Regulation of Thyroid Disrupting Chemicals to Protect the Developing Brain

Synthetic chemicals with endocrine disrupting properties are pervasive in the environment and are present in the bodies of humans and wildlife. As thyroid hormones (THs) control normal brain development, and maternal hypothyroxinemia is associated with neurological impairments in children, chemicals that interfere with TH signaling are of considerable concern for children's health. However, identifying thyroid-disrupting chemicals (TDCs) in vivo is largely based on measuring serum tetraiodothyronine in rats, which may be inadequate to assess TDCs with disparate mechanisms of action and insufficient to evaluate the potential neurotoxicity of TDCs. In this review 2 neurodevelopmental processes that are dependent on TH action are highlighted, neuronal migration and maturation of gamma amino butyric acid-ergic interneurons. We discuss how interruption of these processes by TDCs may contribute to abnormal brain circuitry following developmental TH insufficiency. Finally, we identify issues in evaluating the developmental neurotoxicity of TDCs and the strengths and limitations of current approaches designed to regulate them. It is clear that an enhanced understanding of how THs affect brain development will lead to refined toxicity testing, reducing uncertainty and improving our ability to protect children's health.

Impact/Purpose

Background/Overview: A wide variety of manmade chemicals have the potential to disrupt the thyroid axis act as TDCs. Thyroid hormones (TH) are critical for brain development, but significant knowledge gaps remain on how TH affect brain development. Implementation of novel in vitro approaches and the recent augmentation of existing in vivo screening strategies, have improved detection of TDCs but fail to provide information on if or how the brain is affected. As our general understanding of how THs control brain development has advanced, it is now clear that more clinically relevant models are necessary to evaluate the potential health implications of exposure to TDCs. Relevancy to EPA Program/Regional Research Needs/Priorities: This review addresses Chemical Safety for Sustainability (CSS) Adverse Outcome Pathway Discovery and Development (AOPDD 17.01). The paper reports on the status of current regulatory approaches to identify and characterize the potential health impact of TDCs. It describes two biological substrates that are negatively impacted by moderate degrees of TH in rodent models and serve as critical key events in the refinement of AOP TH-dependent AOPs and neurodevelopment. Advancement in our ability to of TDCs to impair brain functions have been hamstrung by the lack of sufficiently sensitive animal models. The strengths and limitations of current highthroughput screening approaches and in vivo hormone assessments in regulatory studies are discussed and ongoing research efforts that are needed to link these screening level outputs and allow translation to neurodevelopmental outcomes of concern. Name(s) of Program Office Reviewer(s) of Earlier Drafts: N/A Program Office/Regional Office Co-Authors: N/A Description: Two fundamental neurodevelopmental processes controlled by TH action in animal models of TH-dependent brain development are reviewed - neuronal migration and maturation of GABAergic function. We propose that interference with one or both of these processes, disrupts neural circuit formation, and this may underlie the mild cognitive impairments observed in children born to women with mild TH dysfunction. These two processes are highlighted as quantifiable effects in these responses have been observed by more modest TH deficiencies in rodents and as such may be more appropriate measures to model the effects of human exposures to environmental TDCs. The paper synthesizes findings across a number of disciplines, developmental neurobiology, thyroid biology, and neurotoxicology to elucidate how maternal TH insufficiency through these mechansims, leads to cognitive impairments. An update of the status of current issues in the evaluation of the neurotoxicology TDCs is provided, the limitations of current regulatory screening efforts designed to address them is discussed. The paper highlights how more ‘toxicologically relevant’ animal models of TH disruption are essential to define a roadmap to sensitive early indicators of neurodevelopmental disruption by TDCs and how these efforts will allow development of quantitative AOPs for the translation from hazard identification to adverse neurodevelopmental effect. Publication Information (journal, book chapter/book) and Estimated Timelines. This paper is an invited review and is to be published in Endocrinology Contact: Mary E. Gilbert, PhD, ORD, CPHEA, PHITD, Neuroendocrine Toxicology B

Citation

Gilbert, Mary E., K. OShaughnessy, AND M. Axelstad. Regulation of Thyroid Disrupting Chemicals to Protect the Developing Brain. Endocrine Society, 161(10):bqaa106, (2020). [DOI: 10.1210/endocr/bqaa106]

DOI: Regulation of Thyroid Disrupting Chemicals to Protect the Developing Brain