Characterization of inter-tissue and inter-strain variability of TCE glutathione conjugation metabolites DCVG, DCVC, and NAcDCVC in the mouse

Luo, Yu‐Syuan; Furuya, Shinichi; Chiu, Weihsueh A.; Rusyn, Ivan

doi:10.1080/15287394.2017.1408512

Cited by 20 publications

(20 citation statements)

References 51 publications

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“…Tissue-specific variation of these glutathione conjugation metabolites was similar between TCE-treated and PCE-treated mice. The highest level of the glutathione conjugates was found in liver and the highest level of the cysteine conjugates was found in kidney, in accord with recent studies (Luo et al 2017; Luo et al 2018a; Yoo et al 2015a; Yoo et al 2015b).…”

Section: Resultssupporting

confidence: 91%

“…Tissue levels of DCVG/TCVG, DCVC/TCVC, and NAcDCVC/NAcTCVC were measured as detailed in (Luo et al 2017; Luo et al 2018a). In brief, tissue homogenates were subject to a liquid-liquid extraction with 400 μL of methanol:chloroform (1:1) and a solid-phase extraction (SPE) using a weak anion C-18 cartridge (Strata-X-AW, PN: 8E-S038-TGB, Phenomenex, Torrance, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative estimation of inter-individual variability in metabolism is also a critical challenge in human health assessments of TCE and PCE (Cichocki et al 2017b; Cichocki et al 2016; Venkatratnam et al 2017). The inter-strain variability in TCE metabolism has been characterized by using a multi-strain panel of inbred mice (Bradford et al 2011) and the Collaborative Cross mouse population (Luo et al 2018a; Venkatratnam et al 2017; Venkatratnam et al 2018). Mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE (Chiu et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Comparative analysis of metabolism of trichloroethylene and tetrachloroethylene among mouse tissues and strains

et al. 2018

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Trichloroethylene (TCE) and tetrachloroethylene (PCE) are structurally similar chemicals that are metabolized through oxidation and glutathione conjugation pathways. Both chemicals have been shown to elicit liver and kidney toxicity in rodents and humans; however, TCE has been studied much more extensively in terms of both metabolism and toxicity. Despite their qualitative similarities, quantitative comparison of tissue- and strain-specific metabolism of TCE and PCE has not been performed. To fill this gap, we conducted a comparative toxicokinetic study where equimolar single oral doses of TCE (800 mg/kg) or PCE (1000 mg/kg) were administered to male mice of C57BL/6J, B6C3F1/J, and NZW/LacJ strains. Samples of liver, kidney, serum, brain, and lung were obtained for up to 36 h after dosing. For each tissue, concentrations of parent compounds, as well as their oxidative and glutathione conjugation metabolites were measured and concentration-time profiles constructed. A multi-compartment toxicokinetic model was developed to quantitatively compare TCE and PCE metabolism. As expected, the flux through oxidation metabolism pathway predominated over that through conjugation across all mouse strains examined, it is 1,200-3,800 fold higher for TCE and 26-34 fold higher for PCE. However, the flux through glutathione conjugation, albeit a minor metabolic pathway, was 21-fold higher for PCE as compared to TCE. The degree of inter-strain variability was greatest for oxidative metabolites in TCE-treated and for glutathione conjugation metabolites in PCE-treated mice. This study provides critical data for quantitative comparisons of TCE and PCE metabolism, and may explain the differences in organ-specific toxicity between these structurally similar chemicals.

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Section: Resultssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative analysis of metabolism of trichloroethylene and tetrachloroethylene among mouse tissues and strains

et al. 2018

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“…The interstrain variability of PERC and its metabolites was estimated as previously described (Luo et al. 2018a).…”

