The thyroid gland consists of two lobes of endocrine tissue located just below the larynx on each side of the trachea with an isthmus connecting the two lobes (Fig. 21-7; Capen and Martin, 1989; Capen, 2001). A second cell type is also present, the C-cells, or parafollicular cells composing the intrafollicular spaces (Capen and Martin, 1989; Capen, 2001). The C-cells synthesize and secrete calcitonin (CT), a hormone involved in calcium homeostasis (see “Parathyroid gland” section for more details).
Anatomy of the thyroid and parathyroid glands. The schematic shows the thyroid gland in humans, which consists of two lobes of endocrine tissue, located just below the larynx on each side of the trachea with an isthmus connecting the two lobes (Modified from Porterfield, 2007).
The thyroid secretes two hormones known as thyroxine (T4) and triiodothyronine (T3) (Capen and Martin, 1989; Capen, 2001; Hedge et al., 1987). Both of these hormones are produced in epithelial cells in the basic functional unit of the thyroid known as the follicle (Fig. 21-8). Each follicle consists of a sphere of epithelial cells surrounding a colloidal core. The colloid material is composed of the glycoprotein thyroglobulin (TGB), which acts as a storage depot for T4 and T3 (Capen and Martin, 1989; Capen, 2001). In humans, about three months of thyroid hormone is stored as TGB in the colloid (Hedge et al., 1987). This represents the largest reserve of any stored hormone in the body. Generally, the level of secretory activity of follicular cells can be estimated as a direct function of their height. Cells involved in synthesizing thyroid hormone are columnar in shape, whereas quiescent cells are cuboidal (Capen and Martin, 1989; Capen, 2001).
Histology of the thyroid gland. The micrograph shows thyroid follicles (FC) composed of epithelial cells, the site of thyroid hormone synthesis, with colloid (C), the site of thyroid hormone storage, contained in the follicular lumen. The epithelial cell contains a basal and apical face. The interstitial compartment is composed of C cells, the site of synthesis, and secretion of calcitonin (Modified from Porterfield, 2007).
T4 and T3 are important regulators of overall metabolism, and their effects are regulated within a long time frame (Capen, 2001; Hedge et al., 1987). Essentially all tissues are to some degree targets for thyroid hormone. However, the primary target tissues for thyroid hormone include the liver, kidney, heart, brain, pituitary, gonads, and spleen (Capen and Martin, 1989; Capen, 2001; Zoeller et al., 2007).
Some studies indicate that xenobiotics directly affect the structure of the thyroid gland (Capen, 2001). For example, some environmental chemicals such as heavy metals and red dye #3 are known to decrease the size of the colloid space (Bronnikov et al., 2005; Capen and Martin, 1989; Capen, 2001). This is thought to reduce the space required for storing hormones, leading to an impaired ability of the thyroid gland to synthesize and store thyroid hormones. Chemicals such as PCBs are known to alter the appearance of the epithelial cells so that they are hypertrophic or hyperplastic in nature (Capen, 2001; Langer, 2010). This is thought to lead to excessive thyroid hormone production.
Thyroid Hormone Structure and Synthesis
Thyroid hormones are composed of two modified, covalently linked tyrosine amino acids (Fig. 21-9, Capen, 2001; Hedge et al., 1987). Each of the aromatic rings of the tyrosines contains one or two iodides. T4 contains two iodides on each aromatic ring for a total of four, while T3 contains two iodides on the tyrosine closest to the amino acid moiety (amino and carboxy groups), and one iodide on the outer aromatic ring (Capen, 2001; Hedge et al., 1987). The iodide is derived from dietary intake and is required for biologic activity. While the thyroid gland synthesizes and secretes both T4, and T3, it primarily releases T4. In fact, about 90% of thyroid hormone secreted by the thyroid gland is in the form of T4 in humans (Hedge et al., 1987).
