Mechanisms of developmental neurotoxicity mediated by perturbed thyroid hormone homeostasis in the brain: an adverse outcome pathway network.

Thyroid hormone (TH) is crucial for proper neurodevelopment. Insufficient TH concentrations in early life are associated with lower IQ and delayed motor development in children. Intracellular levels of TH are modulated via the transmembrane transport of TH and intracellular deiodination, and can mediate gene transcription via binding to the nuclear TH receptor. Chemical exposure can disrupt TH homeostasis via modes of action targeting intracellular mechanisms, thereby potentially influencing TH transport, deiodination or signaling. Understanding the cause and effect relationships of chemical hazards interfering with TH homeostasis in the developing brain is necessary to identify how chemicals might disturb brain development and result in neurodevelopmental disorders. Adverse Outcome Pathways (AOPs) can provide a template for mapping these relationships, and so far multiple AOPs have been developed for TH homeostasis and adverse effects on cognition. The present review aims to expand current AOP networks by (1) summarizing the most important factors in the regulation of brain development under influence of TH, (2) integrating human-based mechanistic information of biological pathways which can be disturbed by TH disrupting chemicals, and (3) by incorporating brain-specific TH-mediated physiology, including barriers and cell specificity, as well as clinical knowledge. TH-specific pathways in the fetal brain are highlighted and supported by distinguishing cell type specific Molecular Initiating Events (MIEs) and downstream Key Events (KEs) for astrocytes, neurons and oligodendrocytes. Two main pathways leading to adverse outcomes (AOs) in the areas of 'cognition' and 'motor function' are decreased myelination due to oligodendrocyte dysfunction, and decreased synaptogenesis and network formation via the neurons. The proposed AOP framework can form a basis for selecting developmental neurotoxic in vitro and in silico test systems for an innovative human-focused hazard testing strategy and risk assessment of chemical exposure.