Our research (yrs 1-24) has shown that subchronic systemic acrylamide (ACR) exposure causes cumulative neurotoxicity mediated by selective damage of central and peripheral nerve terminals. ACR is an alpha, beta-unsaturated carbonyl derivative of the type-2 alkene chemical class, which includes other structurally related electrophilic chemicals;e.g., acrolein, 4-hydroxy-2-nonenal (HNE) and methyl acrylate (MA). The type- 2 alkenes are prevalent dietary contaminants and environmental pollutants that have significant toxicological consequences. In addition, unsaturated aldehydes such as acrolein and HNE are produced during membrane lipid peroxidation associated with cellular oxidative stress. These endogenous type-2 alkenes appear to play a pathogenic role in many disease processes and traumatic tissue injuries that have oxidative stress as a common molecular etiology;e.g., spinal cord trauma, atherosclerosis and Alzheimer's disease (AD). During the current funding period (yrs 21-24), we demonstrated that the type-2 alkenes cause toxicity through a common mechanism of action;i.e., protein inactivation via formation of Michael-type adducts with nucleophilic sulfhydryl thiolate groups on active site cysteine residues. Therefore, we propose that environmentally-derived type-2 alkene toxicants act either synergistically or additively with endogenously generated unsaturated aldehydes. This interaction could accelerate the onset of the disease/injury process and amplify the extent of cellular damage.
Two specific aims have been designed to investigate the putative interactions of systemically administered toxicants with endogenous neurodegenerative processes in a transgenic mouse model of Alzheimer's disease (AD). Despite the neurocentric focus of these aims, the data and derived concepts are applicable to the type-2 alkene interactions that possibly accelerate certain systemic diseases.
Specific Aim 1 research will test the hypothesis that weak electrophiles of the type-2 alkene chemical class (e.g., ACR, MA) cause cumulative neurotoxicity mediated by nerve terminal dysfunction. This proposal is novel and is consistent with the differential CNS accessibility of weak, but not strong, electrophiles and the unique vulnerability of nerve terminals to electrophili attack. The results have significant implications for how we consider electrophilic environmental toxicants and evaluate their neurotoxic risk potential.
Specific Aim 2 studies will investigate the possibility that weak electrophiles such as ACR and MA administered systemically can interact with endogenously generated type-2 alkenes to accelerate ongoing neurodegenerative processes in the Tg2576 mouse model of AD. This toxicologically plausible proposal could provide a conceptual framework for molecular-level investigations of other disease processes that have suspected environmental components, such as Parkinson's disease (PD) and atherosclerosis. Our research during the current funding period also showed that 2-acetylcyclopentanone and other nucleophilic 1,3-dicarbonyl enols could prevent oxidative stress-induced toxicity in vitro. Consequently, Specific Aim 3 studies will determine the relative abilities of these enols to modify the onset and development of neurodegenerative processes in Tg2576 mice. Pharmacotherapeutic approaches based on 1,3-dicarbonyl enol chemistry might improve management of numerous human disease processes that involve cellular oxidative stress. This cytoprotection could include inhibition of both the endogenous disease process and the exacerbating actions of exogenous type-2 alkenes. Furthermore, most toxic environmental chemicals or their active metabolites are electrophiles (e.g., acrolein, ACR, methyl mercury) that produce cytotoxicity by reacting with nucleophilic targets on macromolecules. The 1,3-dicarbonyl compounds, through their actions as surrogate nucleophiles, could prevent or minimize damage associated with environmentally acquired type-2 alkene toxicity.

Public Health Relevance

The type-2 alkenes constitute a class of chemicals that includes acrylamide, acrolein and other alpha, beta - unsaturated aldehyde, carbonyl and ester derivatives. Members of this class are prevalent environmental and dietary contaminants with substantial toxicological implications. In addition, acrolein, 4-hydroxy-2-nonenal and related unsaturated aldehydes are highly toxic by-products of cellular oxidative stress associated with many disease processes and traumatic states;e.g., Alzheimer's disease, spinal cord injury. Based on a common mechanism of toxicity that involves protein inactivation through amino acid residue binding, we propose that type-2 alkenes present in pollution, diet and cigarette smoke can conspire with endogenously produced class members to accelerate the disease or tissue injury process. The possibility that environmental toxicants can influence pathogenic processes is, therefore, a critical human health issue that requires investigation. Also critical is the development of pharmacotherapeutic approaches that address interactions between the environment and basic disease/injury mechanisms. During the current funding period we showed that a series of nucleophilic (electron rich) 1,3-dicarbonyl enols (e.g., 2-aceytlcyclopentanone) could bind (scavenge) type-2 alkene electrophiles (electron deficient) and thereby prevent in vitro toxicity. We therefore propose research to determine whether 1,3-dicarbonyl compounds can prevent the interactions of environmental type-2 alkenes with endogenous pathogenic processes.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-IFCN-A (02))
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Lawler, Cindy P
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Albert Einstein College of Medicine
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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
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 (2015) Protein adduct formation initiates acrolein-induced endothelial cell toxicity. Toxicol Sci 144:2-3
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; 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
LoPachin, Richard M; Gavin, Terrence (2012) Molecular mechanism of acrylamide neurotoxicity: lessons learned from organic chemistry. Environ Health Perspect 120:1650-7

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