Metabolism of trichloroethylene following inhalation exposure in mice

Trichloroethylene (TCE) is a pervasive environmental pollutant associated with elevated risk of developing Parkinson's disease (PD). Studies characterizing TCE metabolism in humans indicate that 40 - 75% of the absorbed dose is metabolized, suggesting that TCE toxicity may be attributable to its metabolites. However, there is limited knowledge of TCE metabolite neurotoxicity. We conducted a TCE inhalation study in mice followed by high-resolution mass spectrometry (HRMS) on brain, liver, and blood to identify which TCE metabolites were present following human-relevant TCE exposure. Mice were exposed to 100 ppm TCE for 4 hours. Plasma, brain, and liver were collected from each animal up to 24 hours after exposure. We developed a method capable of detecting TCE metabolites trichloroacetic acid (TCA), dichloroacetic acid (DCA), monochloroacetic acid (MCA), trichloroethanol (TCEOH), trichloroethanol glucuronide (TCEOH-gluc), S-(1,2-dichlorovinyl)glutathione (DCVG), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC), and untargeted metabolites using a single extraction protocol on a liquid chromatography-based mass spectrometry system (LC-MS/MS). Targeted analysis of TCE-exposed biological samples identified DCA, TCA, and TCEOH-gluc. Untargeted analysis of TCE-exposed mouse brain revealed previously established and novel pathway perturbations associated with TCE exposure. Together, these findings indicate that DCA, TCA, and TCEOH-gluc are the most prevalent TCE metabolites in mice. The novel pathways perturbed by TCE exposure warrant further exploration to better understand the mechanisms underlying the toxicity of TCE and its metabolites