Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice

Cichocki, Joseph A.; Furuya, Shinichi; Konganti, Kranti; Luo, Yu‐Syuan; McDonald, Thomas J.; Iwata, Yasuhiro; Chiu, Weihsueh A.; Threadgill, David W.; Pogribny, Igor P.; Rusyn, Ivan

doi:10.1124/jpet.116.238790

Cited by 20 publications

(44 citation statements)

References 56 publications

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“…We previously demonstrated in primary rat hepatocytes that the cooperative interaction between B[a]P and ethanol on cell death involved both B[a]P and ethanol metabolism 25 . Besides, a few studies indicated an impact of liver steatosis on xenobiotic metabolism, with possible consequences on drug biotransformation 64 – 69 , and toxicokinetics of environmental contaminants 70 . We therefore decided to focus on xenobiotic metabolism in HepaRG cells, especially that related to B[a]P. As expected from previous works 64 – 67 , steatosis per se down-regulated the expression of several phase I and II XMEs of HepaRG cells, with some exceptions such as CYP2E1, ALDH1A3 and GSTM2P1 whose expression was increased (Table S2 ).…”

Section: Discussionmentioning

confidence: 99%

Co-exposure to benzo[a]pyrene and ethanol induces a pathological progression of liver steatosis in vitro and in vivo

Bucher

Tête

Podechard

et al. 2018

Sci Rep

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Hepatic steatosis (i.e. lipid accumulation) and steatohepatitis have been related to diverse etiologic factors, including alcohol, obesity, environmental pollutants. However, no study has so far analyzed how these different factors might interplay regarding the progression of liver diseases. The impact of the co-exposure to the environmental carcinogen benzo[a]pyrene (B[a]P) and the lifestyle-related hepatotoxicant ethanol, was thus tested on in vitro models of steatosis (human HepaRG cell line; hybrid human/rat WIF-B9 cell line), and on an in vivo model (obese zebrafish larvae). Steatosis was induced prior to chronic treatments (14, 5 or 7 days for HepaRG, WIF-B9 or zebrafish, respectively). Toxicity and inflammation were analyzed in all models; the impact of steatosis and ethanol towards B[a]P metabolism was studied in HepaRG cells. Cytotoxicity and expression of inflammation markers upon co-exposure were increased in all steatotic models, compared to non steatotic counterparts. A change of B[a]P metabolism with a decrease in detoxification was detected in HepaRG cells under these conditions. A prior steatosis therefore enhanced the toxicity of B[a]P/ethanol co-exposure in vitro and in vivo; such a co-exposure might favor the appearance of a steatohepatitis-like state, with the development of inflammation. These deleterious effects could be partly explained by B[a]P metabolism alterations.

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Section: Discussionmentioning

confidence: 99%

Co-exposure to benzo[a]pyrene and ethanol induces a pathological progression of liver steatosis in vitro and in vivo

Bucher

Tête

Podechard

et al. 2018

Sci Rep

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“…As the oxidative and GSH conjugation pathways may compete for the parent compound, individuals with lower levels of GSH-related metabolites could have higher internal doses of TCA, resulting in the increased lipid accumulation. Indeed, compared with control diet–fed mice, mice with diet-induced nonalcoholic fatty liver disease (NAFLD) also show lower levels of TCVG, TCVC, and NAcTCVC, a higher level of TCA, and hepatic lipid accumulation after PERC exposure (Cichocki et al. 2017a).…”

Section: Discussionmentioning

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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“…The same strategy was applied to predict the changes in the activity of transcription factors in mouse models of NAFLD/NASH. We performed IPA upstream activity prediction analysis for publicly available liver transcriptome data from mouse models of steatosis that were established by feeding high caloric diets [ 18 , 207 ] as well as mouse models of NASH that were established by feeding an MCD diet [ 207 ], NASH diet, or a combination of high caloric diets coupled with CCl 4 treatment [ 18 , 208 ]. Additionally, we included the observations of a previously published STZ-induced NASH and HCC model (STAM) [ 7 ].…”

Section: Prediction Of Transcriptional Regulators By Database Analmentioning

confidence: 99%

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

2020

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Obesity is the primary risk factor for the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the worldwide prevalence of which continues to increase dramatically. The liver plays a pivotal role in the maintenance of whole-body lipid and glucose homeostasis. This is mainly mediated by the transcriptional activation of hepatic pathways that promote glucose and lipid production or utilization in response to the nutritional state of the body. However, in the setting of chronic excessive nutrition, the dysregulation of hepatic transcriptional machinery promotes lipid accumulation, inflammation, metabolic stress, and fibrosis, which culminate in NAFLD. In this review, we provide our current understanding of the transcription factors that have been linked to the pathogenesis and progression of NAFLD. Using publicly available transcriptomic data, we outline the altered activity of transcription factors among humans with NAFLD. By expanding this analysis to common experimental mouse models of NAFLD, we outline the relevance of mouse models to the human pathophysiology at the transcriptional level.

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Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice

Cited by 20 publications

References 56 publications

Co-exposure to benzo[a]pyrene and ethanol induces a pathological progression of liver steatosis in vitro and in vivo

Co-exposure to benzo[a]pyrene and ethanol induces a pathological progression of liver steatosis in vitro and in vivo

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

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

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