Details:

Alternative Title:
Neurotoxicology
Personal Author:
Jones, Byron C. ; Miller, Diane B. ; O’Callaghan, James P. ; Lu, Lu ; Unger, Erica L. ; ... More +
Jones, Byron C. ; Miller, Diane B. ; O’Callaghan, James P. ; Lu, Lu ; Unger, Erica L. ; Alam, Gelareh ; Williams, Robert W. Less -
Description:
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 12.5 mg/kg MPTP s.c. (vs. saline) and 48 h 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.
Subject:
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3,4-Dihydroxyphenylacetic Acid
Animals
Article
Biomarkers
Brain
BXD
Disease Models, Animal
Dopamine
Gene Expression Regulation
Genetic Predisposition To Disease
Genetic Variation
Genomics
GFAP
Glial Fibrillary Acidic Protein
Homovanillic Acid
Hydroxyindoleacetic Acid
Iron
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
MPTP Poisoning
Multivariate Analysis
Phenotype
Principal Component Analysis
Recombinant Inbred Strains
Risk Factors
Serotonin
Species Specificity
Systems Biology
Tyrosine 3-Monooxygenase
Multivariate Analysis

Source:
Neurotoxicology. 37:26-34.
Pubmed ID:
23558233
Pubmed Central ID:
PMC4615717
Document Type:
Journal Article
Funding:
CC999999/Intramural CDC HHS/United States ; U01 AA013499/AA/NIAAA NIH HHS/United States ; U01 AA016662/AA/NIAAA NIH HHS/United States
CC999999/Intramural CDC HHS/United States ; U01 AA013499/AA/NIAAA NIH HHS/United States ; U01 AA016662/AA/NIAAA NIH HHS/United States Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:3765726270f2f0bedabb7477d3fd2ca652fa7c8c5f27ddbc2867be70357e4370
File Type:

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