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Annales d’Endocrinologie 69 (2008) 116–122

Environment and endocrinology: The case of thyroidology J. Köhrle Institut für Experimentelle Endokrinologie und EnForCé, Charité Universitätsmedizin Berlin, Humboldt Universität, Charitéplatz 1, 10177 Berlin, Germany Available online 28 April 2008

Abstract Evidence is accumulating for interference of selected endocrine disrupting chemicals (EDC) with the thyroid axis. EDC disturb thyroid hormone (TH) homeostasis leading to developmental defects, hypothyroidism and altered thyroid growth patterns. A rising incidence of papillary thyroid carcinoma (PTC) in several Western countries cannot be definitely accounted for by improved diagnosis or management of thyroid cancer or improved iodine supply. In recent studies, we and others detected, within the thyroid hormone axis, multiple molecular targets of disruption by EDC, which are used in cosmetics, as pesticides or plasticizers or consumed as -derived compounds with the diet or with nutritional supplements. Several of these agents exert adverse effects on thyroid growth and function in animal or in vitro cellular models. Major targets are the sodium iodide symporter (NIS), the hemoprotein thyroperoxidase (TPO), the T4 distributor protein transthyretin (TTR), the deiodinases, TH conjugating enzymes and the TR thyroid hormone receptor family. Still prevailing iodine deficiency in many parts of the world predisposes the thyroid gland to adverse effects of endocrine disrupters especially under phases of vulnerability during development and under adaptive challenges during diseases. © 2008 Elsevier Masson SAS. All rights reserved.

Keywords: Endocrine disrupter; Deiodinase; Transthyretin; Thyroperoxidase; Iodine; Thyroid; Hormone; Cancer; Goiter; Deficiency; Phytosteroid; ; Isoflavonoid

1. Introduction enduring monitoring programmes. However, more economical, political, intellectual and financial resources are still dedicated to Among all environmental influences on the endocrine sys- development, production, trade and annihilation of weapons in tem, the effects of nutritional iodine deficiency, its impact wars and to lethal warfare logistics than to prevention iodine defi- on goitrogenesis and its consequences for fetal, neonatal and ciency, which is the single most important preventable cause of mental development have probably received the longest and mental retardation worldwide and impaired child development. still persisting interest. Iodine deficiency and its sequelae (cre- Improvement of iodine supply has been practiced in many tinism, IQ deficits, hypothyroidism, goiter) still affect major cultures and by physicians (J.R. Coindet, 1820) [1a] even before parts (1.6 billion) of the world population not only in devel- the element iodine had been discovered by F. Courtois and the oping regions but also in highly industrialized countries and thyroid glands main hormonal product had been identified as thy- economies such as the European Union [1]. Though WHO had roxine (T4) by Kendall [2] in 1915 and chemically synthesized declared to eradicate iodine deficiency by the year 2000, this by Harington in 1927 [3]. goal has not been reached. While adequate iodine intake has Thyroid preparations had been systematically administered been reported even for some developing and industrial countries for treatment of hypothyroidism and myxedema since 1882 by such as Bahrain, parts of South-Africa, Peru’s coastal region MacKenzie, Bruns and Magnus-Levy [4]. and Switzerland (> 100 to < 200 ␮g I/d), moderate to mild defi- Nevertheless, underlying iodine deficiency in the whole ciency is known for Germany, New-Zealand, Australia, some world population sets the stage for adverse reactions and effects parts of USA (> 50 to < 100 ␮g/d), also excess has been noticed of agents interfering at one or several steps and targets of the in coastal Hokkaido (> 500 ␮g/d). These observations indicate complex thyroid hormone. Stringent control of multiple and ongoing requirement for worldwide iodine supplementation and redundant feedback circuits allows efficient adaptation to alter- ations in iodine intake and metabolic challenges of thyroid hormone demand during development, growth, aging or states E-mail address: [email protected]. of healthiness or disease in adults.

