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Integration of Computational Toxicology, Toxicogenomics Data Mining, and Omics Techniques to Unveil Toxicity Pathways
- Source :
- ACS Sustainable Chemistry & Engineering. 9:4130-4138
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
Abstract
- Growing numbers of synthetic chemicals have potential endocrine-disrupting effects and cause potential ecological and health risks. However, the primary toxicity pathways and mechanisms of endocrine disruption are poorly understood and the existing risk assessment relies heavily on animal testing. Database mining, omics technology, and computer simulation can serve as an alternative approach to explore the mechanisms by building adverse outcome pathways (AOPs). The present study took a case of thyroid interference with triphenyl phosphate (TPP) to explain the potential toxic effects at levels from submolecules to cells utilizing the AOP framework developed by multiple techniques. This study retrieved the data from a comparative toxicogenomics database (CTD) and screened out the core gene. Molecular dynamics (MD) analysis was used to explore configuration changes and confirm the molecular initiating event (MIE). The transcriptomic analysis was further utilized to supplement the relationships between MIEs and key events (KEs) of the AOP. The thyroid hormone receptor beta (THRB) was identified as the core gene at submolecular levels. MD analysis found that the configuration changes of C-terminal helix 12 (H12) of thyroid hormone receptor beta (TR beta) were discovered as the MIE. The transcriptomic analysis extended the related KE1 at the subcellular level, such as changes in gene expression levels for coding cycle regulation (CCND1), inflammatory response (IL1A and IL6), and cell proliferation and apoptosis (BAD, TP53, and CASP9). Then, the KE2 at cellular levels such as apoptosis, cell cycle control, and cell proliferation were influenced accordingly. As a result, these alterations led to thyroid disorder as adverse outcomes. This study provided an efficient way to facilitate the complement of possible AOPs and brought new insights into understanding the toxic mechanisms of emerging synthetic chemicals.
- Subjects :
- Renewable Energy, Sustainability and the Environment
Cell growth
General Chemical Engineering
Thyroid
02 engineering and technology
General Chemistry
Computational biology
Biology
010402 general chemistry
021001 nanoscience & nanotechnology
01 natural sciences
Thyroid disorder
0104 chemical sciences
Thyroid hormone receptor beta
Transcriptome
medicine.anatomical_structure
IL1A
Adverse Outcome Pathway
medicine
Environmental Chemistry
0210 nano-technology
Toxicogenomics
Subjects
Details
- ISSN :
- 21680485
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- ACS Sustainable Chemistry & Engineering
- Accession number :
- edsair.doi...........401c290ade415d8dd9cf57492bee3a80