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Thyroid Disrupting Chemicals: Mechanisms and Mixtures Kevin M international journal of andrology ISSN 0105-6263 REVIEW ARTICLE Thyroid disrupting chemicals: mechanisms and mixtures Kevin M. Crofton Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA Summary Keywords: Environmental contaminants are known to act as thyroid disrupting chemicals endocrine disruptors, mixtures, thyroid (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or func- tion of the thyroid gland, alter regulatory enzymes associated with thyroid hor- Correspondence: mone (TH) homeostasis or change circulating or tissue concentrations of THs. Kevin M. Crofton, PhD, Neurotoxicology For THs, homeostasis is defined as the normal range of THs and TSH in circu- Division, MD-B105-05, National Health and Environmental Effects Research Laboratory, lation and tissues. TDCs include a wide range chemical structures that act US Environmental Protection Agency, through a variety of mechanisms. Concern about TDCs has increased because Research Triangle Park, NC 27711, USA. of the critical role that thyroid hormones play in brain development. A major E-mail: [email protected] uncertainty regarding the endocrine disrupting potential of environmental xenobiotics is the potential for additive, antagonistic or synergistic effects fol- Received 8 October 2007; revised 7 December lowing exposure to mixtures. In addition, there are a number of uncertainties 2007; accepted 11 December 2007 in both interpretation and extrapolation of results from studies of TDC mix- doi:10.1111/j.1365-2605.2007.00857.x tures. Extrapolation of data from laboratory animals to humans is tempered by uncertainty in how the mechanism(s)-of-action of the TDCs may differ between species. The variety of mechanisms by which TDCs alter thyroid homeostasis also yields a difficulty in determining at what level of biological organization to cumulate effects. Should it be at the molecular level, which could be chemical class specific or at the level of a downstream consequence (e.g. circulating hormone levels, brain biochemistry and behaviour) which would be mechanism-independent? To date, the limited data from TDC mix- ture studies suggest that dose addition is reasonably accurate in predicting the effects on serum T4 concentrations. Assessing the health risks of thyroid dis- ruption by environmental xenobiotics will need to include an improved under- standing of how divergent mechanisms alter THs and consequent adverse impacts on nervous system development. regulatory enzymes associated with thyroid hormone Introduction (TH) homeostasis, or change circulating or tissue concen- A variety of data suggest an increased need for character- trations of THs (Crofton et al., 2005). TDCs include a izing the potential risks of xenobiotics as endocrine dis- wide range of chemical structures that act through a vari- ruptors (IPCS, 2002; Daston et al., 2003; Guillette, 2006). ety of mechanisms. A large number of environmental Environmental chemicals are known to adversely impact chemicals and stressors are known to influence measures a number of hormonal systems, including oestrogen, of thyroid function in experimental animals (Capen, androgens and thyroid hormones. Concern about thyroid 1994; Brouwer et al., 1998; Brucker-Davis, 1998; DeVito hormone disrupting chemicals (TDCs) has increased et al., 1999). There is also evidence that xenobiotics dis- because of the critical role that thyroid hormones play rupt thyroid hormone homeostasis in humans (Gaitan, during development, especially in the nervous system 1990; Longnecker et al., 2003; Delange, 2005; Blount (Porterfield & Stein, 1994; Brucker-Davis, 1998; Zoeller & et al., 2006; Steinmaus et al., 2007). Crofton, 2000; Morreale de Escobar et al., 2004; Zoeller & Uncertainties hamper predictions of the health risks of Tan, 2007). Broadly defined, TDCs are xenobiotics that TDCs. One uncertainty is the potential for additive, alter the structure or function of the thyroid gland, alter antagonistic or synergistic effects following exposure to Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 209–223 No claim to original US government works 209 Thyroid disrupting chemicals and mixtures K. M. Crofton endocrine disrupting mixtures (Wade et al., 2002; Daston Atterwill et al., 1992; Thomas & Williams, 1992). Regula- et al., 2003; De Rosa et al., 2006). In addition, there are a tion of THs includes control of iodine uptake, synthesis number of uncertainties in the interpretation of results and storage of THs in the thyroid gland, release into and from animal studies, as well as extrapolation of findings transport of THs within an out of circulation, tissue-spe- to humans. Extrapolation of data from laboratory