Impact of repeated exposure on toxicity of perchloroethylene in Swiss Webster mice

Journal of Toxicology and Environmental Health, Part A

McDonald

et al. 2017

Tetrachloroethylene (perchloroethylene; PERC) is a high-production volume chemical and a ubiquitous environmental contaminant that is hazardous to human health. Toxicity of PERC is mediated through oxidative and glutathione conjugation metabolites. The conjugation of PERC by glutathione-s-transferase to generate S-(1,2,2-trichlorovinyl) glutathione (TCVG), which is subsequently metabolized to form S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) is of special importance to human health. Specifically, TCVC can be metabolized to N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) which is excreted through urine, or to electrophilic metabolites that are nephrotoxic and mutagenic. Little is known about toxicokinetics of TCVG, TCVC, and NAcTCVC as analytical methods for simultaneous determination of these metabolites in tissues have not yet been reported. Hence, an ultra-high performance liquid chromatography electrospray ionization tandem mass spectrometry-based method was developed for analysis of TCVG, TCVC, and NAcTCVC in liver, kidney, serum, and urine. The method is rapid, sensitive, robust, and selective for detection all three analytes in every tissue examined, with limits of detection ranging from 1.8–68.2 femtomoles on column, depending on the analyte and tissue matrix. This method can be applied to quantify levels of TCVG, TCVC, and NAcTCVC in tissues from mice treated with PERC (10 to 1000 mg/kg, orally) with limits of quantitation of 1–2.5 pmol/g in liver, 1–10 pmol/g in kidney, 1–2.5 pmol/mL in serum, and 2.5–5 pmol/mL in urine. This method is useful for further characterization of the glutathione conjugative pathway of PERC in vivo and improved understanding of PERC toxicity.

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Simultaneous detection of the tetrachloroethylene metabolites S-(1,2,2-trichlorovinyl) glutathione, S-(1,2,2-trichlorovinyl)-L-cysteine, and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine in multiple mouse tissues via ultra-high performance liquid chromatography electrospray ionization tandem mass spectrometry

Luo

Journal of Toxicology and Environmental Health, Part A

McDonald

et al. 2017

“…After 8 weeks of dietary treatments as detailed above, mice were administered a single intragastric dose of PERC (300 mg/kg in 5% Alkamuls-EL620 in saline). This dose was selected as the toxicokinetics of PERC and TCA in male mice after exposure to 150-1000 mg/kg PERC has been characterized in liver and blood (Philip et al, 2007) and was shown to be well-tolerated in acute (Philip et al, 2007) and subchronic studies (National Toxicology Program, 1977). Mice (n 5 5/diet/time point) were euthanized at 1, 2, 4, 12, or 24 hours after gavage (total n 5 75).…”

Section: Methodsmentioning

confidence: 99%

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

Furuya

Konganti

et al. 2017

J Pharmacol Exp Ther

Lifestyle factors and chronic pathologic states are important contributors to interindividual variability in susceptibility to xenobiotic-induced toxicity. Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition that can dramatically affect chemical metabolism. We examined the effect of NAFLD on toxicokinetics of tetrachloroethylene (PERC), a ubiquitous environmental contaminant that requires metabolic activation to induce adverse health effects. Mice (C57Bl/6J, male) were fed a low-fat diet (LFD), high-fat diet (HFD), or methionine/folate/choline-deficient diet (MCD) to model a healthy liver, steatosis, or nonalcoholic steatohepatitis (NASH), respectively. After 8 weeks, mice were orally administered a single dose of PERC (300 mg/kg) or vehicle (aqueous Alkamuls-EL620) and euthanized at various time points (1-36 hours). Levels of PERC and its metabolites were measured in blood/serum, liver, and fat. Effects of diets on liver gene expression and tissue: air partition coefficients were evaluated. We found that hepatic levels of PERC were 6-and 7.6-fold higher in HFD-and MCD-fed mice compared with LFD-fed mice; this was associated with an increased PERC liver:blood partition coefficient. Liver and serum C max for trichloroacetate (TCA) was lower in MCD-fed mice; however, hepatic clearance of TCA was profoundly reduced by HFD or MCD feeding, leading to TCA accumulation. Hepatic mRNA/protein expression and ex vivo activity assays revealed decreased xenobiotic metabolism in HFD-and MCD-, compared with LFD-fed, groups. In conclusion, experimental NAFLD was associated with modulation of xenobiotic disposition and metabolism and increased hepatic exposure to PERC and TCA. Underlying NAFLD may be an important susceptibility factor for PERC-associated hepatotoxicity.

“…However, the epidemiologic evidence is not consistent concerning the noncancer hepatotoxicity of either solvent. In experimental animals, both TCE and PCE have also been shown to elicit hepatotoxicity, typically at doses at or exceeding 100 mg/kg (e.g., Buben and O'Flaherty, 1985;Philip et al, 2007;Yoo et al, 2015a). In addition to elevation of serum liver enzymes, hyperbilirubinemia, cholestatic liver injury, oxidative damage to DNA and cell membranes, changes in lipid metabolism, lipid accumulation (steatosis), and hepatomegaly have all been reported in rodents exposed to TCE or PCE (EPA, 2011a,b;IARC, 2014).…”

Section: Mechanisms Of Toxicitymentioning

confidence: 99%

“…TCE and PCE induce PPARa in rodent studies, likely through formation of TCA and DCA (Bull, 2000;Corton, 2008;Maloney and Waxman, 1999). One study reported that PCE induces PPARa after acute and subacute (less than 14 days) exposure but not after 30 days of exposure (Philip et al, 2007); however, the overall database on the role of PPARa in the effects of PCE is limited. Studies of mice deficient in PPARa have shown that they are more sensitive to TCE-induced hepatosteatosis (Ramdhan et al, 2010) and have lower levels of TCA in their urine (Ramdhan et al, 2010) and in serum, liver, and kidney (Yoo et al, 2015c) compared with wild-type mice.…”

Section: Mechanisms Of Toxicitymentioning

confidence: 99%

Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps

Journal of Pharmacology and Experimental Therapeutics

Guyton

Guha

et al. 2016

Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high-production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent speciesand sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure.