Exposome-wide association study of environmental toxicant exposure and insulin resistance: Findings from US National Health and Nutrition Examination Survey

Prior epidemiological evidence regarding the associations between environmental toxicant and insulin resistance (IR) focused exclusively on single or limited exposure classes, failing to capture the interactions and mixed effects of multiple toxicants with grouping structures. Furthermore, there is a knowledge gap in addressing whether oxidative stress may mediate the relationships in the context of high-dimensional exposure. Based on data from the 2013-2014 and 2015-2016 circles of National Health and Nutrition Examination Survey, we examined the associations of IR with 53 toxicants in 10 categories. IR status was assessed using HOMA-IR, with the highest quartile defined as severe IR. The effects of mixtures were determined using principal component pursuit in combination with multi-pollutant exposure models. Mediation analysis was conducted to examine the mediating effects of oxidative stress indicated by gamma-glutamyl transferase. This study identified 15 environmental toxicants in 5 classes were significantly associated with severe IR risk, including the metabolites of volatile organic compounds (VOCs), CEMA (OR, 1.57; 95 % CI, 1.30-1.91), as well as total nicotine (OR, 1.05; 95 % CI, 1.01-1.09). In co-exposure scenarios, VOCs mixtures dominated the associations and elevated severe IR risk (β, 0.54; 95 % CI, 0.27-0.81), with MHBMA2, 3-HPMA, MA, and CEMA holding the major weights. Individual younger than 60 years and females had greater vulnerability to environmental toxicants compared to their counterparts. Oxidative stress mediated 11.54 %-37.61 % of the total effects. Our findings offer crucial implications on IR management by tailoring interventions to key environmental targets and individuals at high risks.