Investigating complex phenotypes: haplotype association mapping benzene pharmacokinetics in isogenic mouse strains

Persistent Link:
http://hdl.handle.net/10150/202998
Title:
Investigating complex phenotypes: haplotype association mapping benzene pharmacokinetics in isogenic mouse strains
Author:
Knudsen, Gabriel Arther
Issue Date:
2011
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
A role for gene variants in regulating the pharmacokinetics of systemically available toxicants has not yet been established. A panel of 18 genetically-diverse inbred mouse strains was used to determine the range of total exposure kinetic parameters in blood and bone marrow following a single oral administration of benzene (100 μg/kg) to male and female mice. Large ranges in several pharmacokinetic parameters were found when data from blood and bone marrow were analyzed. AUC and CL_F pharmacokinetic parameters in blood and bone marrow pharmacokinetics were strikingly different as were these parameters in males and females. Final clearance (CL_F) was found to be the most statistically robust pharmacokinetic parameter as it accounted for exposure of the matrix (AUC) and normalized for dose variations among the strains. The CL_F values in blood and bone marrow used for haplotype association mapping showed 331 and 164 quantitative trait loci with statistical significance, respectively (male mice; -logP>4). Two loci were found to be shared between males and females QTL bone marrow data sets and one common locus was found for male blood and bone marrow data. No overlap was found among blood QTL in males and females (or between blood and bone marrow data from females). Protein and mRNA expression data for the primary benzene-metabolizing enzymes CYP2E1 and UGT1A6 showed very little strain-dependent variation. Strain dependent differences in mRNA levels of NQO1 and MPO were small but statistically significant, as were those for GAPDH and β2-microglobulin. These data demonstrated that polymorphisms with the greatest contribution toward overall variations in systemic exposures occurred in genes encoding for non-metabolic proteins. While exposure does not equate to toxicity, identification of the genes regulating distribution and clearance may be useful for investigating host susceptibility to toxic effects following benzene exposure. This research was supported in part by the NIEHS NTP Grant N01ES45529, NIEHS Toxicology and Toxicogenomics Training Grant (5T32ES007091-29), NIEHS/NTP Division of Intramural Research, and Southwest Environmental Science Center Grant P3ES06694.
Type:
text; Electronic Dissertation
Keywords:
genomics; haplotype mapping; pharmacokinetics; Medical Pharmacology; benzene; exposure
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Medical Pharmacology
Degree Grantor:
University of Arizona
Advisor:
Sipes, Ivan Glenn

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleInvestigating complex phenotypes: haplotype association mapping benzene pharmacokinetics in isogenic mouse strainsen_US
dc.creatorKnudsen, Gabriel Artheren_US
dc.contributor.authorKnudsen, Gabriel Artheren_US
dc.date.issued2011-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractA role for gene variants in regulating the pharmacokinetics of systemically available toxicants has not yet been established. A panel of 18 genetically-diverse inbred mouse strains was used to determine the range of total exposure kinetic parameters in blood and bone marrow following a single oral administration of benzene (100 μg/kg) to male and female mice. Large ranges in several pharmacokinetic parameters were found when data from blood and bone marrow were analyzed. AUC and CL_F pharmacokinetic parameters in blood and bone marrow pharmacokinetics were strikingly different as were these parameters in males and females. Final clearance (CL_F) was found to be the most statistically robust pharmacokinetic parameter as it accounted for exposure of the matrix (AUC) and normalized for dose variations among the strains. The CL_F values in blood and bone marrow used for haplotype association mapping showed 331 and 164 quantitative trait loci with statistical significance, respectively (male mice; -logP>4). Two loci were found to be shared between males and females QTL bone marrow data sets and one common locus was found for male blood and bone marrow data. No overlap was found among blood QTL in males and females (or between blood and bone marrow data from females). Protein and mRNA expression data for the primary benzene-metabolizing enzymes CYP2E1 and UGT1A6 showed very little strain-dependent variation. Strain dependent differences in mRNA levels of NQO1 and MPO were small but statistically significant, as were those for GAPDH and β2-microglobulin. These data demonstrated that polymorphisms with the greatest contribution toward overall variations in systemic exposures occurred in genes encoding for non-metabolic proteins. While exposure does not equate to toxicity, identification of the genes regulating distribution and clearance may be useful for investigating host susceptibility to toxic effects following benzene exposure. This research was supported in part by the NIEHS NTP Grant N01ES45529, NIEHS Toxicology and Toxicogenomics Training Grant (5T32ES007091-29), NIEHS/NTP Division of Intramural Research, and Southwest Environmental Science Center Grant P3ES06694.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectgenomicsen_US
dc.subjecthaplotype mappingen_US
dc.subjectpharmacokineticsen_US
dc.subjectMedical Pharmacologyen_US
dc.subjectbenzeneen_US
dc.subjectexposureen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMedical Pharmacologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorSipes, Ivan Glennen_US
dc.contributor.committeememberCherrington, Nathan J.en_US
dc.contributor.committeememberDavis, Thomas P.en_US
dc.contributor.committeememberNalonen, Marilyn J.en_US
dc.contributor.committeememberSipes, I. Glennen_US
dc.contributor.committeememberMonks, Terrenceen_US
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