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also antagonistic effects of these agents have been described. Table 2 summarizes some major reports on compounds known to target the thyroid hormone axis, their mechanism of action as far as it is known and species affected. Whether all of the interferences reported in wild life species or laboratory ani- mals as well as in vitro cell culture or model studies also have relevance and impact for humans is still controversial. Several reasons have been listed, which might explain different outcome in animals versus humans such as different serum distributor pro- teins, which affect thyroid hormone pool size, tissue targeting and turnover. For example, the high affinity low capacity TH binding protein thyroxine binding globulin (TBG) is expressed only in higher mammals, most primates and humans, while transthyretin, the most conserved and most prevalent TH dis- tribution protein is expressed and secreted mainly by the liver but also by the choroids plexus in species with a larger fat mass and brain size [6]. Other species rely on albumin as major TH binding protein and during development also fetal TH binding proteins are expressed. Depending on the pool size, biological half life and thyroid reservoir of TH and, at the same time, limited or adequate access to iodine supply nutritional, environmental, developmental of medical exposure to agents potentially dis- rupting the TH axis might have different impact, for example, in young or adult, slim or obese, male or female, pregnant or postmenopausal women or people living in equatorial, moder- ate or extremely cold climate zones [7], where different turnover and demand of TH are required to maintain and regulate body temperature, energy metabolism and thermogenesis [8]. Apart from strong data for EDC indicating goitrogenesis, interference with serum TH distributor proteins, which affects free and total TH concentrations, altered conjugation and elim- ination and impaired T3 formation by Dio, no convincing evidence has been presented for a role of these nutritional and environmental agents in thyroid carcinogenesis in humans. High-dose, long-term or experimental exposure of laboratory Fig. 1. Targets for environmental modulation of the thyroid hormone axis. animals, mainly rats, indicate certain effects of some envi- TRH: thyroliberin; TSH: thyrotropin; T4: L-Thyroxine; T3: 3,3 ,5-Triiodo-L- ronmental or nutritional agents either during tumorigenesis, thyronine; TTR; transthyretin, TR: T3-receptor. promotion, growth, invasion and/or metastasis at least under conditions of chronic iodine deficiency or with concomitant 2. Endocrine disrupters affect several targets of the administration of other adverse agents [9–12]. thyroid hormone axis 3. Several classes of compounds affect thyroid hormone In 2008, most of the relevant physiological, biochemical, axis cellular and molecular mechanisms and components of thyroid hormone (TH) biosynthesis, secretion, transport, cellular uptake, During the recent years, in part funded by public domain metabolism and action have been identified. Furthermore, the research organizations, the European Union and other funds, networks involved in the physiological feedback regulation of several agents have been identified, which adversely affect syn- the thyroid hormone axis and its enormous capability of adapta- thesis, secretion, transport, metabolism and action of thyroid tion to altered nutritional, metabolic, physiological, pathological hormones. Among those are nutritional factors originating from and pharmacological challenges are understood (Fig. 1, Table 1). water, soil, and animals, which enter life stock and human This knowledge now enables us to also examine and partially circulation unintentionally and inadvertedly via the food chain. understand in more detail mechanisms other than iodine defi- Other agents of synthetic origin might be contaminants of the ciency or genetic makeup, which are involved in interference food chain, cosmetics, objects of daily life use and our environ- with the thyroid hormone axis. Apart from well-known pharma- ment. ceutical effects on the thyroid hormone axis, several nutritional, Among those agents are wide spread and abundant but also chemical and industrial environmental components affect one or rare or only locally relevant compounds. Table 2 lists some major more targets of this system [5]. Even additive, synergistic, but groups with known relevance for the thyroid axis. Author's personal copy

118 J. Köhrle / Annales d’Endocrinologie 69 (2008) 116–122

Table 1 Interaction of endocrine disrupting compounds with key components of the thyroid hormone axis Component of thyroid hormone axis Interfering agent References