Section: Methodsmentioning

confidence: 99%

Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene

Luo

Cichocki

Hsieh

et al. 2019

Environ Health Perspect

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Background:Interindividual variability in susceptibility remains poorly characterized for environmental chemicals such as tetrachloroethylene (PERC). Development of population-based experimental models provide a potential approach to fill this critical need in human health risk assessment.Objectives:In this study, we aimed to better characterize the contribution of glutathione (GSH) conjugation to kidney toxicity of PERC and the degree of associated interindividual toxicokinetic (TK) and toxicodynamic (TD) variability by using the Collaborative Cross (CC) mouse population.Methods:Male mice from 45 strains were intragastrically dosed with PERC (1,000mg/kg) or vehicle (5% Alkamuls EL-620 in saline), and time-course samples were collected for up to 24 h. Population variability in TK of S-(1,2,2-trichlorovinyl)GSH (TCVG), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) was quantified in serum, liver, and kidney, and analyzed using a toxicokinetic model. Effects of PERC on kidney weight, fatty acid metabolism–associated genes [Acot1 (Acyl-CoA thioesterase 1), Fabp1 (fatty acid-binding protein 1), and Ehhadh (enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase)], and a marker of proximal tubular injury [KIM-1 (kidney injury molecule-1)/Hepatitis A virus cellular receptor 1 (Havcr1)] were evaluated. Finally, quantitative data on interstrain variability in both formation of GSH conjugation metabolites of PERC and its kidney effects was used to calculate adjustment factors for the interindividual variability in both TK and TD.Results:Mice treated with PERC had significantly lower kidney weight, higher kidney-to-body weight (BW) ratio, and higher expression of fatty acid metabolism–associated genes (Acot1, Fabp1, and Ehhadh) and a marker of proximal tubular injury (KIM-1/Havcr1). Liver levels of TCVG were significantly correlated with KIM-1/Havcr1 in kidney, consistent with kidney injury being associated with GSH conjugation. We found that the default uncertainty factor for human variability may be marginally adequate to protect 95%, but not more, of the population for kidney toxicity mediated by PERC.Discussion:Overall, this study demonstrates the utility of the CC mouse population in characterizing metabolism–toxicity interactions and quantifying interindividual variability. Further refinement of the characterization of interindividual variability can be accomplished by incorporating these data into in silico population models both for TK (such as a physiologically based pharmacokinetic model), as well as for toxicodynamic responses. https://doi.org/10.1289/EHP5105

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“…Studies of chemical effects using population-based models, both in vivo and in vitro , are increasingly common (Abdo et al 2015; Church et al 2015; Cichocki et al 2017; Eduati et al 2015; French et al 2015; Luo et al 2018; Mosedale et al 2017; Venkatratnam et al 2017). Powered by the balanced genetic diversity represented in the DO (Churchill et al 2012) and CC (Threadgill et al 2011) populations, these mouse models enable exploration of causal variants driving molecular variation that result in phenotypic differences (Harrill and McAllister 2017).…”

Section: Introductionmentioning

confidence: 99%

Population-based dose–response analysis of liver transcriptional response to trichloroethylene in mouse

et al. 2018

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Studies of gene expression are common in toxicology and provide important clues to mechanistic understanding of adverse effects of chemicals. Most prior studies have been performed in a single strain or cell line; however, gene expression is heavily influenced by the genetic background, and these genotype-expression differences may be key drivers of inter-individual variation in response to chemical toxicity. In this study, we hypothesized that the genetically diverse Collaborative Cross mouse population can be used to gain insight and suggest mechanistic hypotheses for the dose- and genetic background-dependent effects of chemical exposure. This hypothesis was tested using a model liver toxicant trichloroethylene (TCE). Liver transcriptional responses to TCE exposure were evaluated 24 h after dosing. Transcriptomic dose-responses were examined for both TCE and its major oxidative metabolite trichloroacetic acid (TCA). As expected, peroxisome- and fatty acid metabolism-related pathways were among the most dose-responsive enriched pathways in all strains. However, nearly half of the TCE-induced liver transcriptional perturbation was strain-dependent, with abundant evidence of strain/dose interaction, including in the peroxisomal signaling-associated pathways. These effects were highly concordant between the administered TCE dose and liver levels of TCA. Dose-response analysis of gene expression at the pathway level yielded points of departure similar to those derived from the traditional toxicology studies for both non-cancer and cancer effects. Mapping of expression-genotype-dose relationships revealed some significant associations; however, the effects of TCE on gene expression in liver appear to be highly polygenic traits that are challenging to positionally map. This study highlights the usefulness of mouse population-based studies in assessing inter-individual variation in toxicological responses, but cautions that genetic mapping may be challenging because of the complexity in gene exposure-dose relationships.

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Characterization of inter-tissue and inter-strain variability of TCE glutathione conjugation metabolites DCVG, DCVC, and NAcDCVC in the mouse

Cited by 20 publications

References 51 publications

Comparative analysis of metabolism of trichloroethylene and tetrachloroethylene among mouse tissues and strains

Comparative analysis of metabolism of trichloroethylene and tetrachloroethylene among mouse tissues and strains

Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene

Population-based dose–response analysis of liver transcriptional response to trichloroethylene in mouse

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