2,5-Hexanedione (HD), the neurotoxic diketone metabolite of the industrial solvents methyl n-butyl ketone and n-hexane, causes a toxic neuropathy in occupationally exposed humans. Although axonal swellings have been considered the morphological hallmark, recent quantitative morphometric studies show that axon atrophy is a specific, prevalent effect that is temoporally correlated to the development of neurological defects. These findings suggest that atrophy is an essential pathophysiological component of diketone- induced neurotoxicity. The long-term objectives of this research project are to determine the molecular mechanism of axon atrophy. Studies conducted during the current funding period (yrs 04-07) indicated that HD intoxication of rats was associated with a depletion of mobile neurofilament (NF) proteins. This effect did not involve changes in NF phosphorylation or subunit gene expression. Since HD forms pyrrole adducts with NFs, we hypothesize that adduction interferes with the ability of mobile NFs to interact with the stationary cytoskeleton polymer. As a result, the subunit remains attached to the transport vector kinesin, which in the absence of compensatory changes in protein synthesis, promotes anterograde loss of NF subunits. Atrophy occurs due to depletion of the mobile NF pool and to the ensuing impairment of cytoskeletal turnover. This hypothesis will be tested by the following Specific Aims: 1) Mass spectrometry will be used to characterize HD-induced pyrrole formation in the stationary and mobile NF pools. 2) The effects of pyrrole formation on NF subunit kinesin-based transport, assembly and cytoskeletal incorportation will be determined. 3) The content and spatial relationships among cytoskeletal elements (NFs, microtubules) will be quantified in peripheral myelinated axons of HD-intoxicated rats and age-matched controls. 4) The ability of HD structural analogs (e.g., 3,4-dimethyl 2,5-HD) to predictably alter proteomic, morphological and biochemical parameters will be evaluated. Understanding the role and mechanism of axon atrophy in solvent neurotoxicity has broad-based implications for human occupational health and risk assessment.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Lawler, Cindy P
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Montefiore Medical Center (Bronx, NY)
New York
United States
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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
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 (2015) Toxic neuropathies: Mechanistic insights based on a chemical perspective. Neurosci Lett 596:78-83
LoPachin, Richard M; Gavin, Terrence (2012) Molecular mechanism of acrylamide neurotoxicity: lessons learned from organic chemistry. Environ Health Perspect 120:1650-7
Zhang, Lihai; Gavin, Terrence; DeCaprio, Anthony P et al. (2010) Gamma-diketone axonopathy: analyses of cytoskeletal motors and highways in CNS myelinated axons. Toxicol Sci 117:180-9
DeCaprio, Anthony P; Kinney, Elizabeth A; LoPachin, Richard M (2009) Comparative covalent protein binding of 2,5-hexanedione and 3-acetyl-2,5-hexanedione in the rat. J Toxicol Environ Health A 72:861-9
LoPachin, Richard M; Gavin, Terrence; Petersen, Dennis R et al. (2009) Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity: nucleophilic targets and adduct formation. Chem Res Toxicol 22:1499-508
Lopachin, Richard M; Jortner, Bernard S; Reid, Maria L et al. (2005) gamma-Diketone central neuropathy: quantitative analyses of cytoskeletal components in myelinated axons of the rat rubrospinal tract. Neurotoxicology 26:1021-30
LoPachin, Richard M; He, Deke; Reid, Maria L (2005) 2,5-Hexanedione-induced changes in the neurofilament subunit pools of rat peripheral nerve. Neurotoxicology 26:229-40
LoPachin, Richard M; He, Deke; Reid, Maria L et al. (2004) 2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions. Toxicol Appl Pharmacol 198:61-73

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