Individual susceptibility varies between regional, racial, and cultural groups, and it is commonly assumed that, in addition to environmental and occupational exposures, genetic background and lifestyle (e.g. diet selection) significantly contribute to this variability. In human studies, however, it is difficult to study exposure- gene interactions because human populations contain complex substructures that are the product of social, racial, and regional differences. In addition, different lifestyles are interconnected and often create multiple beneficial or adverse habits. To model a genetically heterogeneous human population, the Collaborative Cross (CC) mice were created to represent a complete intermixed mouse population covering all possible genotypes. In the proposed work, we hypothesize that the variability in susceptibility derived solely from genetic diversity can be modeled in mice by combining the CC model with the 1, 3-butadiene (BD) exposure model. BD was chosen as a model compound because it forms several protein adducts that are biomarkers for BD uptake, metabolic activation, and detoxification. These N-terminal valine adducts will be used to assess susceptibility of the CC population. BD metabolism is dependent on P450 2e1 activity, and therefore we further hypothesize that BD-derived protein adducts correlate with P450 2e1 activity. To test these hypotheses we propose in aim 1 to demonstrate the range of carcinogen metabolism derived from genetic diversity and in aim 2 to determine whether differences in carcinogen metabolism are mediated via regulation of P450 2e1 activity. Therefore, we propose to expose CC mice to BD and determine relative potency for metabolic activation versus detoxification derived solely from genetic diversity. The Relative potency for metabolic activation (RPoMA) will be calculated from BD-derived protein adducts by applying a recently established multiplicative risk model. Because 90% of BD is metabolized by P450 2e1, its enzymatic activity in liver tissues from CC mice will be determined to specifically investigate the role of P450 2e1 in BD metabolism as it relates to susceptibility. If successful, this proposal will show the relatie contributions of genetic background on carcinogen metabolism and reveal the importance of P450 2e1 across various genetic backgrounds.

Public Health Relevance

This study will investigate the variability in metabolic activation of carcinogens derived solely from genetic diversity. As a model for human genetic diversity, the unique Collaborative Cross mouse population will be treated with the model carcinogen 1, 3-butadiene (BD) and variability in BD metabolism will be determined based on protein adducts as biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES023046-01A1
Application #
8700622
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Carlin, Danielle J
Project Start
2014-05-07
Project End
2016-04-30
Budget Start
2014-05-07
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$238,754
Indirect Cost
$58,990
Name
University of Arkansas for Medical Sciences
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205