Adverse Outcome Pathways for Thyroid System Disrupting Chemicals and Neurodevelopment– Multiple Sites of Action
Citation:
Gilbert, Mary E. Adverse Outcome Pathways for Thyroid System Disrupting Chemicals and Neurodevelopment– Multiple Sites of Action. 12th International Die Akademie Fresenius Conference Endocrine Disruptors-Virtual, Research Triangle Park, NC, November 23 - 24, 2021.
Impact/Purpose:
Relevancy to EPA Program/Regional Research Needs/Priorities: This abstract examines two chemicals that reduce serum T4 in rat dams and offspring by their purported action at extrathyroidal sites (ie., liver and serum binding proteins). Serum TH profiles were examined across multiple ages in dams and offspring and markers of developmental neurotoxicity assessed. This work addresses Chemical Safety for Sustainability (CSS) Adverse Outcome Pathway Discovery and Development (AOPDD 17.01), Thyroid Related AOPs and is relevant to OPPTS and OW needs for decision making.Name(s) of Program Office Reviewer(s) of Earlier Drafts: Information contained in this presentation has been presented in different forms, abstracts, presentations, published manuscripts. As such it has been reviewed by program office staff in various forms over the past couple of years. Program Office/Regional Office Co-Authors: None Impact/Potential Implications of the Findings: It appears that additional measures of neurodevelopmental impairment are needed to more fully characterize the risk of chemicals with extrathyroidal sites of action. n their absence, the use of serum TH appears to be protective of the fetus and developing neonate. Findings Advancing Existing Scientific Knowledge: These findings indicate that additional metrics of TH-mediated neurodevelopmental impairment are needed for the further development and refinement of quantitative AOPs for thyroid disruption.
Description:
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.