Structure of thyroid hormone (T3and T4). The schematic shows the structures required to make T3, T4, and reverse T3 (rT3). At the apical membrane of the follicular cells, I2 combines with tyrosine residues on thyroglobulin (TGB) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). Coupling between MIT and DIT occurs such that combined MIT and DIT forms T3, whereas combined DIT and DIT forms T4. T4 from the thyroid gland can be peripherally converted to T3 (active hormone) or rT3 (inactive metabolite), then successively deiodinated by the monodeiodinases (Modified from Hedge et al., 1987).
TGB, a glycoprotein containing large numbers of tyrosine amino acid residues, is synthesized in the epithelial cell and serves as the backbone for thyroid hormone synthesis (Capen, 2001; Hedge et al., 1987). Iodine in the form of iodide (I−) is actively transported into the epithelial cell, where it is oxidized to I2 by thyroid peroxidase. At the apical membrane, I2 combines with tyrosine residues on TGB to form monoiodotyrosine (MIT) and diiodotyrosine (DIT), which remain attached to TGB (Capen, 2001; Hedge et al., 1987). Coupling between MIT and DIT occurs such that a combined MIT and DIT forms T3; whereas a combined DIT and DIT forms T4 (Hedge et al., 1987; Capen, 2001).
The iodinated TGB is stored in the follicular lumen as colloid until the thyroid gland is stimulated to secrete hormone (Capen, 2001; Hedge et al., 1987). Upon stimulation, iodinated TGB is endocytosed into the epithelial cell and transported in the direction of the basal membrane where lysosomal enzymes hydrolyze peptide bonds to release T3 and T4 for passive diffusion into the circulation (Capen, 2001; Hedge et al., 1987). Remaining MIT and DIT are recycled in the epithelial cell for synthesis of new TGB (Capen, 2001; Hedge et al., 1987).
T4 from the thyroid gland can be peripherally converted to T3 (active hormone) or reverse T3 (rT3, the inactive metabolite) then successively deiodinated by the monodeiodinases (Capen, 2001; Hedge et al., 1987). About 40% of circulating T4 is metabolized to T3 by 5′-monodeiodinase, and 40% is converted to rT3 by 5-monodeiodinase (Capen, 2001; Hedge et al., 1987; Zoeller et al., 2007). Additionally, about two-thirds of T3 and all rT3 in circulation are produced from T4 by peripheral conversion (Capen, 2001; Hedge et al., 1987). As a result, the ratio of circulating T4 and T3 does not reflect the ratio of these two substances when they were released from the thyroid gland. Based on a variety of observations, it appears that circulating T4 levels provide a “sink” of prohormone that can serve as a ready supply for peripheral conversion to T3 (the active form; Hedge et al., 1987).
Several studies indicate that xenobiotics can interfere with thyroid gland function by adversely affecting the process of thyroid hormone synthesis (Jugan et al., 2010; Kortenkamp, 2008; Lynch et al., 2002; Mastorakos et al., 2007; Sauvage et al., 1998). For example, environmental chemicals such as perchlorate, chlorate, and bromate inhibit uptake of iodide and thus, decrease thyroid hormone synthesis (Crofton, 2008). Some chemicals such as genistein and daidzein in soy products, thionamides, and substituted phenols can inhibit thyroid peroxidase, blocking incorporation of iodide into TGB (Delclos and Newbold, 2007; Doerge and Chang, 2002). Further, some chemicals may interfere with monodeiodinases, leading to decreased levels of thyroid hormones. Specifically, studies have shown that red dye #3 and propylthiouracil inhibit 5′-monodeiodinase, leading to reduced serum levels of T3 (Capen, 2001; Crofton, 2008).
Thyroid Hormone Binding Proteins
Once released into the blood, thyroid hormones are rapidly bound to high affinity serum binding proteins (Capen, 2001; Hedge et al., 1987). The result is that less than 1% of the T3 (99.7% bound) and less than 0.1% of the T4 (99.97% bound) are free in circulation (Hedge et al., 1987). Only the small unbound fraction of the total hormone pool has access to receptors in target cells, and thus only the unbound fraction can exert biological activity.
