Toxicogenetics of PERC Metabolism and Toxicity: Collaborative Cross Mouse Population Approach to Address Remaining Gaps in Human Health Assessments

摘要

Tetrachloroethylene (Perchloroethylene, PERC) is a high-production chemical of great concern to both risk assessors and public health officials worldwide. It has long been assumed that PERC metabolism and toxicity closely mimic those of trichloroethylene (TCE), a structurally similar chlorinated solvent. However, recent human health assessments of these chemicals determined that major differences in toxicokinetics and toxicodynamics exist between TCE and PERC. Furthermore, it was concluded that critical gaps remain in understanding of the human health hazard of PERC, including toxicokinetics, toxicodynamics and population variability. Thus, the long-term objective of our project was to uncover the mechanistic linkages between the genome (e.g., variation in DNA sequence among individuals), metabolism (e.g., formation of organ-specific toxic intermediates), and adverse molecular events (e.g., transcriptional changes associated with toxicity) in response to PERC. The central hypotheses of this proposal were (ⅰ) genetic variability-associated differences in PERC metabolism affect organ-specific toxicity of PERC; and (ⅱ) a population-based experimental design utilizing Collaborative Cross (CC) can be used to exploit the variability in toxicity responses to better characterize uncertainties in human health assessments. We have successfully characterized variability in the toxicokinetics and toxicodynamics of PERC by using the Collaborative Cross mouse model of the human population. In addition we evaluate the effects of nonalcoholic fatty liver disease (NAFLD), an increasingly prevalent condition that can dramatically affect chemical metabolism, on PERC-associated liver and kidney effects.