Systems analysis of genetic variation in MPTP neurotoxicity in mice

Jones, Byron C.; Miller, Diane B.; O’Callaghan, James P.; Lu, Lu; Unger, Erica L.; Alam, Gelareh; Williams, Robert W.

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Systems analysis of genetic variation in MPTP neurotoxicity in mice

Published Date:

Apr 01 2013

Source:

Neurotoxicology. 37:26-34.

[PDF-671.87 KB]

Details:

Alternative Title:

Neurotoxicology

Personal Author:

Jones, Byron C. ; Miller, Diane B. ; O’Callaghan, James P. ; Lu, Lu ; Unger, Erica L. ; ... More ▼

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:

[+]

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 ;

Collection(s):

CDC Public Access

Main Document Checksum:

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