There are three types of thyroid hormone binding proteins: thyroid binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (Hedge et al., 1987; Capen, 2001). TBG binds about 80% of the thyroid hormones, whereas TBPA and albumin each bind about 10% of the thyroid hormones (Hedge et al., 1987). Environmental chemicals such as the PCBs and PBDEs are known to displace thyroid hormones from serum binding proteins (Jugan et al., 2010; Patrick 2009; Yamauchi and Ishihara, 2006). The displacement of thyroid hormones from the binding proteins often leads to a rapid decline in serum thyroid hormone levels.
Thyroid Hormone Receptors
Thyroid hormones act by binding to thyroid hormone receptors (TRs) (Zoeller, 2005). TRs are members of the nuclear receptor superfamily of ligand-inducible transcription factors. TRs can form homodimers or heterodimers with other nuclear hormone receptors such as the retinoid X receptor (Zoeller, 2005). The homodimers and heterodimers bind to thyroid hormone response elements located in target genes and interact with coactivators and corepressors to regulate transcription. In humans, thyroid hormone receptors are the products of two genes that encode three thyroid hormone receptor isoforms known as TRα, TRβ1, and TRβ2 (Zoeller, 2005). While all three isoforms are present in most tissues, their expression differs spatially and temporally during development (Zoeller, 2005). TRα is abundant in the brain, heart, and immune system, whereas TRβ1 is particularly expressed in the brain, liver, and kidney (Zoeller, 2005).
Environmental chemicals can interfere with thyroid hormone binding to TRs and thyroid-hormone related transcription at multiple levels (Jugan et al., 2010; Kitamura et al., 2002; Patrick, 2009; Zoeller, 2005). First, some chemicals such as PBDEs can bind directly to TRs and induce either agonistic or antagonist effects (Zoeller, 2005). Interestingly, some PBDE congeners have different affinities for TRα and TRβ, whereas some congeners can bind to more than one isoform. Second, some environmental chemicals interfere with thyroid hormone binding to receptors via indirect mechanisms (Zoeller, 2005). In such cases, it is thought that the chemicals exert their effects by promoting coactivators or inhibiting corepressors. For example, BPA impairs thyroid hormone action by inhibiting T3 binding to TR and by recruiting the nuclear corepressor N-CoR to the TR, resulting in repression of transcription (Patrick, 2009; Zoeller, 2005). Similarly, some PCBs are able to suppress TR/coactivator (SRC-1) complex-mediated transactivation, leading to suppression of TR-mediated transcription (Crofton, 2008). Third, some xenobiotics can interfere with cross talk between TRs and other nuclear receptors. For example, hydroxyl-PCBs can partially dissociate the heterodimer TR/retinoic acid receptor from the T3-response element (Crofton, 2008). Finally, some chemicals such as BPA and phthalates can inhibit expression of TRs (Patrick, 2009).
Thyroid Hormone Clearance
The main pathway for clearance of thyroid hormones from the serum is via conjugation to glucuronic acid or sulfate by phase II enzymes such as glucuronyl transferases (UDPGTs) and sulfo transferases (SULTs), respectively (Patrick, 2009; Zoeller, 2010). The metabolites then are transported across plasma membranes for elimination by phase III transporters, including the multidrug resistance protein 1 and the multidrug resistance-associated protein 2 (MRP2).
Some studies indicate that some xenobiotics may increase the clearance of thyroid hormones from the serum, limiting the availability of thyroid hormones to act on tissues and often resulting in symptoms of hypothyroidism (Brouwer et al., 1998; Yamauchi and Ishihara, 2006). For example, coplanar and noncoplanar PCB congeners have been shown to induce UDPGTs and SULTs, resulting in low serum T4 levels (Crofton, 2008; Patrick, 2009). In contrast, a few studies have shown that xenobiotics such as pentachlorophenol or triclosan may inhibit SULTs, increasing the availability of thyroid hormones to act on tissues (Crofton, 2008; Jekat et al., 1994; Patrick, 2009). Studies have also shown that xenobiotics such as dioxin, rifampicin, and phenobarbital may decrease the transport of thyroid hormones into the brain and liver by inhibiting phase III transporters (Crofton, 2008).
