Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Comprehensive Evaluation System for Post-Metabolic Activity of Potential Thyroid-Disrupting Chemicals

  • Yurim Jang (Interdisciplinary Program in Agricultural Genomics, Seoul National University) ;
  • Ji Hyun Moon (Department of Agricultural Biotechnology, Seoul National University) ;
  • Byung Kwan Jeon (Department of Bio and Fermentation Convergence Technology, Kookmin University) ;
  • Ho Jin Park (Department of Food Science and Biotechnology, Chung-Ang University) ;
  • Hong Jin Lee (Department of Food Science and Biotechnology, Chung-Ang University) ;
  • Do Yup Lee (Interdisciplinary Program in Agricultural Genomics, Seoul National University)
  • Received : 2023.01.28
  • Accepted : 2023.05.26
  • Published : 2023.10.28
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Abstract

Endocrine-disrupting chemicals (EDCs) are compounds that disturb hormonal homeostasis by binding to receptors. EDCs are metabolized through hepatic enzymes, causing altered transcriptional activities of hormone receptors, and thus necessitating the exploration of the potential endocrine-disrupting activities of EDC-derived metabolites. Accordingly, we have developed an integrative workflow for evaluating the post-metabolic activity of potential hazardous compounds. The system facilitates the identification of metabolites that exert hormonal disruption through the integrative application of an MS/MS similarity network and predictive biotransformation based on known hepatic enzymatic reactions. As proof-of-concept, the transcriptional activities of 13 chemicals were evaluated by applying the in vitro metabolic module (S9 fraction). Identified among the tested chemicals were three thyroid hormone receptor (THR) agonistic compounds that showed increased transcriptional activities after phase I+II reactions (T3, 309.1 ± 17.3%; DITPA, 30.7 ± 1.8%; GC-1, 160.6 ± 8.6% to the corresponding parents). The metabolic profiles of these three compounds showed common biotransformation patterns, particularly in the phase II reactions (glucuronide conjugation, sulfation, GSH conjugation, and amino acid conjugation). Data-dependent exploration based on molecular network analysis of T3 profiles revealed that lipids and lipid-like molecules were the most enriched biotransformants. The subsequent subnetwork analysis proposed 14 additional features, including T4 in addition to 9 metabolized compounds that were annotated by prediction system based on possible hepatic enzymatic reaction. The other 10 THR agonistic negative compounds showed unique biotransformation patterns according to structural commonality, which corresponded to previous in vivo studies. Our evaluation system demonstrated highly predictive and accurate performance in determining the potential thyroid-disrupting activity of EDC-derived metabolites and for proposing novel biotransformants.

Keywords

Acknowledgement

This research was supported by a grant (19162MFDS099, 20163MFDS120) from the Ministry of Food and Drug Safety and by the Bio Industrial Technology Development Program (20018494, Discovery of new microbiome-based gut-liver axis control biomaterials and development of commercialization technology to overcome non-alcoholic fatty liver disease) from the Ministry of Trade, Industry and Energy (MOTIE, Korea).

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