Grantee Research Project Results
Final Report: Toxicogenetics of tetrachloroethylene metabolism and toxicity: Using Collaborative Cross mouse population approach to address remaining gaps in human health assessments
EPA Grant Number: R835612Title: Toxicogenetics of tetrachloroethylene metabolism and toxicity: Using Collaborative Cross mouse population approach to address remaining gaps in human health assessments
Investigators: Rusyn, Ivan , Wright, Fred A.
Institution: Texas A & M University , North Carolina State University at Raleigh
EPA Project Officer: Aja, Hayley
Project Period: September 1, 2014 through March 30, 2017
Project Amount: $800,000
RFA: Susceptibility and Variability in Human Response to Chemical Exposure (2013) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability
Objective:
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 this research proposal 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 that: (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. The proposal included three specific objectives:
Specific Objective 1: To characterize variability in the toxicokinetics of PERC by using the Collaborative Cross mouse model of the human population.
Specific Objective 2: To characterize variability in the toxicodynamics of PERC by evaluating inter-strain differences in dose-dependent effects on the liver and kidney in a sub-acute study.
Specific Objective 3: To evaluate the effects of inter-strain variability in PERC metabolism on liver and kidney toxicity in a sub-chronic study.
In addition, the scope of the study was expanded [request from December 15, 2015] to also include comparative analyses of the effects of PERC and TCE, including a comparison among three currently available novel mouse populations, the Collaborative Cross (CC), the RIX intercrosses between CC lines, and the Diversity Outbred models, in a 90‐day study with TCE.
Summary/Accomplishments (Outputs/Outcomes):
This research was conducted to address an important public health challenge, widespread exposure to two related chemicals, trichloroethylene and tetrachloroethylene, that pose human health hazard. These chemicals have been used in dry cleaning, in degreasing and cleaning solvents, and in chemical manufacturing. While their use is diminishing, especially in areas where consumers may come in contact with them through commercial products or services, they are ubiquitous in the environment and explores may occur through vapor intrusion from contaminated ground water, air and soil. Drinking water contamination is also possible. Moreover, these two chemicals have been chosen by EPA to be among the first 10 chemicals evaluated for potential risks to human health and the environment under the Toxic Substances Control Act (TSCA) as amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act. These two chemicals have been studied for decades and much is known about their cancer and non-cancer hazards; however, little is known about how genetic and other variability in the population may affect the risk of the individuals. Therefore, we focused our work on using genetically diverse mouse strains, or animals fed high-fat diets, to model two important population variability factors, genetic differences, and co-morbidity factors (such as non-alcoholic fatty liver disease). First, in order to better characterize the role of toxicokinetic variability in causing toxicity and disease, we developed several new sensitive methods to measure levels of metabolites produced by these chemicals in the body, as these secondary and tertiary species are known to react with cellular proteins and DNA. We were able to quantify population-wide and underlying disease-associated variability in how these chemicals are metabolized, and also determine which of the metabolites and genetic variants had the most appreciable effect. Second, our observations that experimental non-alcoholic liver disease was associated with modulation of chemical disposition and metabolism, with increased tissue levels of these hazardous chemicals and their metabolites, uncovers a very important susceptibility factor for tetrachloroethylene-associated hepatotoxicity.
Conclusions:
Overall, these data are not only important for better understanding of how these chemicals may cause harm to human health, but also allow greater precision in determining what levels of exposure may be without appreciable harm, thus guiding environmental cleanup targets and other risk management decisions. In addition, our findings demonstrate how novel genetic tools, such as genetically diverse mouse strains, are a valuable research tool for exploring the extent and the molecular mechanisms of inter-individual variability in toxicity and metabolism of chemicals.
Journal Articles on this Report : 9 Displayed | Download in RIS Format
Other project views: | All 14 publications | 9 publications in selected types | All 9 journal articles |
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Cichocki JA, Guyton KZ, Guha N, Chiu WA, Rusyn I, Lash LH. Target organ metabolism, toxicity, and mechanisms of trichloroethylene and perchloroethylene: key similarities, differences, and data gaps. Journal of Pharmacology and Experimental Therapeutics 2016;359(1):110-123. |
R835612 (2016) R835612 (Final) |
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Cichocki JA, Furuya S, Konganti K, Luo Y-S, McDonald TJ, Iwata Y, Chiu WA, Threadgill DW, Pogribny IP, Rusyn I. Impact of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene. Journal of Pharmacology and Experimental Therapeutics 2017;361(1):17-28. |
R835612 (2016) R835612 (Final) |
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Cichocki JA, Furuya S, Venkatratnam A, McDonald TJ, Knap AH, Wade T, Sweet S, Chiu WA, Threadgill DW, Rusyn I. Characterization of variability in toxicokinetics and toxicodynamics of tetrachloroethylene using the Collaborative Cross mouse population. Environmental Health Perspectives 2017;125(5):057006 (12 pp.). |
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Cichocki JA, Luo YS, Furuya S, Venkatratnam A, Konganti K, Chiu, WA, Threadgill DW, Pogribny IP. Modulation of Tetrachloroethylene-Associated Kidney Effects by Nonalcoholic Fatty Liver or Steatohepatitis in Male C57BL/6J Mice. Toxicological Sciences 2019;167(1):126-137. |
R835612 (Final) |
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Dalaijamts C, Cichocki J, Luo Y, Rusyn I, Chiu W. PBPK modeling of impact of nonalcoholic fatty liver disease on toxicokinetics of perchloroethylene in mice. Toxicology and Applied Pharmacology 2020;400(115069). |
R835612 (Final) |
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Ferguson KC, Luo YS, Rusyn I, Chiu WA. Comparative analysis of Rapid Equilibrium Dialysis (RED) and solid phase micro-extraction (SPME) methods for In Vitro-In Vivo extrapolation of environmental chemicals. Toxicology in Vitro2019;60:245-251 |
R835612 (Final) |
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Luo Y, Ferguson K, Rusyn I, Chiu W. In Vitro Bioavailability of the Hydrocarbon Fractions of Dimethyl Sulfoxide Extracts of Petroleum Substances. Toxicological Sciences 2020;174(2):168-177. |
R835612 (Final) |
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Rusyn I, Chiu W, Wright F. Model systems and organisms for addressing inter-and intra-species variability in risk assessment. REGULATORY TOXICOLOGY AND PHARMACOLOGY 2022;132(105197). |
R835612 (Final) |
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Venkatratnam A, Furuya S, Kosyk O, Gold A, Bodnar W, Konganti K, Threadgill DW, Gillespie KM, Aylor DL, Wright FA, Chiu WA, Rusyn I. Collaborative Cross mouse population enables refinements to characterization of the variability in toxicokinetics of trichloroethylene and provides genetic evidence for the role of PPAR pathway in its oxidative metabolism. Toxicological Sciences 2017;158(1):48-62. |
R835612 (Final) |
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Supplemental Keywords:
risk assessment, effects, health effects, human health, metabolism, vulnerability, sensitive populations, dose-response, carcinogen, animal, mammalian, organism, population, stressor, diet, genetic pre-disposition, genetic polymorphisms, susceptibility, chemicals, solvents, decision making, genetics, toxicology, chemistry, analytical, measurement methodsProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.