animals cific deiodination and degradation by catabolic hepatic to humans is tempered by the uncertainty in how the enzymes (Fig. 1). The hypothalamic-pituitary axis con- mechanism(s)-of-action of the TDCs may differ between trols the synthesis and secretion of THs in the thyroid species [cf. (McClain, 1995; Capen, 1997; Tabb et al., gland via production of thryotropin releasing hormone 2004)]. The variety of mechanisms by which TDCs alter (TRH) and thyroid stimulating hormone (TSH). Once thyroid homeostasis yields yet another difficulty in deter- released into circulation, THs are bound to plasma trans- mining at what level of organization to cumulate effects. port proteins. Circulating levels of T3 and T4 provide a Should it be at the molecular level, which could be negative feedback to the hypothalamus and pituitary; con- chemical class specific or at the level of a downstream versely, lowered levels of T3 and T4 active the feedback consequence (e.g. circulating hormone levels, brain bio- mechanism, resulting in increased TRH and TSH, which chemistry and behaviour) which would be mechanism then increases TH production in the thyroid gland. T3 independent? Assessing the health risks of thyroid disrup- and T4 levels are also controlled by extra-thyroidal mech- tion by environmental xenobiotics will need to include an anisms. Peripheral tissue deiodinases are responsible for improved understanding of how divergent mechanisms conversion of T4 to T3 (the major source of circulating alter THs and consequent adverse impacts on nervous T3) and also metabolites of T3 and T4 (e., reverse T3, system development. T2) (Kohrle, 2002). There are also two other important regulatory processes. The first are cellular thyroid hor- mone transporters (e.g. OATP1C1, MCT8), responsible Impact of xenobiotics on thyroid hormones for moving T4, T3 and metabolites into and out of cells Thyroid hormone homeostasis involves a complex inter- (Friesema et al., 2005; Kohrle, 2007). The other play of homeostatic regulatory processes (Hill et al., 1989; major regulatory process is hepatic catabolism of THs. _ Hypothalamus Blood TRH Liver + _ Free-TH PBDEs Dioxins Pituitary Ah - Receptor T3 & T4 THT4 TTR/TBG TTR/TBG T4 TSH HO-PCBs Transporters T4 EMD 49209 UDPGTsUDPGTs 3 & Thyroid + T Bound-TH T3 & T4 T4-Gluc CAR/PXR PBDEs PTU T4 T3 PCBs Mancozeb Thyroperoxidase Pronamide Thyroperoxidase T3 & T4 Transporters Deiodinases I ++ tyrosinetyrosine T4 > T3 PTU Octyl-methoxycinnamate Biliary excretion NIS Peripheral tissues Perchlorate Thiocyanate Iodine Figure 1 Thyroid hormone control pathways and sites of disruption by xenobiotic chemicals. Sites or processes where xenobiotics are known or hypothesized to act as TDCs are indicated in the boxes and ovals. Xenobiotics that block, inhibit or upregulate these processes are shown in red text. Journal compilation ª 2008 Blackwell Publishing Ltd • International Journal of Andrology 31, 209–223 210 No claim to original US government works K. M. Crofton Thyroid disrupting chemicals and mixtures A number of hepatic uridine diphospho-glucuronosyl- a direct effect on type I or II 5¢-deiodinase (Schroder-van transferase (UGT) or sulfotransferase (SULT) isozymes der Elst et al., 1998). are responsible for Phase II metabolism of THs, resulting Recent evidence supports the conclusion that xenobiot- in biliary excretion of glucuronide or sulphate conjugates ics alter the expression of cellular proteins important of T4 or T3 (Kester et al., 2003; Mackenzie et al., 2005). for hormone transport into and out of cells. Xenobiotic- A wide range of structurally diverse xenobiotics act induced changes in mRNA and proteins levels of a through a variety of mechanisms to alter thyroid hor- number of multi-drug resistant proteins and organic mone homeostasis (Fig. 1, Table 1) (Atterwill et al., 1992; anion-transporting polypeptides (OATP) have been Brouwer et al., 1998; Brucker-Davis, 1998; Hurley, 1998; demonstrated with both in vivo and in vitro preparations DeVito et al., 1999). Table 1 lists chemicals with known (Staudinger et al., 2001; Guo et al., 2002; Jigorel et al., or suspected mechanisms-of-action and the effects on 2006; Petrick & Klaassen, 2007). Some of these transport- thyroid hormones. Some chemicals such as perchlorate or ers control thyroid hormone influx into brain and liver thiocyanate, inhibit the uptake of iodide into the thyroid cells (Friesema et al., 2005). Changes in the expression of and subsequently decrease TH synthesis (Wolff, 1998). these transporter proteins may interact with other Other chemicals decrease TH synthesis by inhibition of changes induced by TDCs and exacerbate alterations in thyroid peroxidase thus blocking incorporation
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