2,5-Hexanedione (HD), the neurotoxic metabolite of methyl n-butyl ketone and n-hexane, causes nerve damage classified as a central-peripheral distal axonopathy. The morphological hallmark of this neuropathy is giant neurofilamentous axonal swellings which have been the focus of substantial mechanistic research. However, other evidence suggests that axonal atrophy is a potentially significant pathogenic event. Studies from this laboratory have demonstrated that in peripheral nerve of HD-treated rats atrophy was a prevalent, route-independent phenomenon that might have functional and mechanistic implications. In contrast, the development of axonal swelling was dependent upon length and route of exposure. It is hypothesized that atrophy is an essential component of gamma-diketone-induced neuropathy and is mediated by reduced perikaryal neurofilament (NF) synthesis and possibly deficient posttranslational NF phosphorylation. The long-term objectives of this research project are to evaluate the neurotoxicological relevance of axonal atrophy and determine the corresponding molecular mechanism. The following Specific Aims are proposed to investigate the role of axonal atrophy in gamma-diketone neurotoxicity: 1). The pharmacokinetic basis of axonal swellings and atrophy will be assessed using two different i.p. dosing rates and measurements of serum HD levels. 2) Studies have been designed to determine whether atrophy is mediated by a reduction in perikaryal NF subunit synthesis. 3). The effects of HD intoxication on NF phosphorylation and phosphate group turnover will be quantitated in dorsal root ganglion and sciatic nerve. If alterations in phosphorylation are observed, we will determine whether this effect is mediated by HD-induced changes in phosphate or kinase activity. The proposed project could provide new information regarding the mechanism of hexacarbon axonopathy. In addition, this proposal might have broad-based implications for other toxic chemicals (acrylamide, carbon disulfide) and disease processes (diabetes) associated with axonal atrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007912-02
Application #
2634342
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (02))
Project Start
1997-01-01
Project End
1999-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
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
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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