William Valentine
Last active: 2/15/2016


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.


The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. The microstructural correlates of T1 in white matter. Harkins KD, Xu J, Dula AN, Li K, Valentine WM, Gochberg DF, Gore JC, Does MD (2016) Magn Reson Med 75(3): 1341-5
    › Primary publication · 25920491 (PubMed) · PMC4624612 (PubMed Central)
  2. A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress. Kraemer BR, Snow JP, Vollbrecht P, Pathak A, Valentine WM, Deutch AY, Carter BD (2014) J Biol Chem 289(31): 21205-16
    › Primary publication · 24939843 (PubMed) · PMC4118083 (PubMed Central)
  3. In-vivo multi-exponential T2, magnetization transfer and quantitative histology in a rat model of intramyelinic edema. Harkins KD, Valentine WM, Gochberg DF, Does MD (2013) Neuroimage Clin : 810-7
    › Primary publication · 24179832 (PubMed) · PMC3777678 (PubMed Central)
  4. Electrophilic adduction of ubiquitin activating enzyme E1 by N,N-diethyldithiocarbamate inhibits ubiquitin activation and is accompanied by striatal injury in the rat. Viquez OM, Caito SW, McDonald WH, Friedman DB, Valentine WM (2012) Chem Res Toxicol 25(11): 2310-21
    › Primary publication · 22874009 (PubMed) · PMC3502677 (PubMed Central)
  5. Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted. Caito SW, Milatovic D, Hill KE, Aschner M, Burk RF, Valentine WM (2011) Brain Res : 1-12
    › Primary publication · 21636077 (PubMed) · PMC3114300 (PubMed Central)
  6. Compartment-specific enhancement of white matter and nerve ex vivo using chromium. Dortch RD, Apker GA, Valentine WM, Lai B, Does MD (2010) Magn Reson Med 64(3): 688-97
    › Primary publication · 20806376 (PubMed) · PMC2933086 (PubMed Central)
  7. Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury. Valentine HL, Viquez OM, Valentine WM (2010) Toxicology 274(1-3): 10-7
    › Primary publication · 20452388 (PubMed) · PMC2900428 (PubMed Central)
  8. Multiexponential T2, magnetization transfer, and quantitative histology in white matter tracts of rat spinal cord. Dula AN, Gochberg DF, Valentine HL, Valentine WM, Does MD (2010) Magn Reson Med 63(4): 902-9
    › Primary publication · 20373391 (PubMed) · PMC2852261 (PubMed Central)
  9. Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity. Liu F, Ichihara S, Valentine WM, Itoh K, Yamamoto M, Sheik Mohideen S, Kitoh J, Ichihara G (2010) Toxicol Sci 115(2): 596-606
    › Primary publication · 20211940 (PubMed)
  10. N,N-diethyldithiocarbamate promotes oxidative stress prior to myelin structural changes and increases myelin copper content. Viquez OM, Lai B, Ahn JH, Does MD, Valentine HL, Valentine WM (2009) Toxicol Appl Pharmacol 239(1): 71-9
    › Primary publication · 19467251 (PubMed) · PMC2727155 (PubMed Central)
  11. Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury. Valentine HL, Viquez OM, Amarnath K, Amarnath V, Zyskowski J, Kassa EN, Valentine WM (2009) Chem Res Toxicol 22(1): 218-26
    › Primary publication · 19093748 (PubMed) · PMC2665870 (PubMed Central)
  12. A specific HPLC-UV method for the determination of cysteine and related aminothiols in biological samples. Amarnath K, Amarnath V, Amarnath K, Valentine HL, Valentine WM (2003) Talanta 60(6): 1229-38
    › Primary publication · 18969150 (PubMed)
  13. Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy. Viquez OM, Valentine HL, Amarnath K, Milatovic D, Valentine WM (2008) Toxicol Appl Pharmacol 229(1): 77-85
    › Primary publication · 18284930 (PubMed) · PMC2429851 (PubMed Central)
