Exposure of humans and laboratory animals to acrylamide (ACR) produces cumulative neurotoxicity characterized by gait abnormalities, muscle weakness and a central-peripheral neuropathy. ACR is an 1,2-unsaturated carbonyl derivative and is classified as a type-2 alkene. This is a large class of electrophilic chemicals that have broad industrial, agricultural and pharmaceutical uses. These chemicals are also well-recognized dietary contaminants and environmental pollutants. Data collected during yrs. 17-20 have provided evidence that ACR impairs nerve terminal function by forming irreversible covalent adducts with nucleophilic sulfhydryl groups on functionally important proteins. Proteomic analyses indicate that the protein targets of ACR and the type-2 alkenes are also acceptors for nitric oxide (NO) signaling. NO is a biological electrophile and has been classically thought to influence cell processes through guanylyl cyclase activation. However, NO can also modulate cell physiology by forming reversible adducts with cysteine thiolates in protein catalytic triads. At the nerve terminal, NO signaling is critically involved in neurotransmission through modulation of the synaptic vesicle cycle and other presynaptic processes. Thus, NO and ACR interact at common cysteine sulfhydryl sites and, therefore, we hypothesize that irreversible adduction of these receptors by ACR blocks reversible NO binding. The disruption of NO signaling and ensuing loss of neuromodulatory control produces presynaptic toxicity. Therefore, Specific Aim #1 research will define the interactions of ACR with the S-nitrosylated (SNO) proteome of CNS nerve terminals. SNOSID (S-nitrosylated site identification) proteomic analysis will be used to demonstrate ACR adduction of SNO-cysteine sites on nerve terminal proteins.
Specific Aim #2 studies will evaluate the specificity of the ACR-NO interaction by considering alternative mechanisms of action;i.e., we will determine the effects of ACR on soluble quanylyl cyclase and nitric oxide synthase (NOS) activity/gene expression. Because NO modulates physiological processes in most cells, it is unclear why nerve terminal NO signaling might be selectively targeted by ACR. Therefore, Specific Aim #3 studies will consider several anatomical and molecular features that might predispose nerve terminals to electrophilic attack. Identifying the mechanism of ACR neurotoxicity could offer global insight regarding the toxicological processes of other type-2 alkenes. Results of the proposed research could also help us understand the pathogenesis of Alzheimer's disease (AD) and other chronic neurodegenerative conditions that presumably involve cellular oxidative stress and endogenous generation of acrolein and other type-2 alkenes.

Public Health Relevance

Human exposure to conjugated type-2 alkenes (e.g., acrylamide, methyl acrylate, methylvinyl ketone) occurs through pervasive environmental sources (e.g., industrial exposure, cigarette smoking, car exhaust, combustion, pharmaceuticals) and can result in significant toxicity in nervous tissue and other organ systems (liver, kidney). There is also evidence that endogenous production of type-2 alkenes (e.g., acrolein, 2-hydryoxy-4-nonenal) is critically involved in mediating nerve cell injury associated with accidental neurotrauma and certain human neurodegenerative conditions such as Alzheimer's disease. Therefore, the proposed studies of type-2 alkene neurotoxicity could lead to a better understanding of brain injuries caused by environmental toxicant exposure or disease processes, which would ultimately help in the development of effective therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003830-23
Application #
7848369
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Lawler, Cindy P
Project Start
2008-08-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
23
Fiscal Year
2010
Total Cost
$297,094
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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