Citation:

O'Shaughnessy, Katherine AND M. Gilbert. Thyroid disrupting chemicals and developmental neurotoxicity – New tools and approaches to evaluate hormone action. Molecular and Cellular Endocrinology. ELSEVIER, AMSTERDAM, Holland, 518:11063, (2020). https://doi.org/10.1016/j.mce.2019.110663

Impact/Purpose:

This manuscript is an invited review for a special issue for the journal Molecular and Cellular Endocrinology. The goal of this issue was to provide a comprehensive understanding of original data on endocrine disruption (ED) that will improve the overall knowledge on ED and identify gaps that remain in the ED research field. The special issue is organized around scientific questions related to those knowledge gaps and we were tasked with addressing the need for new tools/models for a better characterization/ prediction of neurotoxicity in the framework of regulatory evaluation. This review summarized the current strategies for hazard identification in in vivo studies which focus on serum hormone measures in rodents. A clear need for more brain-based metrics of TH-dependent developmental neurotoxicity is evident. We review several intermediate reproducible phenotypes that have been described in the literature and propose several candidate endpoints/assays that could be developed and optimized in a targeted testing approach.

Description:

It is well documented that thyroid hormone (TH) action is critical for normal brain development and is mediated by both nuclear and extranuclear pathways. Given this dependence, the impact of environmental endocrine disrupting chemicals that interfere with thyroid signaling is a major concern with direct implications for children's health. However, identifying thyroid disrupting chemicals in vivo is primarily reliant on serum thyroxine (T4) measurements within greater developmental and reproductive toxicity assessments. These studies do not examine known TH-dependent phenotypes in parallel, which complicates chemical evaluation. Additionally, there exist no recommendations regarding what degree of serum T4 dysfunction is adverse, and little consideration is given to quantifying TH action within the developing brain. This review summarizes current testing strategies in rodent models and discusses new approaches for evaluating the developmental neurotoxicity of thyroid disrupting chemicals. This includes assays to identify adverse cellular effects of the brain by both immunohistochemistry and gene expression, which would compliment serum T4 measures. While additional experiments are needed to test the full utility of these approaches, incorporation of these cellular and molecular assays could enhance chemical evaluation in the regulatory arena.

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