  14. Neurodegeneration in mice resulting from loss of functional selenoprotein P or its receptor apolipoprotein E receptor 2. Valentine WM, Abel TW, Hill KE, Austin LM, Burk RF (2008) J Neuropathol Exp Neurol 67(1): 68-77
    › Primary publication · 18172410 (PubMed)
  15. Globin s-propyl cysteine and urinary N-acetyl-S-propylcysteine as internal biomarkers of 1-bromopropane exposure. Valentine H, Amarnath K, Amarnath V, Li W, Ding X, Valentine WM, Ichihara G (2007) Toxicol Sci 98(2): 427-35
    › Primary publication · 17517825 (PubMed)
  16. Multicomponent T2 analysis of dithiocarbamate-mediated peripheral nerve demyelination. Valentine HL, Does MD, Marshall V, Tonkin EG, Valentine WM (2007) Neurotoxicology 28(3): 645-54
    › Primary publication · 17350098 (PubMed) · PMC1976306 (PubMed Central)
  17. Peripheral nerve protein expression and carbonyl content in N,N-diethlydithiocarbamate myelinopathy. Viquez OM, Valentine HL, Friedman DB, Olson SJ, Valentine WM (2007) Chem Res Toxicol 20(3): 370-9
    › Primary publication · 17323979 (PubMed) · PMC2525616 (PubMed Central)
  18. Dietary copper enhances the peripheral myelinopathy produced by oral pyrrolidine dithiocarbamate. Valentine HL, Amarnath K, Amarnath V, Valentine WM (2006) Toxicol Sci 89(2): 485-94
    › Primary publication · 16291825 (PubMed)
  19. Brainstem axonal degeneration in mice with deletion of selenoprotein p. Valentine WM, Hill KE, Austin LM, Valentine HL, Goldowitz D, Burk RF (2005) Toxicol Pathol 33(5): 570-6
    › Primary publication · 16105800 (PubMed)
  20. Interdisciplinary neurotoxicity inhalation studies: carbon disulfide and carbonyl sulfide research in F344 rats. Sills RC, Harry GJ, Valentine WM, Morgan DL (2005) Toxicol Appl Pharmacol 207(2 Suppl): 245-50
    › Primary publication · 16002115 (PubMed)
  21. Neurologic abnormalities in workers of a 1-bromopropane factory. 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 (2004) Environ Health Perspect 112(13): 1319-25
    › Primary publication · 15345346 (PubMed) · PMC1247523 (PubMed Central)
  22. N,N-diethyldithiocarbamate produces copper accumulation, lipid peroxidation, and myelin injury in rat peripheral nerve. Tonkin EG, Valentine HL, Milatovic DM, Valentine WM (2004) Toxicol Sci 81(1): 160-71
    › Primary publication · 15187237 (PubMed)
  23. Characterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the Rat. Zimmerman LJ, Valentine HL, Valentine WM (2004) Chem Res Toxicol 17(2): 258-67
    › Primary publication · 14967014 (PubMed)
  24. 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. Johnson DJ, Amarnath V, Amarnath K, Valentine H, Valentine WM (2003) Toxicol Sci 76(1): 65-74
    › Primary publication · 12972631 (PubMed)
  25. Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation. Tonkin EG, Valentine HL, Zimmerman LJ, Valentine WM (2003) Toxicol Appl Pharmacol 189(2): 139-50
    › Primary publication · 12781632 (PubMed)
  26. Cytotoxic mechanisms of hydrosulfide anion and cyanide anion in primary rat hepatocyte cultures. Thompson RW, Valentine HL, Valentine WM (2003) Toxicology 188(2-3): 149-59
    › Primary publication · 12767687 (PubMed)
  27. Activation of the transcription factor NF-kappaB in Schwann cells is required for peripheral myelin formation. Nickols JC, Valentine W, Kanwal S, Carter BD (2003) Nat Neurosci 6(2): 161-7
    › Primary publication · 12514737 (PubMed)
  28. In vivo and in vitro hepatotoxicity and glutathione interactions of N-methyldithiocarbamate and N,N-dimethyldithiocarbamate in the rat. Thompson RW, Valentine HL, Valentine WM (2002) Toxicol Sci 70(2): 269-80
    › Primary publication · 12441372 (PubMed)