Hypothalamus TRH No reports Pituitary TRH receptor No reports TSH Plant [46–48] Thyroid TSHr polyphenols [46–48] NIS perchlorate, nitrate, smoking [43,44,71] Pendrin No reports Tg No reports TPO soy products, BP2, F21388, [32,33,36] Duox2 No reports Dehal1 No reports Distributor TBG No reports pro- TTR , glycitein, , natural and synthetic (iso-) flavonoids [16,24,70,39,72–77] teins Albumin No reports Lipoproteins No reports Cellular MCT8 No reports uptake OATP14 No reports Cellular Dio1 natural and synthetic (iso-) flavonoids, OMC, MBC4 [5,12,16,70] metabolism Dio2 No reports Dio3 No reports sulfotransferase No reports sulfatase No reports glucuronidyl transferase No reports Cellular action TR␣,TR␤ [72,73,78,79]

Limited information is available for direct interference of Natural and synthetic polyphenols, flavonoids and EDC with the hypothalamus or anterior pituitary components of isoflavonoids have been known for a long time to impair the thyroid axis such as TRH, its receptor and TSH. However, thyroid function. Especially soy products, including the by disruption of the TH negative feedback by EDC induced isoflavone genistein, widely used even in concentrate extracts alterations in TH synthesis, metabolism and action elevated, as phytosteroid with intended effects on sex hormone decreased or unchanged serum TSH levels have been reported receptor signaling in steroid hormone replacement therapy, are after exposure of laboratory animals to various EDC. A fre- known as goitrogens inhibiting TPO, potent competitors for quent observation is an inadequately normal, or decreased serum T4 and T3 binding to transthyretin and TH deiodination by TSH, though elevated levels should be expected due to decreased deiodinases. These adverse effects may lead to goitrogenesis serum T4 and/or T3 concentrations. Such constellations indicate especially under conditions of inadequeate iodine supply an either normal intracellular T4 and T3, compensatory local [16–23]. Whether such effects are relevant also for an iodine increase of T3 by altered deiodinase activities, or even concomi- sufficient thyroid gland remains an open issue, especially for tant increase in systemic or local proinflammatory cytokine and long-term administration. Especially children, pregnant and growth factor levels, which might interrupt the negative feed- lactating women who have higher iodine turnover and demands back loop at the hypothalamic or pituitary level, there including might be at risk for goitrogenic effects of genistein, daidzein or the paracrine effects of folliculo-stellate cells [13–15]. their isoflavone or flavone congeners [24].

Table 2 Selected representative compounds affecting thyroid axis Compound Origin or occurence Target or effect on the thyroid axis References Nutritonal (iso-) flavonoids, polyphenols Plant dyes and components TTR, deiodinases [16,70] Kojic acid Malting rice byproduct NIS [9,10] Synthetic Perchlorate Rocket fuel NIS [43,44,71] PCB Chemical industry TTR [72–75,39] PBDE Flame retardants TTR [76,77] Bisphenol A Plasticizer TR, multiple [12,63–68] PAH Combution processes UDP-glucuronytransferase [12] UV screens Cosmetics, daily life household products TPO, NIS [32,33,69] Pesticides Ubiquitous TR & Transcription [78,79] Author's personal copy

