Adverse Outcome Pathways for Thyroid System Disrupting Chemicals and Neurodevelopment– Multiple Sites of Action
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Thyroid hormones (TH) are critical for brain development. Serum measures of TH are used for regulatory decision-making purposes because of concern for neurodevelopmental disorders and serum T4 represents a key integrator node in the Adverse Outcome Pathway (AOP) upstream from impaired neurodevelopment. Predictions stemming from altered T4 in this AOP are largely based on data from agents known to disrupt the thyroid system by inhibiting TH synthesis at the level of the thyroid gland (i.e., propylthiouracil, methimazole). Many other chemicals with distinct modes of action are also capable of reducing serum T4, but confirmation of their link to neurodevelopmental deficits has remained elusive. This presentation will provide an overview of the thyroid system in mammals and the multiple site of potential of chemical interaction as these sites. Adverse outcome pathways have been developed that link serum to brain hormone deficits and downstream neurodevelopmental events in rodent models. Thus far, these have been limited to chemicals that have their primary action at the level of the thyroid gland. For chemicals that also reduce serum hormones but through extrathyroidal sites, there is more uncertainty. Recently published data from our laboratory on chemicals with presumed action at distributer proteins or as liver metabolism inducers will be presented. These data identify significant knowledge gaps in our understanding of thyroid biology and its complex interaction with the developing brain.