Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals

• Kevin Crofton

Revision dates for related pages

• Chemicals: This AOP may be restricted to a limited number of chemical structures that antagonize thyroid receptors.  Recent work from high-throughput testing of the Tox21 library of pharmaceutial and environmental chemcials suggests that only a 3 of the 8,305 unique structures tested were confirmed as antagonists (Paul-Friedman et al., 2019).  This is likely due to the very restrictive ligand-binding pocket for TRs (Meerts et al. 2001).
• Sex: This AOP applies to males and females. Disruption of thyroid receptor mediated gene expression during fetal and early postnatal develop, as well as the subsequent adverse impacts on nervous system development are similar in both sexes. There are no compelling data to suggest sex differences in susceptibility.
• Life stages: The relevant life stages for this AOP are fetal and early postnatal ages during critical windows of nervous system development where thyroid receptor gene expresion guides normal development of the brain. Many studies have demonstrated clear windows of developmental susceptibility, with different brain regions showing distinct ontogenetic profiles for TH driven brain development.  It should be noted that the majority of evidence for this statement is derived from stressor expsoures that alter TH levels in tissues rather than perturbations of TR action. This AOP does not apply to adult life states.
• Taxonomic: Based on the majority of the available evidence the taxonomic applicability domains of this AOP is mammals. Most evidence for this AOP has been gathered primarily from laboratory rodents and humans. However, there are supporting data from amphibians demonstrating the importance of TR mediatived gene expresion for development of the brain.  Due to the conserved nature of TR transcriptional activity, this AOP is likely to be applicable to other classes of vertebrates where thyroid hormones drive development of the nervous system (e.g., birds, fish, reptiles). However, species-specific differences in development and compensatory endocrine responses may influence the outcomes, particularly from a quantitative standpoint.

It is widely accepted that each of the key events is essential.

• Molecular Initiating Event: The molecular initiating event, i.e. antagonism fo TRs, is the essential event that initiates this AOP, as supported by in vitro and in vivo evidence. TRs control and mediate a wide varity of genes during development.  A number of studies have demonstrated that mutations in TRA1 and TRa2 result in clear alteration in gene expression in the developing brain.
• Hippocampal Gene Expression, Altered: It is well established specific genomic pathways underlie the progression of a number of neurodevelopmental processes in the hippocampus. There is some evidence from ex vivo studies that administration of growth factors will reverse the hippocampal dysplasia seen in Jacob/Nsfm knockout mice (Spilker et al., 2016). Less is known about the impact of hormone replacement on TH-responsive gene expression and the qualitative and quantitative relationships between altered TH-dependent gene expression in this brain region and altered hippocampal cytoarchitectural anatomy.
• Hippocampal anatomy, altered: It is well accepted that normal hippocampal anatomy is critical for hippocampal physiological function, and that alterations in anatomy lead to altered neuronal activity in the hippocampus (Lee et al., 2015; Grant et al., 1992; Spilker et al., 2016).
• Hippocampal physiology, altered: It is a well-accepted assertion that hippocampal synaptic integrity and neuronal plasticity are essential for spatial information processing in animals and spatial and episodic memory in humans. However, other brain regions also can influence these complex behaviors. Limited data from studies in BDNF knockout animals demonstrate that deficits in hippocampal synaptic transmission and plasticity, and downstream behaviors can be rescued with recombinant BDNF (Aarse et al., 2016; Andero et al., 2014).
• Cognitive function, decreased: It is a well-known fact that TH are critical for normal nervous system development (Williams et al., 2008). And this includes development of the hippocampus which plays a major role in spatial, temporal, and contextual memory. Indeed, most developed countries check for childhood hypothyroidism at birth to immediately begin replacement therapy. This has been shown to alleviate most adverse impacts of hypothyroidism in congenitally hypothyroid children (Derksen-Lubsen and Verkerk 1996; Zoeller and Rovet, 2004). The essentiality of the relationship between decreased TH levels and this adverse outcome is well accepted. Decreased cognitive function specific to the hippocampal region are particularly associated with decrements in memory and learning domains of cognition.

Assessment of quantitative understanding of the AOP:  Currently, there are no data that allow a quantiative assement of the impact of modulation of TR mediated gene expression and changes in gene expression in the brain.  The majority of the evidence for the KER linking the MIE to altered gene expression in the brain is derived from TR knockout models in mice and mutations in both mice and humans.  For the rest of the KERs in this AOP, there is a limited amount of data from dose-response studies (mostly from studies on TPO inhition - see AOP42)  demonstrating increasing impact with increasing chemical dose for all the KEs, and the direct and indirect KERs. At present, the overall quantitative understanding of the AOP is insufficient to directly link a measure of chemical potency as a TR antagonist to a quantitative prediction of effect on cognitive function (e.g., IQ in humans, learning deficits in rodents). Empirical information on dose-response relationships for the MIE and intermediate KEs, currently unavailable, would inform a computational, predictive model for TR antagonist mediated gene changes that resutl in adverse congnitive development.