William M. Valentine, D.V.M, , Ph.D.
Associate Professor of Pathology
Vanderbilt University Medical Center
1161 21st Ave, C-3321A MCN
Nashville, TN 37232-2561
Mechanisms of Environmental Neurotoxicants and Neurodegenerative Disease
Parkinson disease (PD) is the second most common neurodegenerative disease and the prevalence of PD is predicted to double in the US and more than double in developing countries during the next 25 years; however a definite etiology or unifying sequence of molecular events for the most common form of PD, late onset sporadic idiopathic PD, has not been established. Because a growing number of epidemiological studies have associated an increased risk for PD with various conditions, environmental factors must be considered as a risk for PD. The goal of our research is to identify mechanisms of environmental agents that contribute to increased risk for PD. We are currently investigating whether four classes of pesticides, that have established human exposure, can impair ubiquitin based protein processing and cell signaling that promotes neurodegenerative changes contributing to PD. Animal models are being used to determine whether these pesticides inhibit E1 activating enzyme through a common mechanism in vivo leading to nigrostriatal and extra nigral toxicity. These studies are determining the dose-response for changes in brain E1 enzyme activity, characterizing E1 covalent modifications by shotgun LC/MS/MS, mapping neurodegenerative changes both in the nigral striatal pathway and in potentially more sensitive nonmotor brain regions and enteric ganglia involved in PD using immunohistochemistry and silver degeneration staining. In vitro systems are being used to ascertain the cause and effect relationship for ubiquitin pathway inhibition and dopaminergic cell death through determining the influence of constitutively compromised and increased E1 function on viability and the localization and expression of the dopamine transporter and activation of the Cdk5 complex in differentiated MN9D cells exposed to either the proposed pesticides, their metabolites or specific pharmacologic E1 inhibitors. We believe that the mechanistic data and structure activity relationships derived from these studies will assist in the formulation of more informed risk management for the large population exposed to these agents and will facilitate strategies of intervention to decrease the risk of PD and slow the progression of disease in PD patients.
- Caito, SW, Milatovic, D, Hill, KE, Aschner, M, Burk, RF, Valentine, WM Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted. Brain Res, 13981-12, 2011.
- Dortch, RD, Apker, GA, Valentine, WM, Lai, B, Does, MD Compartment-specific enhancement of white matter and nerve ex vivo using chromium. Magn Reson Med, 64(3), 688-97, 2010.
- Dula, AN, Gochberg, DF, Valentine, HL, Valentine, WM, Does, MD Multiexponential T2, magnetization transfer, and quantitative histology in white matter tracts of rat spinal cord. Magn Reson Med, 63(4), 902-9, 2010.
- Valentine, HL, Viquez, OM, Valentine, WM Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury. Toxicology, 274(1-3), 10-7, 2010.
- Viquez, OM, Lai, B, Ahn, JH, Does, MD, Valentine, HL, Valentine, WM N,N-diethyldithiocarbamate promotes oxidative stress prior to myelin structural changes and increases myelin copper content. Toxicol Appl Pharmacol, 239(1), 71-9, 2009.
- Valentine, HL, Viquez, OM, Amarnath, K, Amarnath, V, Zyskowski, J, Kassa, EN, Valentine, WM Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury. Chem Res Toxicol, 22(1), 218-26, 2009.
- Viquez, OM, Valentine, HL, Amarnath, K, Milatovic, D, Valentine, WM Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy. Toxicol Appl Pharmacol, 229(1), 77-85, 2008.
- Valentine, WM, Abel, TW, Hill, KE, Austin, LM, Burk, RF Neurodegeneration in mice resulting from loss of functional selenoprotein p or its receptor apolipoprotein e receptor 2. J Neuropathol Exp Neurol, 67(1), 68-77, 2008.
- Valentine, H, Amarnath, K, Amarnath, V, Li, W, Ding, X, Valentine, WM, Ichihara, G Globin S-Propyl Cysteine and Urinary N-Acetyl-S-Propyl Cysteine as Internal Biomarkers of 1-Bromopropane Exposure. Toxicol Sci, 2007.
- Valentine, HL, Does, MD, Marshall, V, Tonkin, EG, Valentine, WM Multicomponent T(2) analysis of dithiocarbamate-mediated peripheral nerve demyelination. Neurotoxicology, 2007.
- Viquez, OM, Valentine, HL, Friedman, DB, Olson, SJ, Valentine, WM Peripheral nerve protein expression and carbonyl content in N,N-diethlydithiocarbamate myelinopathy. Chem Res Toxicol, 20(3), 370-9, 2007.