  29. Identification of a S-hexahydro-1H-azepine-1-carbonyl adduct produced by molinate on rat hemoglobin beta(2) and beta(3) chains in vivo. Zimmerman LJ, Valentine HS, Amarnath K, Valentine WM (2002) Chem Res Toxicol 15(2): 209-17
    › Primary publication · 11849047 (PubMed)
  30. Identification of a new urinary metabolite of carbon disulfide using an improved method for the determination of 2-thioxothiazolidine-4-carboxylic acid. Amarnath V, Amarnath K, Graham DG, Qi Q, Valentine H, Zhang J, Valentine WM (2001) Chem Res Toxicol 14(9): 1277-83
    › Primary publication · 11559044 (PubMed)
  31. Disulfiram produces a non-carbon disulfide-dependent schwannopathy in the rat. Tonkin EG, Erve JC, Valentine WM (2000) J Neuropathol Exp Neurol 59(9): 786-97
    › Primary publication · 11005259 (PubMed)
  32. Disulfiram generates a stable N,N-diethylcarbamoyl adduct on Cys-125 of rat hemoglobin beta-chains in vivo. Erve JC, Jensen ON, Valentine HS, Amarnath V, Valentine WM (2000) Chem Res Toxicol 13(4): 237-44
    › Primary publication · 10775322 (PubMed)
  33. Characterization of carbon disulfide neurotoxicity in C57BL6 mice: behavioral, morphologic, and molecular effects. Sills RC, Valentine WM, Moser V, Graham DG, Morgan DL (2000) Toxicol Pathol 28(1): 142-8
    › Primary publication · 10669001 (PubMed)
  34. Toluene-3,4-dithiol analysis of blood for assessing carbon disulfide exposure. Valentine WM, Valentine HL, Amarnath K, Amarnath V (1999) Toxicol Sci 50(2): 155-63
    › Primary publication · 10478851 (PubMed)
  35. Exposure of C57BL/6 mice to carbon disulfide induces early lesions of atherosclerosis and enhances arterial fatty deposits induced by a high fat diet. Lewis JG, Graham DG, Valentine WM, Morris RW, Morgan DL, Sills RC (1999) Toxicol Sci 49(1): 124-32
    › Primary publication · 10367350 (PubMed)
  36. Characterization of a valine-lysine thiourea cross-link on rat globin produced by carbon disulfide or N,N-diethyldithiocarbamate in vivo. Erve JC, Amarnath V, Sills RC, Morgan DL, Valentine WM (1998) Chem Res Toxicol 11(10): 1128-36
    › Primary publication · 9778308 (PubMed)
  37. Carbon disulfide and N,N-diethyldithiocarbamate generate thiourea cross-links on erythrocyte spectrin in vivo. Erve JC, Amarnath V, Graham DG, Sills RC, Morgan AL, Valentine WM (1998) Chem Res Toxicol 11(5): 544-9
    › Primary publication · 9585486 (PubMed)
  38. Reactions of 4-hydroxy-2(E)-nonenal and related aldehydes with proteins studied by carbon-13 nuclear magnetic resonance spectroscopy. Amarnath V, Valentine WM, Montine TJ, Patterson WH, Amarnath K, Bassett CN, Graham DG (1998) Chem Res Toxicol 11(4): 317-28
    › Primary publication · 9548802 (PubMed)
  39. Carbon disulfide neurotoxicity in rats: VIII. Summary. Harry GJ, Graham DG, Valentine WM, Morgan DL, Sills RC (1998) Neurotoxicology 19(1): 159-61
    › Primary publication · 9498231 (PubMed)
  40. Covalent modification of hemoglobin by carbon disulfide: III. A potential biomarker of effect. Valentine WM, Amarnath V, Amarnath K, Erve JC, Graham DG, Morgan DL, Sills RC (1998) Neurotoxicology 19(1): 99-107
    › Primary publication · 9498226 (PubMed)
  41. Release of carbon disulfide is a contributing mechanism in the axonopathy produced by N,N-diethyldithiocarbamate. Johnson DJ, Graham DG, Amarnath V, Amarnath K, Valentine WM (1998) Toxicol Appl Pharmacol 148(2): 288-96
    › Primary publication · 9473537 (PubMed)
  42. CS2-mediated cross-linking of erythrocyte spectrin and neurofilament protein: dose response and temporal relationship to the formation of axonal swellings. Valentine WM, Amarnath V, Graham DG, Morgan DL, Sills RC (1997) Toxicol Appl Pharmacol 142(1): 95-105
    › Primary publication · 9007038 (PubMed)
