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

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Dioxin-like compound exposures alter metabolism, particularly related compounds, impacting amino acid, lipid, and nucleotide pathways. This chemical-wide metabolomics approach reveals broader metabolic disruption than previously understood.

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Area of Science:

  • Environmental health
  • Metabolomics
  • Toxicology

Background:

  • Dioxin-like compounds are associated with adverse health outcomes, including cancer.
  • Metabolic alterations from these exposures are not well understood.
  • Existing research often focuses on specific dioxin-like compounds, neglecting co-exposures.

Purpose of the Study:

  • To investigate metabolic alterations induced by a broad range of dioxin-like-related compounds using a chemical-wide approach.
  • To assess endogenous metabolite changes in occupational workers exposed to these chemicals.
  • To explore the utility of untargeted metabolomics for comprehensive environmental chemical exposure assessment.

Main Methods:

  • A chemical-wide association study was conducted on 137 occupational workers.
  • Endogenous metabolites were profiled using untargeted metabolomics (C18-negative and HILIC-positive chromatography).
  • A metabolome-wide association study identified features associated with dioxin-like-related compounds at a 20% false discovery rate.

Main Results:

  • No significant metabolic features were associated with polychlorinated dibenzo-p-dioxins (PCDDs) themselves.
  • Thousands of metabolic features were linked to PCDD-related, polychlorinated dibenzofuran-related, and polychlorinated biphenyl-related compounds.
  • Enrichment analysis revealed significant alterations in amino acid, lipid, fatty acid, carbohydrate, cofactor, and nucleotide metabolic pathways.

Conclusions:

  • Chemical-wide analysis combined with metabolomics provides a more comprehensive assessment of environmental chemical exposures and their metabolic impacts.
  • Metabolic disruption extends beyond targeted dioxin-like compounds to related chemicals, affecting key biochemical pathways.
  • This approach enhances our understanding of the toxicological mechanisms of complex chemical mixtures.