Regulation of Thyroid Hormone Release
Thyroid hormone secretion is regulated by thyroid-stimulating hormone (TSH, thyrotropin) from the anterior pituitary gland (Capen, 2001; Hedge et al., 1987). The rate of release of TSH is under a hypothalamic–pituitary–thyroid regulatory axis involving negative feedback (Fig. 21-10). Specifically, a hypothalamic releasing hormone known as TRH directly stimulates release of TSH from the anterior pituitary gland (Hedge et al., 1987). TSH then increases secretion of T4 and T3 from the thyroid gland. In turn, T4 and T3 can feedback to the anterior pituitary to inhibit TSH release and they can feedback to the hypothalamus to inhibit TRH release. Interestingly, most inhibition by thyroid hormones is by T4, although T3 can also provide some degree of inhibition (Hedge et al., 1987). Further, the feedback effect is mediated primarily at the level of the anterior pituitary, although some degree of negative feedback occurs at the level of the hypothalamus (Hedge et al., 1987).
Hypothalamic–pituitary–thyroid axis. The hypothalamus synthesizes and secretes thyroid-releasing hormone (TRH). TRH travels to the anterior pituitary via the portal plexus and stimulates the thyrotropes to synthesize and secrete TSH. TSH acts on the thyroid gland to stimulate production and/or release of T3 and T4. T3 and T4 can then exert negative feedback control at the level of the anterior pituitary to inhibit further release of TSH (Modified from Hedge et al., 1987).
In addition to these methods of regulating thyroid hormone secretion, there is a circadian rhythm of TRH and TSH release, with a decrease following the onset of sleep (Hedge et al., 1987). Overall, the thyroid axis responds rapidly at the hypothalamo-pituitary unit, but beyond this level, the system is governed by processes that have extremely long time constants. Therefore, the long half-lives of thyroid hormones in circulation dampen the diurnal rhythm that is obvious in TSH levels. As a result, this rhythm is not reflected in circulating thyroid hormone concentrations. This contributes to the “sluggishness” of the system.
Xenobiotics have been shown to alter the ability of the hypothalamic–pituitary–thyroid regulatory axis to control thyroid hormone levels (Patrick, 2009; Zoeller, 2005). For example, chemicals such as PBDEs may increase TSH levels, leading to increased levels of T4 and T3 (Darnerud et al., 2001). Alternatively, xenobiotics may inhibit TRH or TSH levels, leading to decreased levels of T4 and T3 (Patrick, 2009).
Thyroid hormones influence nearly every tissue in the body, in a variety of ways (Capen, 2001; Hedge et al., 1987; Patrick, 2009). In spite of complexities of hormone action on target tissues, it is reasonably accurate to simply view thyroid hormone as the primary determinant of the overall metabolic rate of the body. The effects are exaggerated in states of thyroid excess (hyperthyroidism) or deficiency (hypothyroidism) and produce the clinical and biochemical manifestations of these disorders. In general, thyroid hormone stimulates both anabolic and catabolic biochemical pathways; however, its over-riding effect is catabolism (energy mobilization).
Thyroid hormone also produces significant effects on growth and development (Capen, 2001; Hedge et al., 1987; Zoeller et al., 2002; Zoeller, 2005). It is essential for normal development of the CNS and for maturation of the skeleton (Dickerson and Gore, 2007; Gore, 2011; Zoeller et al., 2002). A deficiency of thyroid hormone in early life leads to a delay in development of the brain in animal models and humans (Dickerson and Gore, 2007; Gore, 2011; Zoeller et al., 2002). Brain development is especially dependent on thyroid hormone during the first several months after birth in humans (Zoeller, 2005). If thyroid hormone levels are inadequate during this period, severe irreversible mental retardation in the form of cretinism occurs. Early diagnosis and immediate replacement with thyroid hormones can prevent these effects, and are; therefore, essential.
