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

Abstract

Background. Thyroid hormones (THs) are essential for normal human fetal development and play a major role in the regulation of glucose and lipid metabolism. Delivery of TH to target tissues is dependent on processes including TH synthesis, transport, and metabolism. Thyroid hormone endocrine disruptors (TH-EDCs) are chemical substances that interfere with these processes, potentially leading to adverse pregnancy outcomes. Objectives. This review focuses on the effects of prenatal exposures to combinations of TH-EDCs on fetal and neonatal glucose and lipid metabolism and also discusses the various mechanisms by which TH-EDCs interfere with other hormonal pathways. Methods. We conducted a comprehensive narrative review on the effects of TH-EDCs with particular emphasis on exposure during pregnancy. Discussion. TH imbalance has been linked to many metabolic processes and the effects of TH imbalance are particularly pronounced in early fetal development due to fetal dependence on maternal TH for proper growth and development. The pervasive presence of EDCs in the environment results in ubiquitous exposure to either single or mixtures of EDCs with deleterious effects on metabolism. Conclusions. Further evaluation of combined effects of TH-EDCs on fetal metabolic endpoints could improve advice provided to expectant mothers.

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.

Figure 2

TH-EDCS targets and effect on fetal fuel metabolism. Thyroid hormone endocrine disrupting chemicals (TH-EDCs) disrupt the thyroid economy by altering the hypothalamus, anterior pituitary, and thyroid axis (HPT-axis) which results in altered thyroid stimulating hormone (TSH) levels and in turn the thyroid hormone (TH) levels. TH-EDCs also interfere with the synthesis of TH by inhibiting thyroid peroxidase (TPO) activity, iodine uptake, and deiodinase activity, TH binding to transport proteins, and TH metabolism and excretion which all result in the alteration of TH levels. TH-EDCs inhibit TH binding at the TH receptors and at the TH response elements (TREs); this results in the inhibition of TH action on target genes. Alterations in the TH levels as well as its action lead to altered fuel metabolism and eventually in fetal metabolic reprogramming.

Figure 3

Placental transfer and biotransformation of TH-EDCs. Thyroid hormone endocrine disrupting chemicals (TH-EDCs) enter the placenta from the maternal compartment via various transporters located at the maternal interface of the placenta and are biotransformed by metabolizing enzymes to various metabolites that then enter the fetal compartment through transporters located at the fetal interface of the placenta. TR indicates transporters.