Susceptibility to xenobiotics toxication is dictated by the time of the day that exposures occur

摘要

Aim: Non-persistent environmental chemicals (NOPEC) are xenobiotics with short half-lives of elimination (<7h). NOPEC metabolism may follow diurnal hepatic patterns of cytochrome P450 activity, which may be under the liver clock influence. Metabolic activation (toxication) of trihalomethanes (THM) by CYP2E1 leads to harmful metabolites, enhancing susceptibility to xenobiotic toxication. We investigated the diurnal patterns of exposures to THM (NOPEC class of disinfection byproducts) and their metabolism catalyzed by circadian patterns of hepatic CYP2E1 enzyme activity (4-hydroxynonenal (4HNE). Methods: We implemented three time-series studies with adult volunteers conducting specific cleaning activities at predefined times of the day. An activity day was designed where each participant conducted four well-controlled activities that could generate THM in the surrounding indoor environment (showering, hand dishwashing, mopping, and bathroom cleaning); another sampling day was included with none of the aforementioned activities (control). Each participant collected spot urine samples at predetermined intervals on both days. Urinary THM and HNE-His levels were measured using gas chromatography tandem mass spectrometry (GC-MS/MS) and immunoassay test, respectively. Nychthemeral variation in lipoperoxidation rhythm of 4HNE patterns was assessed with a cosinor model. Results: The time of exposure in the day dictated the magnitude of urinary THM levels and their toxication effect; in all three studies and relative to urinary THM before the activity, lower and higher median urinary THM were measured after the activity in morning and afternoonight, respectively, consistent with higher diurnal CYP2E1 activity in light/active phase. Conclusions: The inclusion of diurnal measurements in exposome studies is warranted to better describe the dynamic changes in exposure patterns between and within subjects that are prospectively followed during critical life stages.