Given the influence of thyroid hormones on numerous tissues in the body, it is not surprising that xenobiotics that affect thyroid hormone levels often cause symptoms of hypothyroidism, hyperthyroidism, or lead to significant impairment in brain development and function. Below are some specific examples of environmental chemicals that have been shown to affect thyroid hormone levels through a variety of mechanisms, resulting in adverse physiological outcomes.
PCBs are some of the best characterized thyroid disrupting chemicals (Boas et al., 2009; Dickerson and Gore, 2007; Gore, 2011; Jugan et al., 2010; Patrick, 2009; Zoeller, 2010). PCBs are industrial chemicals that were widely used in capacitors and transformers. They are made of two phenyl rings with varying degrees of chlorination, resulting in 209 different congeners. The production of PCBs was banned in the 1970s, but unfortunately, PCBs are persistent chemicals and thus, they are still routinely found in humans and wildlife blood samples and tissues.
PCBs are known to interfere with the thyroid system in a manner that leads to serious neurocognitive effects (Gore, 2011; Porterfield, 2000; Zoeller et al., 2002). Several human studies indicate that PCB exposure in prenatal life is associated with lower full-scale and verbal IQ scores and less short-term and long-term memory and attention in postnatal life (Porterfield, 2000; Zoeller et al., 2002). Rodent studies indicate that prenatal PCB exposure increases hyperactivity (Porterfield, 2000; Zoeller et al., 2002). Further, rodent studies indicate that PCB exposure causes hearing disorders because the developing auditory system is sensitive to thyroid hormones (Porterfield, 2000; Zoeller et al., 2002).
While PCBs may exert negative effects on animals and humans via several mechanisms, the most common pathway is thought to include PCB inhibition of thyroid hormone levels or activity (Gore, 2011; Patrick, 2009). Several studies indicate that PCBs decrease the levels of thyroid hormone by inhibiting thyroid hormone synthesis and/or increasing the metabolism of thyroid hormones by increasing phase II enzymes (Zoeller, 2010). Further, some studies indicate that PCBs interfere with thyroid hormone action by inhibiting the binding of thyroid hormones to binding proteins or blocking the ability of thyroid hormones to bind to TRs (Zoeller, 2010).
PBDEs are also well-known thyroid disrupting chemicals (Boas et al., 2009; Jugan et al., 2010; Zoeller, 2010). These chemicals are flame retardants that are used in a variety of products, including electric equipment, clothing, furniture, carpeting, plastics, and paints. PBDEs are not chemically bound to products in which they are used; thus, they can leach from the products into human and wildlife tissues and into the environment over time.
The structure of PBDEs often resembles that of PCBs. Thus, it is not surprising that many of the toxic effects of PBDEs are similar to those elicited by PCBs. Like PCBs, PBDEs have been shown to inhibit thyroid hormone levels and/action, leading to serious neurocognitive deficits. PBDEs inhibit thyroid hormone levels by inducing hepatic phase II enzymes, resulting in increased metabolism of circulating thyroid hormones (Zoeller, 2010). They also can downregulate proteins required for transporting thyroid hormone into target cells and they can bind to TRs, blocking the ability of thyroid hormones to bind to TRs (Zoeller, 2010).
Perchlorate is another thyroid disrupting chemical (Crofton, 2008; Jugan et al., 2010; Patrick, 2009; Zoeller, 2010). This chemical is widely used as a rocket propellant as well as a chemical in fireworks and airbag deployment systems. Perchlorate is also used in pharmaceutical industries. It is a highly stable and water-soluble compound and thus, it is known to persist in the environment, particularly in the water and food supply. While less is known about the effects of perchlorate on the thyroid system than about PCBs and PDBEs, a few studies indicate that perchlorate exposure inhibits thyroid hormone levels, possibly leading to hypothyroid-like outcomes (Crofton, 2008; Patrick, 2009). The mechanism of action of perchlorate is thought to be primarily by reducing iodide uptake, which ultimately reduces thyroid hormone synthesis (Patrick, 2009). It is important to note, however, that the effects of perchlorate on the thyroid gland have not been well studied and the results to date in humans are equivocal.
