Systems analysis of genetic variation in MPTP neurotoxicity in mice.
Neurotoxicology
; 37: 26-34, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23558233
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 12.5 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Variação Genética
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Encéfalo
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Intoxicação por MPTP
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Biologia de Sistemas
Tipo de estudo:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Neurotoxicology
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos