Perturbed thyroid hormone homeostasis leading to developmental neurotoxicity (WP5517)

The Adverse Outcome Pathway (AOP) for thyroid hormone-mediated neurodevelopmental adversities describes how disruptions in thyroid hormone homeostasis lead to impaired neurodevelopment. It begins with molecular initiating events (MIEs) such as altered thyroid hormone transport, metabolism, or receptor signaling, affecting key players like MCT8 (SLCO1A2), OATP1C1 (SLCO1C1), and thyroid hormone receptors (TRα1). These disruptions impair cellular processes essential for neurodevelopment, including myelination, synaptogenesis, and neural network formation, particularly in astrocytes, neurons, and oligodendrocytes. As a result, key events (KEs) such as reduced thyroid hormone availability in the brain, altered neuronal differentiation, and impaired synaptic function occur, ultimately leading to adverse outcomes like cognitive deficits and neurodevelopmental disorders.

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