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Systems analysis of genetic variation in MPTP neurotoxicity in mice.

Authors
Jones-BC; Miller-DB; O'Callaghan-JP; Lu-L; Unger-EL; Alam-G; Williams-RW
Source
Neurotoxicology 2013 Jul; 37:26-34
NIOSHTIC No.
20042706
Abstract
We analyzed genetic variation in severity of neuronal damage using the known dopaminergic neurotoxicant, MPTP, as a prototypical chemical denervation agent. Male mice from ten members of the BXD family of recombinant inbred strains received 12.5mg/kg MPTP s.c. (vs. saline) and 48h later brains were taken for multiple related biochemical analyses. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, and serotonin and its metabolite, 5-HIAAA, were analyzed by HPLC. DA turnover was assessed using DOPAC/DA and HVA/DA ratios. Striatal tyrosine hydroxylase (TH), glial fibrilary acidic protein (GFAP), and iron content in ventral midbrain were quantified. All dopamine measures, as well as TH and GFAP, demonstrated wide, genotype-dependent differences in response to MPTP. Serotonin was largely unaffected. Principal components analysis (PC) on difference values, saline minus MPTP, for DA, DOPAC, HVA, and TH, yielded a dominant principal component. The PC trait residuals for each genotype were compared against complementary expression data for striatum of the same strains. Three transcripts representing Mtap2, Lancl 1, and Kansl1l were highly correlated with the PC, as was the difference score, MPTP minus saline for GFAP. This systems approach to the study of environmental neurotoxicants holds promise to define individual genetic differences that contribute to variability in susceptibility to risk factors for diseases such as Parkinson's disease.
Keywords
Genetics; Genes; Neurological-reactions; Neurological-system; Neuromotor-system; Neuromotor-system-disorders; Neuromuscular-function; Neuromuscular-system; Neuromuscular-system-disorders; Neurophysiology; Nervous-system-function; Nerves; Nerve-function; Animals; Laboratory-animals; Analytical-processes; Biochemical-analysis; Metabolites; Metabolism; Proteins; Brain-function; Risk-factors; Diseases; Author Keywords: BXD; Recombinant inbred strains; Multivariate analysis; Iron; GFAP; Dopamine
Contact
Byron C. Jones, Department of Biobehavioral Health, 315 E. HHD Building, The Pennsylvania State University, University Park, PA 16802
CODEN
NRTXDN
Publication Date
20130701
Document Type
Journal Article
Email Address
bcj1@psu.edu
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
B20130625
ISSN
0161-813X
NIOSH Division
HELD
Priority Area
Healthcare and Social Assistance; Transportation, Warehousing and Utilities
Source Name
Neurotoxicology
State
PA; WV; TN
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