title: Role of the Nrf2-ARE pathway in acrylamide neurotoxicity.
abstract: Acrylamide (ACR) intoxication is associated with selective nerve terminal damage in the central and peripheral nervous systems. As a soft electrophile, ACR could form adducts with nucleophilic sulfhydryl groups on cysteine residues of kelch-like erythroid cell-derived protein with CNS homology-associated protein 1 (Keap1) leading to dissociation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 activation of the antioxidant-responsive element (ARE) and subsequent upregulated gene expression of phase II detoxification enzymes and anitoxidant proteins might provide protection in neuronal regions with transcriptional capabilities (e.g., cell body). In contrast, non-transcriptional cell regions (axons, nerve terminals) might be vulnerable to electrophile-induced damage. To test this possibility, immunoblot analysis was used to measure protein products of Nrf2-activated ARE genes in nerve terminals and in cytosolic/nuclear factions of neuronal cell bodies isolated from rats intoxicated at two different ACR dose-rates; i.e., 50mg/kg/d×10 days, 21mg/kg/d×38 days. To detect possible differences in cell-specific induction, the cytoprotective response to ACR intoxication was determined in hepatic cells. Results show that control brain and hepatic cell fractions exhibited distinct subcellular distributions of Nrf2, Keap1 and several ARE protein products. ACR intoxication, however, did not alter the levels of these proteins in synaptosomal, brain cytoplasm or liver cell fractions. These data indicate that ACR was an insufficient electrophilic signal for ARE induction in all subcellular fractions tested. Because a cytoprotective response was not induced in any fraction, nerve terminal vulnerability to ACR cannot be ascribed to the absence of transcription-based defense mechanisms in this neuronal region.
authors.affiliation: Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10467-2490, United States.
authors.forename: Lihai
authors.initials: L
authors.lastname: Zhang
authors.forename: Terrence
authors.initials: T
authors.lastname: Gavin
authors.forename: David S
authors.initials: DS
authors.lastname: Barber
authors.forename: Richard M
authors.initials: RM
authors.lastname: LoPachin
mesh_terms: D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002469:Cell Separation; D002498:Centrifugation; D004591:Electrophoresis, Polyacrylamide Gel; D022781:Hepatocytes / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D009411:Nerve Endings / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013574:Synaptosomes / Q000378:metabolism / Q000502:physiology
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011506:Proteins; D020106:Acrylamide