Improving Human Risk Assessment Through Identification of Genetic Factors that Underlie Sensitivity to Chemical-Induced Adverse Health Effects in a Mouse Strain PanelEPA Grant Number: F07D10650
Title: Improving Human Risk Assessment Through Identification of Genetic Factors that Underlie Sensitivity to Chemical-Induced Adverse Health Effects in a Mouse Strain Panel
Investigators: Hege, Alison
Institution: University of North Carolina at Chapel Hill
EPA Project Officer: Manty, Dale
Project Period: August 17, 2007 through August 17, 2008
RFA: STAR Graduate Fellowships (2007) RFA Text | Recipients Lists
Research Category: Fellowship - Toxicogenomics , Fellowship - Risk Assessment , Health Effects , Academic Fellowships
A major challenge to defining human sensitivity to toxicities imposed by environmental pollutants and chemical agents is a lack of validated rodent models that reflect the genetic diversity inherent within the human population. An important concern for extrapolation of human risk estimates from rodent data is consistency across the biological systems being compared. Current research indicates that varying the strain of mouse in a toxicity study can have significant impact on chemically-induced adverse health effects. The hypothesis is that, by combining classical toxicological endpoints with an extensive knowledge base of rodent genetics, genetic susceptibility to organ-specific injury from a chemical exposure can be effectively modeled within a panel of inbred mouse strains.
These data will be used to determine genetic markers that will be sensitive, non-invasive, and predictive of toxicity phenotype, and that are useful for protecting genetically susceptible human populations.
In this work, a bedside-to-bench-to-bedside paradigm will be explored using acetaminophen (APAP)-induced liver injury as a model exposure. Acetaminophen was selected as a model chemical agent because hepatotoxicity due to overdose has been extensively characterized within the literature and it is a drug that is approved for safe therapeutic use. A recent clinical study showed that some human subjects who were administered the maximum recommended daily dose of APAP for 14 days experienced small elevations in serum alanine aminotransferase (ALT) levels, indicating liver injury (Watkins et al, JAMA, 2006). These responses will be modeled in a panel of 36 genetically diverse inbred mouse strains, by administering an acute dose of APAP. Serum toxicity markers and a percent liver necrosis score will be assessed at 4- and 24- hours after dosing. The toxicity data will be utilized for haplotype-association mapping across a 160,000 single nucleotide polymorphism (SNP) dataset across mouse strains to identify genomic regions associated with sensitivity to liver injury. Candidate genes will be sequenced across mouse strains and in DNA derived from human subjects enrolled in an acetaminophen clinical trial to assess their ability to predict genetic sensitivity to liver injury.
This project will establish a method in which a Mouse Model of the Human Population (MMHP) will be utilized to predict genetic sensitivity to toxicity. By showing that toxicity phenotypes vary across genetically-diverse mouse strains following a single dose of a model hepatotoxicant, the utility of using an MMHP in toxicity risk assessment over using a single mouse strain will be demonstrated. The validated experimental techniques will be useful in informing regulatory decisions and determining genetic risk of sensitive subpopulations for environmentally-relevant toxicants or contaminants.