Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy?

Abstract

Maternal euthyroidism during pregnancy is crucial for normal development and, in particular, neurodevelopment of the foetus. Up to 3.5 percent of pregnant women suffer from hypothyroidism. Industrial use of various chemicals-endocrine disrupting chemicals (EDCs)-has been shown to cause almost constant exposure of humans with possible harmful influence on health and hormone regulation. EDCs may affect thyroid hormone homeostasis by different mechanisms, and though the effect of each chemical seems scarce, the added effects may cause inappropriate consequences on, for example, foetal neurodevelopment. This paper focuses on thyroid hormone influence on foetal development in relation to the chemicals suspected of thyroid disrupting properties with possible interactions with maternal thyroid homeostasis. Knowledge of the effects is expected to impact the general debate on the use of these chemicals. However, more studies are needed to elucidate the issue, since human studies are scarce.

Figure 1

The complex mechanisms of regulation of thyroid hormone homeostasis and the possible mechanism of action of the thyroid disrupting chemicals. The thyroid and the thyroid hormones, tri-iodothyronine (T3) and thyroxine (T4), participate with the hypothalamus, secreting thyrotropin releasing hormone (TRH), and pituitary, secreting thyrotropin (TSH) in a classical feedback controlled loop. Iodide is transported into the cell by the sodium-iodine symporter (NIS) and oxidized by thyroid peroxidase (TPO). TPO also catalyzes the iodination of thyrosine residues on thyroglobulin (Tg). All processes in the cell are stimulated by binding of TSH to the TSH receptor (TSH-R). In the circulation, thyroid hormones are bound to thyroxine-binding globulin (TBG), albumin and prealbumin, and in some cases transthyretin (TTR). T4 is deiodinated by deiodinases in the liver and target tissues. In the target cells, T3 binds to nuclear thyroid hormone receptor (TR), and with the retinoid X receptor, it binds at specific sequences at the DNA string, forming the thyroid hormone response elements (TRE). In the liver, thyroid hormones are metabolized by UDP-glucuronyl transferase (UDPGT), and finally, the metabolites are excreted in the urine. (1) Inhibition of iodine uptake in the cells by inhibition of NIS: perchlorate, thiocyanate, nitrate, and phthalates. (2) TPO inhibition: NP and isoflavones. (3) Inhibition of TSH-R: DDT and PCB. (4) Binding to transport proteins: PCB, phthalates, phenol, flame retardants, and HCB. (5) Cellular uptake of thyroid hormones: phthalates and chlordanes. (6) Binding to thyroid hormone receptor and affecting gene expression: PCB, phenols, flame retardants, BPA and HCB. (7) Inhibition of deiodinases: Styrenes and UV-filters, (8) Activation of hepatic UDPGT: dioxins and pesticides, (9) Inhibition of the hypothalamo-pituitary-thyroid axis: lead. (10) Excretion/clearance of thyroid hormones: PCB, dioxin, phenols, flame retardants, HCB, and BPA.