- Valentine, HL, Amarnath, K, Amarnath, V, Valentine, WM Dietary copper enhances the peripheral myelinopathy produced by oral pyrrolidine dithiocarbamate. Toxicol Sci, 89(2), 485-94, 2006.
- Valentine, WM, Hill, KE, Austin, LM, Valentine, HL, Goldowitz, D, Burk, RF Brainstem axonal degeneration in mice with deletion of selenoprotein p. Toxicol Pathol, 33(5), 570-6, 2005.
- Sills, RC, Harry, GJ, Valentine, WM, Morgan, DL Interdisciplinary neurotoxicity inhalation studies: Carbon disulfide and carbonyl sulfide research in F344 rats. Toxicol Appl Pharmacol, 207(2 Suppl), 245-50, 2005.
- Zimmerman, Lisa J, Valentine, Holly L, Valentine, William M Characterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the Rat. Chem Res Toxicol, 17(2), 258-67, 2004.
- Tonkin, EG, Valentine, HL, Milatovic, DM, Valentine, WM N,N-diethyldithiocarbamate produces copper accumulation, lipid peroxidation, and myelin injury in rat peripheral nerve. Toxicol Sci, 81(1), 160-71, 2004.
- Ichihara, G, Li, W, Shibata, E, Ding, X, Wang, H, Liang, Y, Peng, S, Itohara, S, Kamijima, M, Fan, Q, Zhang, Y, Zhong, E, Wu, X, Valentine, WM, Takeuchi, Y Neurologic abnormalities in workers of a 1-bromopropane factory. Environ Health Perspect, 112(13), 1319-25, 2004.
- Kapil Amarnath, Venkataraman Amarnath, Kalyani Amarnath, Holly L. Valentine and William M. Valentine "A specific HPLC-UV method for the determination of cysteine and related aminothiols in biological samples." Talanta, 601229-1238, 2003.
- Amarnath, K, Amarnath, V, Amarnath, K, Valentine, HL, Valentine, WM A specific HPLC-UV method for the determination of cysteine and related aminothiols in biological samples. Talanta, 60(6), 1229-38, 2003.
- Nickols, JC, Valentine, W, Kanwal, S, Carter, BD Activation of the transcription factor NF-kappaB in Schwann cells is required for peripheral myelin formation. Nat Neurosci, 6(2), 161-7, 2003.
- Johnson, D J, Amarnath, V, Amarnath, K, Valentine, H, Valentine, W M Characterizing the influence of structure and route of exposure on the disposition of dithiocarbamates using toluene-3,4-dithiol analysis of blood and urinary carbon disulfide metabolites. Toxicol Sci, 76(1), 65-74, 2003.
- Thompson, Rodney W, Valentine, Holly L, Valentine, William M Cytotoxic mechanisms of hydrosulfide anion and cyanide anion in primary rat hepatocyte cultures. Toxicology, 188149-59, 2003.
- Tonkin, Elizabeth G, Valentine, Holly L, Zimmerman, Lisa J, Valentine, William M Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation. Toxicol Appl Pharmacol, 189139-50, 2003.
- Zimmerman, Lisa J, Valentine, Holly S, Amarnath, Kalyani, Valentine, William M Identification of a S-hexahydro-1H-azepine-1-carbonyl adduct produced by molinate on rat hemoglobin beta(2) and beta(3) chains in vivo. Chem Res Toxicol, 15209-17, 2002.
- Thompson, Rodney W, Valentine, Holly L, Valentine, William M In vivo and in vitro hepatotoxicity and glutathione interactions of N-methyldithiocarbamate and n,n-dimethyldithiocarbamate in the rat. Toxicol Sci, 70269-80, 2002.
- Amarnath, V, Amarnath, K, Graham, D G, Qi, Q, Valentine, H, Zhang, J, Valentine, W M Identification of a new urinary metabolite of carbon disulfide using an improved method for the determination of 2-thioxothiazolidine-4-carboxylic acid. Chem Res Toxicol, 141277-83, 2001.
- Erve, J C, Jensen, O N, Valentine, H S, Amarnath, V, Valentine, W M Disulfiram generates a stable N,N-diethylcarbamoyl adduct on Cys-125 of rat hemoglobin beta-chains in vivo. Chem Res Toxicol, 13237-44, 2000.
- Tonkin, E G, Erve, J C, Valentine, W M Disulfiram produces a non-carbon disulfide-dependent schwannopathy in the rat. J Neuropathol Exp Neurol, 59786-97, 2000.