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Cruciferous plants, such as cabbage, Brussels sprouts, 4-MBC and BP2, resulting in goiter and thus possibly providing legumes and cassava, especially, if inadequately processed due a basis for thyroid neoplasia. to lack of energy resources, contain goitrogenous substances that Exposition to polybrominated diphenyl ethers (PBDE) or either interfere with iodine uptake by NIS, iodide organification polychlorinated biphenyls (PCB) during work or in our envi- by TPO or other reactions of the TH axis. These adverse actions ronment may also cause hypothyroidism [39]. Polychlorinated can be prevented or partially ameliorated by improving iodine biphenyls are effective as thyroid tumor promoters in rats after intake by diversified diet. As iodine content of natural food and initiation by diisopropanol-nitrosamine [40]. As several EDC water depends primarily on the supply of iodine in the soil, exhibit estrogenic potency they might contribute to thyroid consequent use of iodized salt or comparably effective strate- carcinogenesis similar to [40a]. This effect might gies for iodination campaigns in many regions of our planet provide a link to observations on female preponderance of remain a permanent challenge to balance or counteract nutri- benign and malignant thyroid dysfunctions (autoimmune dis- tional and environmental exposure to agents interfering with eases M. Hashimoto and M. Basedow, thyroid nodules and the thyroid hormone axis. The normal human thyroid can han- cancer), which remains to be analysed. dle exposure to excess iodide supply via the Wolff-Chaikoff Recently, the potentially harmful effects of perchlorate expo- effect, which prevents further iodide uptake by downregulation sure by drinking water for thyroid function received major of NIS expression and functional integration into the basolateral attention in the scientific and public discussion. Perchlorate is plasma membrane. Therefore, also long-term intake of iodized a potent and even diagnostically used inhibitor of iodide uptake salt is considered safe. In rare cases iodine induced goiter, hypo- catalyzed by NIS, which is located in the basolateral thyrocyte or hyperthyroidism have been observed, probably on a back- membrane [41]. Perchlorate is one of the major rocket fuels and ground of higher genetic susceptibility or in association with several areas around civilian or militaric rocket-related sites and other diseases. their draining rivers are contaminated by perchlorate, easily sol- Nutrient- or fermentation-derived soy metabolites (e.g., kojic uble in water. Whether this exposure leads to goitrogenesis or acid, also used for skin bleaching in Japan and some develop- other forms of thyroid dysfunction needs to be considered and ing countries) lead to thyroid dysfunction including neoplasia if examined in more detail and extent [42–45]. applied to rodents for extended periods at higher concentrations While NIS and TPO seem to be the major EDC targets in [25,26]. thyroid hormone biosynthesis, thyroglobulin, dual function oxi- Using F21388, a synthetic flavonoid, inhibition of type 1 dase 2 and cathepsins involved in hydrolysis of iodinated Tg are 5-deiodinase (5DI), displacement of T4 from the TH dis- not affected by EDC. In contrast, TSH receptor, the key regula- tributor protein transthyretin and altered TH secretion and tor of thyrocyte function and its subsequent signal transduction metabolism was shown in rats [27–30]. Apart from Genistein, are affected by some EDC such as polyphenols, (iso-)flavonoids a soy isoflavone, also xanthohumol, a hop , com- and a few other compounds [46–50]. Whether these effects are petes with T4 for TTR binding [16]. F49209, another synthetic the basis of therapeutic effects exerted by some plant extracts flavonoid, crosses the rat placenta and may affect T4 avail- used in traditional folk remedies has not been finally proven. ability in the fetal rat brain [31]. In the rat model, altered expression and activity of the TH-regulated endpoints malic 4. The serum TH distributor protein transthyretin is a enzyme and 5DI in the liver and the kidney and changes major target for several EDC in pituitary TSH ␣ and ß and in 5DI mRNA levels were observed after acute or chronic administration of various EDC Strong effects of many EDC are exerted on the serum thyroid [32–38]. TPO, NIS, 5DI and TSH receptor mRNA levels hormone distributor protein transthyretin. While TH binding to were altered in the rat thyroid. In vitro, the UV screen ben- the high affinity binding protein TBG and the high capacity low zophenone 2 (BP2) in combination with H2O2 inactivated affinity binding protein albumin are not affected by EDC, the TPO, an effect that was prevented by adequate or excess TH binding site of transthyretin is a rather specific target of sev- iodide. Another UV screen, 4-methylbenzylidene- (4- eral classes of EDC such as (iso-)flavonoids, PCB, PBDE and MBC), inhibited iodide uptake by NIS in FRTL-5 rat thyroid others. The molecular basis of this rather selective interaction of cells. EDC with the TH binding site of transthyretin remains unclear, In vivo, in rats, these two UV screens (BP2, 4-MBC) caused because other TH binding sites such as TBG, albumin, TR are decreased serum levels of T4 and T3, while TSH and thyroid unaffected. Among all EDC, the highest affinity for transthyretin weight were increased, classical indicators of hypothyroidism has been described for genistein, which is equipotent to T4 [35]. Thus, by interfering with thyroid hormone synthesis, BP2 in binding and also the natural flavonoid luteolin of the syn- and 4-MBC increased TSH serum levels and triggered an abnor- thetic derivative F21388 show avid and selective transthyretin mal growth stimulus for the thyroid resulting in goitrogenesis. binding [24]. T4 (and T3) are displaced and shifted to albu- As all of these reactions represent essential steps in TH min (or TBG if present in the respective species). The result biosynthesis, this data suggests complex interference of EDC of this competition is a transient increase in free TH concentra- with the thyroid axis affecting both individual endpoints and tions, altered tissue uptake and elimination. Long-term exposure hormonal feedback regulation. While for some EDC, compen- to these compounds might result in loss of circulating TH by satory or adaptive mechanisms may have ensured a still normal the urine or feces and if not compensated by enhanced thyroid thyroid growth, they appear inadequate in other cases, especially hormone synthesis and secretion result in goitrogenesis. This Author's personal copy

