title: Systems analysis of genetic variation in MPTP neurotoxicity in mice.
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.
authors.affiliation: Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA 16802, USA. bcj1@psu.edu
authors.forename: Byron C
authors.initials: BC
authors.lastname: Jones
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Erica L
authors.initials: EL
authors.lastname: Unger
authors.forename: Gelareh
authors.initials: G
authors.lastname: Alam
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D020267:MPTP Poisoning / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015999:Multivariate Analysis; D010641:Phenotype; D025341:Principal Component Analysis; D012307:Risk Factors; D012701:Serotonin / Q000378:metabolism; D013045:Species Specificity; D049490:Systems Biology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid
references.citation: J Occup Environ Med. 2005 Oct;47(10):1059-87
references.pmid: 16217247
references.citation: Neurotoxicol Teratol. 1991 May-Jun;13(3):275-81
references.pmid: 1886537
references.citation: J Biol Chem. 2012 Oct 5;287(41):34189-201
references.pmid: 22891245
references.citation: J Stud Alcohol. 1997 Nov;58(6):590-9
references.pmid: 9391918
references.citation: Annu Rev Neurosci. 2000;23:39-71
references.pmid: 10845058
references.citation: BMC Genet. 2004 Apr 29;5:7
references.pmid: 15117419
references.citation: Genes Brain Behav. 2009 Apr;8(3):296-308
references.pmid: 19191878
references.citation: Brain Res. 1990 Jun 25;521(1-2):73-80
references.pmid: 1976416
references.citation: Brain Res Mol Brain Res. 2003 Feb 20;110(2):279-88
references.pmid: 12591164
references.citation: Proc Soc Exp Biol Med. 1973 Jul;143(3):629-33
references.pmid: 4719448
references.citation: J Neurochem. 2001 Oct;79(2):225-36
references.pmid: 11677250
references.citation: Curr Treat Options Neurol. 2012 Jun;14(3):230-40
references.pmid: 22547255
references.citation: Environ Health Perspect. 2012 Mar;120(3):340-7
references.pmid: 22389202
references.citation: J Neurosci. 2003 Sep 10;23(23):8247-53
references.pmid: 12967986
references.citation: Neurotoxicol Teratol. 2011 May-Jun;33(3):415-21
references.pmid: 21371552
references.citation: Neurogenetics. 2012 May;13(2):147-57
references.pmid: 22457016
references.citation: Anal Biochem. 1985 Oct;150(1):76-85
references.pmid: 3843705
references.citation: J Nutr. 1997 Oct;127(10):2030-8
references.pmid: 9311961
references.citation: J Biol Chem. 2004 May 7;279(19):19936-47
references.pmid: 14996842
references.citation: J Neurosci. 2008 Aug 20;28(34):8545-52
references.pmid: 18716213
references.citation: Curr Protoc Toxicol. 2002 May;Chapter 12:Unit12.8
references.pmid: 23045073