Endocrine Abstracts

Thyroid hormone (TH) biosynthesis, storage and secretion is organized in a complex series of biochemical reactions round an evolutionary conserved functional unit, the thyroid follicle, a highly vascularised epithelial structure enclosing the colloidal lumen mainly composed of thyroglobulin (Tg). The luminal apical surface of this tight epithelial monolayer is the site of H₂O₂ dependent TH biosynthesis and is involved in mobilization of Tg, the colloidal matrix and storage protein. The initial step of biosynthesis, basolateral iodide uptake by the sodium-iodide symporter NIS, is blocked by voluminous anions (e.g. ClO₄⁻), a rocket fuel increasingly contaminating the global surface. Nutritive components have been identified as goitrogens, such as C-and O-glycosidic glucosinolates (cruciferacea), cyanates, isocyanates and thiocyanates (e.g. cassava), which (irreversibly) inhibit thyroperoxidase (TPO). Several flavonoids and isoflavonoids, widely used as ‘green’ ‘natural plant steroids’ in postmenopausal hormone replacement therapy such as genistein and UV screens (e.g. benzophenone 2) regularly applied as sun protectants to prevent erythema, sun burns and skin cancer are potent TPO inhibitors and lead to goiter formation if iodine supply is inadequate as in many parts of the world. No specific inhibitors of thyrooxidase (Duox) or cathepsins involved in T4 and T3 liberation from Tg or of plasma membrane transporters (MCT8, OATP14, LATs) involved in thyroid secretion or cellular uptake of T4 and T3 have been identified among endocrine disrupters. Several endocrine disrupters have been reported to displace T4 and T3 from its binding to the serum distributor protein transthyretin (TTR), resulting in altered free TH levels, increased cellular uptake or renal excretion. Among these agents are flavonoids (F21388), flame retardants (TBBPA) and other phenolic or aromatic compounds with structural similarities to T4. However, several endocrine disrupters are also potent inhibitors of intracellular deiodinase enzymes, (de-)conjugating enzymes (sulfotransferase, glucuronidase, sulfatase) and T3 receptors, thus interfering with intracellular availability and action of the ligand T3, which modulates gene expression by T3 receptors TRα and TRβ. Therefore, several of the identified endocrine disruptors exhibit multiple modes of interference in the TH axis and raise major concern especially under conditions of inadequate iodine supply and during life phases sensitive to altered TH availability such as fetal, neonatal, pubertal development, pregnancy, aging and euthyroid sick syndrome. More data on human exposure and risk assessment need to be collected in the REACH project of the EU.