Xenobiotic modalities impacting the thyroid 3H framework of hormonogenesis, homeostasis, and human health

The thyroid gland is a central endocrine organ regulating growth, metabolism, and energy balance, and is increasingly vulnerable to interference by diverse xenobiotic compounds from pharmaceuticals, environmental pollutants, diet, and consumer products. This review introduces a thyroid '3H' framework - hormonogenesis, homeostasis, and human health - to integrate current understanding of how thyroid endocrine-disrupting chemicals (Thy-EDCs) perturb thyroid physiology and the hypothalamic-pituitary-thyroid axis. A systematic literature search was conducted using PubMed, Scopus, and Web of Science, supplemented by reference screening to ensure comprehensive coverage of mechanistic and toxicological evidence. The synthesis indicates that various exogenous compounds - including tyrosine kinase inhibitors, immune checkpoint inhibitors, heavy metals, industrial endocrine disruptors, and certain dietary phytochemicals - affect thyroid function through multiple molecular initiating events. These include inhibition of thyroperoxidase, disruption of iodine uptake and organification, altered deiodinase activity, modulation of thyroid hormone receptor signaling, and immune-mediated effects on thyroid tissue. Such perturbations lead to abnormalities in hormone synthesis, metabolism, and systemic hormone homeostasis. Emerging structure-activity relationship (SAR) and computational modeling approaches provide further insight into how specific chemical features determine thyroid-disruptive potential, supporting the advancement of predictive toxicology and risk assessment. The novelty of this review lies in its integrated 3H perspective, linking physiological, molecular, immunological, and toxicological dimensions of thyroid disruption. This conceptual framework supports improved diagnosis of thyroid dysfunction, promotes safer chemical and drug design, and informs regulatory strategies aimed at protecting endocrine health.