  43. The measurement of 2-thiothiazolidine-4-carboxylic acid as an index of the in vivo release of CS2 by dithiocarbamates. Johnson DJ, Graham DG, Amarnath V, Amarnath K, Valentine WM (1996) Chem Res Toxicol 9(5): 910-6
    › Primary publication · 8828929 (PubMed)
  44. Crosslinking of apolipoprotein E by products of lipid peroxidation. Montine TJ, Huang DY, Valentine WM, Amarnath V, Saunders A, Weisgraber KH, Graham DG, Strittmatter WJ (1996) J Neuropathol Exp Neurol 55(2): 202-10
    › Primary publication · 8786379 (PubMed)
  45. Dialkyldithiocarbamates inhibit tyrosine hydroxylase activity in PC12 cells and in fibroblasts that express tyrosine hydroxylase. Montine TJ, Underhill TM, Valentine WM, Graham DG (1995) Neurodegeneration 4(3): 283-90
    › Primary publication · 8581560 (PubMed)
  46. Covalent cross-linking of erythrocyte spectrin by carbon disulfide in vivo. Valentine WM, Graham DG, Anthony DC (1993) Toxicol Appl Pharmacol 121(1): 71-7
    › Primary publication · 8337701 (PubMed)
  47. The mechanism of nucleophilic substitution of alkylpyrroles in the presence of oxygen. Amarnath V, Valentine WM, Amarnath K, Eng MA, Graham DG (1994) Chem Res Toxicol 7(1): 56-61
    › Primary publication · 8155825 (PubMed)
  48. Characterization of protein adducts produced by N-methyldithiocarbamate and N-methyldithiocarbamate esters. Valentine WM, Amarnath V, Amarnath K, Graham DG (1995) Chem Res Toxicol 8(2): 254-61
    › Primary publication · 7766809 (PubMed)
  49. Intermediates in the Paal-Knorr synthesis of pyrroles. 4-Oxoaldehydes. Amarnath V, Amarnath K, Valentine WM, Eng MA, Graham DG (1995) Chem Res Toxicol 8(2): 234-8
    › Primary publication · 7766806 (PubMed)
  50. Carbon disulfide mediated protein cross-linking by N,N-diethyldithiocarbamate. Valentine WM, Amarnath V, Amarnath K, Rimmele F, Graham DG (1995) Chem Res Toxicol 8(1): 96-102
    › Primary publication · 7703373 (PubMed)
  51. Pathogenetic studies of hexane and carbon disulfide neurotoxicity. Graham DG, Amarnath V, Valentine WM, Pyle SJ, Anthony DC (1995) Crit Rev Toxicol 25(2): 91-112
    › Primary publication · 7612176 (PubMed)
  52. Diagnostic and clinically important aspects of cyanobacterial (blue-green algae) toxicoses. Beasley VR, Dahlem AM, Cook WO, Valentine WM, Lovell RA, Hooser SB, Harada K, Suzuki M, Carmichael WW (1989) J Vet Diagn Invest 1(4): 359-65
    › Primary publication · 2518710 (PubMed)
  53. Algae intoxication in livestock and waterfowl. Beasley VR, Cook WO, Dahlem AM, Hooser SB, Lovell RA, Valentine WM (1989) Vet Clin North Am Food Anim Pract 5(2): 345-61
    › Primary publication · 2503241 (PubMed)
  54. Toxicology of selected pesticides, drugs, and chemicals. Short-chain alcohols. Valentine WM (1990) Vet Clin North Am Small Anim Pract 20(2): 515-23
    › Primary publication · 2180193 (PubMed)
  55. Toxicology of selected pesticides, drugs, and chemicals. Pyrethrin and pyrethroid insecticides. Valentine WM (1990) Vet Clin North Am Small Anim Pract 20(2): 375-82
    › Primary publication · 2180183 (PubMed)
  56. Electromyographic assessment of the neuromuscular blockade produced in vivo by anatoxin-a in the rat. Valentine WM, Schaeffer DJ, Beasley VR (1991) Toxicon 29(3): 347-57
    › Primary publication · 1904660 (PubMed)
  57. The molecular mechanism of the carbon disulfide mediated cross-linking of proteins. Amarnath V, Anthony DC, Valentine WM, Graham DG (1991) Chem Res Toxicol 4(2): 148-50
    › Primary publication · 1782343 (PubMed)
  58. Covalent cross-linking of proteins by carbon disulfide. Valentine WM, Amarnath V, Graham DG, Anthony DC (1992) Chem Res Toxicol 5(2): 254-62
    › Primary publication · 1643256 (PubMed)