Project Summary (2011-2018)

Dr. Rusyn's previous research under the Superfund Research Program established that the genetic makeup of the host plays a key role in metabolism and its biological effects of trichloroethylene (TCE) in mouse liver. Genetic polymorphisms have a profound effect on differences between individuals who may have developed disease after exposure to environmental agents, yet these factors are not being fully considered in risk assessment. Indeed, the need to account for differences among humans in cancer susceptibility other than from possible early-life susceptibility is becoming ever more evident to both the scientific community and the regulatory agencies. A hypothesis that apparent species- and organ-specific metabolism and toxicity of TCE are genetically controlled and that the mechanisms of susceptibility can be successfully elucidated using a panel of inbred mice is being addressed in this project.

First, the research group is elucidating genetic determinants of inter-individual differences in TCE metabolism by collecting time course, dose-response, and repeat dose data on TCE metabolites in blood and tissues from a large panel of genetically diverse inbred mouse strains. The data will be used to investigate the genetic causes of variation in the metabolism of TCE, a step crucial for understanding the potential for TCE-induced adverse health effects in a heterogeneous human population. Second, they are building population-wide pharmacokinetic models for TCE metabolism, which will account for inter-individual variability in metabolism from the genetics point of view by using the time-course and dose-response data obtained on the genetically-diverse animals. Third, the researchers are determining liver and kidney gene expression signatures of TCE and applying novel biostatistical tools to model dose-response and determine genetic loci that may control gene expression changes in response to exposure.

Collectively, this project is timely in utilizing a research paradigm that not only offers valuable insights into the molecular basis for genetically-determined variability in response to TCE, but also may provide necessary science-based underpinnings for the new paradigms being incorporated into the risk assessment and decision-making on TCE and related chlorinated solvents, as well as other environmental agents.