Dioxin(-like)-Related Biological Effects through Integrated Chemical-wide and Metabolome-wide Analyses

• DOI: 10.1021/acs.est.3c07588
• Publication Date: 2023-12-27T12:56:56Z
• Authors: Yujia Zhao; Jeroen Meijer; Douglas I. Walker; Juni Kim; Lützen Portengen; Dean P. Jones; Fatemeh Saberi Ho...; Jelle Vlaanderen; Roel Vermeulen
• Keywords: metabolome-wide association study; 0301 basic medicine; Polychlorinated Dibenzodioxins; chemical-wide association study; dioxin(-like) exposures; General Chemistry; exposome; Dioxins; Polychlorinated Biphenyls; 03 medical and health sciences; SDG 3 - Good Health and Well-being; occupational population; Neoplasms; Metabolome; Environmental Chemistry; Humans; biological pathways

Dioxin(-like) exposures are linked to adverse health effects, including cancer. However, metabolic alterations induced by these chemicals remain largely unknown. Beyond known dioxin(-like) compounds, we leveraged a chemical-wide approach to assess chlorinated co-exposures and parent compound products [termed dioxin(-like)-related compounds] among 137 occupational workers. Endogenous metabolites were profiled by untargeted metabolomics, namely, reversed-phase chromatography with negative electrospray ionization (C18-negative) and hydrophilic interaction liquid chromatography with positive electrospray ionization (HILIC-positive). We performed a metabolome-wide association study to select dioxin(-like) associated metabolic features using a 20% false discovery rate threshold. Metabolic features were then characterized by pathway enrichment analyses. There are no significant features associated with polychlorinated dibenzo-p-dioxins (PCDDs), a subgroup of known dioxin(-like) compounds. However, 3,110 C18-negative and 2,894 HILIC-positive features were associated with at least one of the PCDD-related compounds. Abundant metabolic changes were also observed for polychlorinated dibenzofuran-related and polychlorinated biphenyl-related compounds. These metabolic features were primarily enriched in pathways of amino acids, lipid and fatty acids, carbohydrates, cofactors, and nucleotides. Our study highlights the potential of chemical-wide analysis for comprehensive exposure assessment beyond targeted chemicals. Coupled with advanced endogenous metabolomics, this approach allows for an in-depth exploration of metabolic alterations induced by environmental chemicals.