Human exposure to dithiocarbamates derives from their many uses in agriculture, industry and medicine. Although the degradative pathways of dithiocarbamates are fairly well understood, there is presently little knowledge regarding the molecular targets and mechanisms underlying the observed biological effects of dithiocarbamates. One of the major decomposition products of dithiocarbamates, CS2, is a known neurotoxicant. The principal objectives of this project are to delineate the potential interactions of dithiocarbamates and their decomposition products within biological systems and to determine both the relevance of these interactions as mechanisms of toxicity and the utility of these interactions as biomarkers of exposure and effect. This investigation is guided by the following working hypotheses: 1) dialkyldithiocarbamates and bis(thiocarbamoyl) disulfides exert neurotoxicity through liberation of carbon disulfide, producing derivatization and cross-linking of proteins; and 2) that covalent modification of proteins by carbon disulfide including dithiocarbamate formation and covalent cross-linking can be used as biomarkers of exposure and effect for dithiocarbamates, bis(thiocarbamoyl) disulfides and CS2. These hypotheses will be tested through determining the morphological changes in the nervous system and the covalent modifications produced on peripheral marker proteins and putative target proteins within the nervous system by bis(thiocabamoyl) disulfides; and through determination of the dose response, sensitivity for detection and the rate of accumulation and elimination of CS2-mediated cross-linking on hemoglobin and dithiocarbamate formation on blood proteins following acute, subacute and chronic exposures to environmentally relevant levels of dithiocarbamates and CS2. Delineation of the molecular mechanisms and the development of valid biomarkers will facilitate the performance of mechanistically based risk assessments and the formulation of structure activity relationships for these widely used compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES006387-05A1S1
Application #
2892694
Study Section
Special Emphasis Panel (ZRG4 (01))
Project Start
1994-01-01
Project End
2001-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Valentine, Holly L; Viquez, Olga M; Valentine, William M (2010) Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury. Toxicology 274:10-7
Viquez, Olga M; Lai, Barry; Ahn, Jae Hee et al. (2009) N,N-diethyldithiocarbamate promotes oxidative stress prior to myelin structural changes and increases myelin copper content. Toxicol Appl Pharmacol 239:71-9
Valentine, Holly L; Viquez, Olga M; Amarnath, Kalyani et al. (2009) Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury. Chem Res Toxicol 22:218-26
Valentine, William M; Abel, Ty W; Hill, Kristina E et al. (2008) Neurodegeneration in mice resulting from loss of functional selenoprotein P or its receptor apolipoprotein E receptor 2. J Neuropathol Exp Neurol 67:68-77
Viquez, Olga M; Valentine, Holly L; Amarnath, Kalyani et al. (2008) Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy. Toxicol Appl Pharmacol 229:77-85
Valentine, Holly L; Does, Mark D; Marshall, Vivian et al. (2007) Multicomponent T2 analysis of dithiocarbamate-mediated peripheral nerve demyelination. Neurotoxicology 28:645-54
Valentine, Holly; Amarnath, Kalyani; Amarnath, Venkataraman et al. (2007) Globin s-propyl cysteine and urinary N-acetyl-S-propylcysteine as internal biomarkers of 1-bromopropane exposure. Toxicol Sci 98:427-35
Viquez, Olga M; Valentine, Holly L; Friedman, David B et al. (2007) Peripheral nerve protein expression and carbonyl content in N,N-diethlydithiocarbamate myelinopathy. Chem Res Toxicol 20:370-9
Valentine, Holly L; Amarnath, Kalyani; Amarnath, Venkataraman et al. (2006) Dietary copper enhances the peripheral myelinopathy produced by oral pyrrolidine dithiocarbamate. Toxicol Sci 89:485-94
Valentine, William M; Hill, Kristina E; Austin, Lori M et al. (2005) Brainstem axonal degeneration in mice with deletion of selenoprotein p. Toxicol Pathol 33:570-6

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