Specific alteration of gene expression profile in rats by treatment with thyroid toxicants that inhibit thyroid hormone synthesis

J Appl Toxicol. 2018 Dec;38(12):1529-1537. doi: 10.1002/jat.3693. Epub 2018 Jul 25.


Transcriptomics technologies have been used for risk assessment of chemicals, mainly to predict the modes of action (MOAs) of chemicals or identify biomarkers. Transcriptomics data may also be helpful to understand MOAs of chemicals at the molecular level in more detail. As an example of the known MOAs, there are two MOAs of thyroid toxicity: inhibition of thyroid hormone synthesis ("direct" effect) and hypermetabolism of thyroid hormone by enzyme induction in liver ("indirect" effect). In the present study, global profiles of gene expression were analyzed in rats treated with chemicals acting directly on the thyroid (thyroid peroxidase inhibitors such as propylthiouracil and methimazole) and chemicals acting indirectly on the thyroid (hepatic enzyme inducers such as phenobarbital and pregnenolone-16α-carbonitrile) using microarrays. Using a subtraction method between these two types of chemicals, we identified characteristic gene expression changes on the thyroid hormone synthesis pathway by direct-acting chemicals. Based on the functions of these genes, alterations of their expression seem to indicate the results of thyroid peroxidase inhibition, and might be helpful in more accurate evaluation of MOAs for thyroid toxicity.

Keywords: microarray; mode of action; thyroid hormone synthesis; thyroid toxicity; transcriptomics.

MeSH terms

  • Animals
  • Antithyroid Agents / toxicity*
  • Enzyme Induction / drug effects
  • Gene Expression Profiling
  • Iodide Peroxidase / antagonists & inhibitors
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Methimazole / toxicity
  • Microarray Analysis
  • Phenobarbital / toxicity
  • Propylthiouracil / toxicity
  • Rats, Wistar
  • Thyroid Gland / drug effects*
  • Thyroid Gland / metabolism
  • Thyroid Hormones / biosynthesis*
  • Transcriptome / drug effects*


  • Antithyroid Agents
  • Thyroid Hormones
  • Methimazole
  • Propylthiouracil
  • Iodide Peroxidase
  • Phenobarbital