The impact of occupational exposure to dioxins and dioxin-like compounds on the blood metabolome

BACKGROUND AND AIM: Dioxins and dioxin-like compounds are a group of recognized environmental pollutants associated with an increase in all cancer combined. Evidence for specific cancer sites is more limited to non-Hodgkin lymphoma, an immune-related cancer. Our aim is to broaden our mechanistic understanding of metabolome alterations associated with dioxins and dioxin-like compounds, and link these metabolic changes to immunological markers. METHODS: 139 workers from two chlorophenoxy herbicides factories, who had been exposed to dioxins and dioxin-like compounds more than 30 years before blood collection were included. Blood levels of 21 dioxins, dioxin-like furans and biphenyls were determined, and historical 2,3,7,8-tetrachlorodibenzo-p-dioxin levels were estimated using a one-compartment first order kinetic model. Plasma metabolites were measured using dual column liquid chromatography with high-resolution mass spectrometry. A metabolome-wide association study (MWAS), based on linear regression and 20% false discovery rate, was used to evaluate the relationship between metabolic features and exposures. Enrichment of biological pathways was investigated using Mummichog. Differential network analysis was applied to link changed metabolic features to immunological markers. RESULTS:MWAS identified 1157 metabolic features associated with at least one dioxin species, with the majority associated with dioxin-like furans and biphenyls. Metabolic pathway enrichment identified 15 pathways associated with exposure, including pathways of de novo fatty acid biosynthesis, fatty acid activation, omega-3 fatty acid metabolism, fatty acids metabolism and linoleate metabolism, some of which have been previously observed in animal models and human studies exposed to dioxin-like compounds. Other lipid species, including glycerophospholipid, glycosphingolipid, leukotriene, androgen and estrogen were also identified. Besides inflammation mediators (arachidonic acid, prostaglandin, leukotriene), immunological markers were related to fatty acids and cell membrane lipids, which also participate in immune regulation and signaling. CONCLUSIONS:Our results emphasize the metabolome-regulated potency of dioxin-like compounds, mainly on disruption of lipid metabolism especially fatty acids, and provide further plausibility for immunotoxicity mechanism in human. KEYWORDS: dioxin-like compounds, untargeted metabolomics, immunotoxicity, metabolic pathway enrichment