Exposure to acrylamide (ACR) produces ataxia and muscle weakness, which have been presumed to be caused by distal preterminal axon degeneration. However, research conducted during the current funding period has suggested that nerve terminals, and not axons, are primary sites of ACR action. This is in agreement with evidence suggesting that defective neurotransmission and terminal degeneration are early consequences of ACR intoxication. Whereas the nerve terminal might be a pathophysiologically relevant site, the mechanism of damage has not been addressed. Therefore, the goal of this project is to determine how ACR produces nerve terminal dysfunction and degeneration. We hypothesize that ACR impairs membrane fusion processes that mediate presynaptic exocytosis and docking of transport vesicles with nerve terminal plasmalemma. The fusion of opposing membranes is accomplished by formation of SNARE (Soluble NSF attachment protein receptors) core complexes that are subsequently disassembled by the actions of NSF (N-ethylmaleimide sensitive factor). NSF activity is exquisitely sensitive to inhibition by thiol oxidation and such inhibition has been shown to block membrane fusion. We propose that ACR binds to NSF through thiol adduction and that subsequent inhibition of NSF activity is responsible for functional and structural damage to nerve terminals. The following research has been designed to test this hypothesis. (1) Chemical interactions of ACR with different nerve terminals proteins (e.g., NSF, SNAP-25) will be characterized by mass spectroscopy. (2) The site of ACR inhibition within the synaptic vesicle cycle (e.g., docking, fusion, endocytosis) will be identified. (3) Formation of the SNARE core complex will be assessed in ACR-exposed synaptosomes. (4) SNARE core functionality will be determined during ACR exposure. (5) Effects of ACR on NSF-dependent dissolution of the SNARE complex will be examined. The hypothesis that ACR disrupts the SNARE core apparatus is novel. ACR is considered to be prototypical among chemicals that cause toxic neuropathies and, therefore, deciphering the corresponding molecular mechanism could provide insight into neurotoxicant mechanisms. Determining how these chemicals work will provide a rational basis for establishing occupational exposure conditions and for development of efficacious pharmacotherapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003830-20
Application #
7081365
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Lawler, Cindy P
Project Start
1988-08-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
20
Fiscal Year
2006
Total Cost
$285,890
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
041581026
City
New York
State
NY
Country
United States
Zip Code
10467
LoPachin, Richard M; Gavin, Terrence (2016) Reactions of electrophiles with nucleophilic thiolate sites: relevance to pathophysiological mechanisms and remediation. Free Radic Res 50:195-205
Zhang, Lihai; Geohagen, Brian C; Gavin, Terrence et al. (2016) Joint toxic effects of the type-2 alkene electrophiles. Chem Biol Interact 254:198-206
LoPachin, Richard M; Gavin, Terrence (2015) Protein adduct formation initiates acrolein-induced endothelial cell toxicity. Toxicol Sci 144:2-3
Kosharskyy, Boleslav; Vydyanathan, Amaresh; Zhang, Lihai et al. (2015) 2-Acetylcyclopentanone, an enolate-forming 1,3-dicarbonyl compound, is cytoprotective in warm ischemia-reperfusion injury of rat liver. J Pharmacol Exp Ther 353:150-8
LoPachin, Richard M; Gavin, Terrence (2015) Toxic neuropathies: Mechanistic insights based on a chemical perspective. Neurosci Lett 596:78-83
LoPachin, Richard M; Gavin, Terrence (2014) Molecular mechanisms of aldehyde toxicity: a chemical perspective. Chem Res Toxicol 27:1081-91
Zhang, Lihai; Gavin, Terrence; Geohagen, Brian C et al. (2013) Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 346:259-69
Martyniuk, Christopher J; Feswick, April; Fang, Bin et al. (2013) Protein targets of acrylamide adduct formation in cultured rat dopaminergic cells. Toxicol Lett 219:279-87
LoPachin, Richard M; Gavin, Terrence (2012) Molecular mechanism of acrylamide neurotoxicity: lessons learned from organic chemistry. Environ Health Perspect 120:1650-7
Lopachin, Richard M; Gavin, Terrence; Decaprio, Anthony et al. (2012) Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant--target interactions. Chem Res Toxicol 25:239-51

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