Prenatal Exposures to Multiple Thyroid Hormone Disruptors: Effects on Glucose and Lipid Metabolism

Figure 1

Thyroid hormone synthesis and secretion regulated through a negative feedback loop. In the hypothalamus, Thyrotropin- (TSH-) releasing hormone (TRH) stimulates the anterior pituitary gland to secrete thyroid stimulating hormone (TSH) which then initiates thyroid hormone (TH) synthesis and release from the thyroid gland by the action of thyroid peroxidase enzyme (TPO) on thyroglobulin (Tg). TRH and TSH are inhibited by negative (−) feedback of the thyroid hormones. Thyroxine (T4) and triiodothyronine (T3) are released into the circulation where they bind thyroid hormone binding proteins, namely, transthyretin (TTR), thyroxine binding globulin (TBG), and albumin. These complexes are then transported into cells via TH transporters. In the cell, Types 1 and 2 deiodinase enzymes convert T4 to T3, which then enters the nucleus and binds with thyroid hormone receptors (TRs) which in turn bind other nuclear receptors (e.g., retinoid X receptor (RXR)). These receptor complexes then bind thyroid hormone responsive elements (TREs) on target genes which results in the transcription of the DNA sequence to messenger ribonucleic acid (mRNA). Deiodinase Type 3 (D3) also regulates thyroid hormones by converting T4 and T3 to reverse T3 (rT3) and 3,5-diiodo-L-thyronine (T2), respectively. In the liver, deiodinase Type 1 (D1) enzyme is involved in both T3 production and clearance of plasma rT3. Thyroid hormone is also metabolized by conjugation to sulphate (by sulfotransferases (SULTs)) and glucuronic acid (by UDP-glucuronosyltransferase (UGTs)). Conjugation increases the water solubility of TH, facilitating its rapid degradation. In the kidney, Type 1 (D1) deiodinase is also involved in T3 production and excretion of thyroid hormones.