPA plays a key role in mediating BPA toxicity in N2a neurons via apoptosis-inducing factor (AIF)-driven apoptosis, increased autophagic flux, AMPK activation, and Bcl-2 down-regulation
The detectable distribution of this substance in the brain and cerebrospinal fluid indicates that the blood–brain barrier does not limit the access of lipophilic BPA to the brain
Summary
Bisphenol A (BPA) is a common endocrine-disrupting chemical widely used in the manufacture of polycarbonate plastics and epoxy resins, and people inevitably come into contact with it in daily life [1,2,3,4]. The mechanisms accounting for the neurotoxic BPA effects on brain development and AD-related neurodegeneration remain largely unknown. Apoptosis and autophagy are two major modes of cellular self-degradation that play an important role in brain neurogenesis and neurodegeneration [12,13]. The effect of HO-1 on the modulation of apoptosis and autophagy in the context of BPA-induced neurotoxicity is unknown. Emerging evidence suggests the potential involvement of AMPK in controlling neural cell survival and death via regulating autophagy and apoptosis [25,26,27,28]. AMPK modulation of autophagy and apoptosis in BPA-induced neurotoxicity has not been clarified and, requires further investigation. We found that BPA induces N2a neurotoxicity characterized by p62 accumulation-related autophagy flux inhibition and apoptosis-inducing factor (AIF)-driven apoptosis through HO-1 up-regulation and AMPK activation.
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