Citation:

Gilbert, M. Thyroid hormones and the developing brain: Rodent models to define phenotypes, elucidate mechanisms, and inform quantitative predictive modeling. European Teratology Society, Berlin, N/A, GERMANY, September 10 - 14, 2018.

Impact/Purpose:

Invited participant to symposium at European Teratology Society meeting entitled "Endocrine Disruption: Focus on Thyroid"

Description:

Adverse neurodevelopmental consequences remain a primary concern when evaluating the effects of thyroid disrupting chemicals (TDC). The inherent complexity of the thyroid system allows for a variety of potential target sites for chemical interference and disruption of the system. Many TDCs are identified and so classified by their ability to reduce circulating levels of thyroid hormones. Several regulatory bodies require biochemical indices of thyroid hormones in serum following test chemical exposure to inform their assessment of potential risk. However, the well accepted dogma of the essentiality for adequate supplies of thyroid hormone for optimal brain development has been largely derived from studies of severe hormone deprivation, deficiencies that are rarely if ever achieved by environmental contaminants in humans or in animal test species. As such, focus on the mechanisms and consequences of severe disruption have failed to provide the tools necessary to define the potential impact of more moderate thyroid hormone insufficiencies on development of the brain. There is a lack of data on structural or functional apical measures of adversity that could be specifically tied to moderate degrees of thyroid hormone disruption. Our work in rodents with a model chemical, propylthiouracil (PTU) has been directed to: 1) conduct a dose-response analysis with a focus on moderate degrees of hormone disruption; 2) identify brain phenotypes – functional, neuroanatomical, molecular- that may be used to characterize the effects of TDC downstream from serum hormone reductions; 3) examine the stage-specificity of these insults and the fidelity of timing on hormone reduction to resultant phenotype; 4) define mechanisms underlying thyroid-signaling pathways that lead to such deficits; and finally to 5) provide quantitative information that is useful for predictive modeling. Functionally, dose-dependent decrements in synaptic neurotransmission in the hippocampus, and impairments in synaptic plasticity mechanisms tied to learning impairments will be presented. Anatomical defects in the process of neurogenesis in the adult hippocampus and neuronal migration in the immature brain will be described. Timing, duration, and severity of insult are all critical components to consider when determining the relationship of exposure to outcome. Elucidating mechanistic underpinnings of thyroid signaling pathways will increase our understanding of the many roles of thyroid hormone in the brain and potentially provide more direct measures of brain dysfunction. Establishing these key linkages at various levels of biological complexity will aid in the interpretation of serum hormone data gathered within a regulatory context. This work does not reflect US EPA policy.

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