Pesticides such as dichlorodiphenyltrichloroethane (DDT) and hexachlorobenzene (HCB) are known thyroid disrupting chemicals (Boas et al., 2009). While both DDT and HCB have been banned in many countries, they persist in the environment due to their long environmental half-lives and thus, they may place humans and wildlife at risk for thyroid disorders. Pesticide mixtures containing DDT have been shown to increase thyroid volume and to induce antibodies that attack the thyroid gland, resulting in autoimmune thyroid disease (Boas et al., 2009; Crofton, 2008; Patrick, 2009). Further, DDT has been shown to inhibit TSH receptors, blocking the ability of TSH to induce secretion of T4 and T3 and in turn, resulting in low circulating T4 and T3 levels (Boas et al., 2009; Patrick, 2009). HCB has been shown to interfere with thyroid function by blocking the ability of thyroid hormones to bind to TR (Boas et al., 2009; Crofton, 2008; Patrick 2009).
Perfluorinated chemicals (PFCs) are a family of chemicals used in many products due to their surface protection properties. Such products include stains and oil-resistant coatings, floor polishes, and insecticides. Some studies have shown that a PFC known as perfluorooctane sulfonate (PFOS) decreases T4 levels in pregnant dams as well as their pups (Boas et al., 2009). The PFC known as perfluorooctanic acid (PFOA) has been shown to decrease T3 levels. While the mechanisms by which PFOS and PFOA decrease thyroid hormone levels are not completely clear, studies suggest that they upregulate phase II metabolic enzymes in the liver and increase deiodinases in the thyroid gland (Boas et al., 2009).
BPA is a suspected possible thyroid hormone disrupting chemical (Boas et al., 2009; Zoeller, 2010). It is primarily used in the manufacture of polycarbonate plastics such as those used in baby bottles, toys, and food containers. It is also a component of dental sealants and the linings of food cans. BPA can leach out of products and enter the blood and organs. In fact, recent studies indicate that over 95% of human urine samples contain BPA, indicating continuous and widespread exposure to this chemical. Given the vast exposure of humans to BPA, it is important to consider its potential effects on the thyroid gland. Some laboratory studies have shown that BPA blocks T3 action by antagonizing the binding of T3 to its receptor (Zoeller, 2010). Further, some studies have shown that BPA inhibits T3-mediated gene expression in cell lines (Zoeller, 2010). While the effects of BPA-induced inhibition of thyroid hormone action in humans are unclear, several studies suggest that BPA leads to symptoms of hypothyroidism or thyroid resistance syndrome in animal models. Further, prenatal BPA exposure has been shown to cause attention deficit hyperactivity disorder like symptoms in rodents in postnatal life (Zoeller, 2010). This effect is thought to be due to the BPA-induced inhibition of normal thyroid function, which in turn affects normal development of the neurological system (Zoeller, 2010).
A few recent studies suggest that phthalates may act as thyroid disrupting agents; however, they are not thought to do so to the same degree as PCBs and PBDEs (Boas et al., 2009; Jugan et al., 2010). Phthalates are used to improve the flexibility of plastics used in a variety of products, including toys, medical tubing, plastic bottles, and cosmetics. To date, a few small human studies have shown that phthalate exposures may alter the levels of T4 and T3 levels in adult men and pregnant women (Jugan et al., 2010). Interestingly, a by-product of phthalates produced by gram-negative bacteria has been shown to inhibit thyroperoxidase, an enzyme required for thyroid hormone synthesis (Jugan et al., 2010). This results in low thyroid hormone levels and to symptoms of hypothyroidism in humans. A few rodent studies have shown that a phthalate known as di-n-butyl phthalate decreases T3 and T4 in a dose-dependent manner (Boas et al., 2009; Jugan et al., 2010). The consequences of phthalate-induced changes in thyroid hormone levels in humans or rodents are unclear at this time and should be investigated in future studies.