title: MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains.
abstract: Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical School, Rootstown, OH, United States.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Alam
authors.affiliation: Centers for Disease Control and Prevention-National Institute for Occupational Safety and Health, Morgantown, WV, United States.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: Centers for Disease Control and Prevention-National Institute for Occupational Safety and Health, Morgantown, WV, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.affiliation: University of Tennessee Health Science Center, Memphis, TN, United States; Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical School, Rootstown, OH, United States; University of Tennessee Health Science Center, Memphis, TN, United States. Electronic address: bjone129@UTHSC.edu.
authors.forename: Byron C
authors.initials: BC
authors.lastname: Jones
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D020267:MPTP Poisoning / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D012727:Sex Characteristics; D013045:Species Specificity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid
keywords: QTL; Recombinant inbred mice; Sex differences