120 J. Köhrle / Annales d’Endocrinologie 69 (2008) 116–122 also requires adequate iodide intake to account for the enhanced more detail. While inhibition of in vitro deiodination of TH (renal) elimination of intact TH. Along these lines of reasoning by various ED in membrane preparations or cell culture mod- EDC, especially (iso-)flavones chronically consumed in high els is quite effective, administration of these agents in vivo not extract doses might impose a significant risk to develop goiter, necessarily impairs T3 formation and TH homeostasis. Sev- especially if inadequate iodine is not warranted. EDC induced eral reasons account for this observation. Inhibition of Dio1 goiters (isoflavone goiters) thus might be a major risk factor activity can be compensated by Dio2 action or reduced activ- for women on long-term high-dose phytosteroid-based hormone ity of Dio3, constellations which would maintain circulating replacement therapy. Apart from (peri- and postmenopausal) serum T3 levels. In addition, several of the ED which are potent women, babies and young children might be another risk group, in vitro Dio1 inhibitors also show high binding and competi- as their thyroidal iodine and iodinated Tg stores are rather lim- tion with the TH binding to transthyretin. This would lead to ited in contrast to adults living in areas with adequate iodine limitations of cellular uptake and availability of ED to intracel- supply, whose stored iodinated Tg would last for up to three lular Dio1 and impaired inhibitory potency. Such scenarios have months of necessary TH release without de novo synthesis. been demonstrated for the synthetic flavonoid F21388, which is an avid ligand for transthyretin but apparently dose not reach 5. Cellular uptake, metabolism and action of TH is sufficiently high intracellular concentrations for effective Dio1 affected by EDC inhibition [27–30,62]. Apparently, the network of thyroid hor- mone homeostasis exhibits several redundant or compensatory Not much is known whether EDC affect TH uptake into cells, fail-safe mechanisms required for maintenance and adaptation which is enabled by the recently discovered TH transporters of adequate circulating serum and tissue T3 levels, which are MCT8 and OATP14and other permeases. More detailed data and required for control and maintenance of T3-dependent energy systematic structure activity relationships have been reported and intermediary metabolism. for EDC interaction with the intracellular TH deiodinases and Considering the interference of ED with the serum thyroid conjugating enzymes. Here, especially Dio1 is strongly inhib- hormone distributor protein transthyretin and intracellular deio- ited by EDC from different categories (see tables). In general dinases, their potential interference with the T3 receptors could trend, both Dio2 and Dio3 are less potently affected by EDC by a further target. However, only few of the ED were shown to than Dio1. Based on these considerations the major target sites significantly compete with T3 binding to TRs, while interference for generation of circulating T3, catalyzed by hepatic, renal and at the prereceptor control levels of ligand availability to TRs is thyroid Dio1, are candidates for EDC inhibition, while the T3 quite obvious. TR-binding has been demonstrated, for example, forming Dio2 and the TH inactivating Dio2 might be less effi- for bisphenol A in several in vitro and in vivo models [63–68,12]. ciently affected. Apart from Dio reactions several EDC also As bisphenol A also strongly interferes in the sex steroid sig- inhibit TH conjugating enzymes such as sulfotransferase, glu- naling pathways, cause-effect relationships are quite difficult to curonidase and sulfatases. Interference with TH conjugation is establish. Nevertheless, the decision of a toxicology panel of known for many PCB, PBDE and related compounds [51–54], the National Toxicology Program, U.S. Department Of Health which under chronic exposure lead to an altered relation between And Human Services (http://cerhr.niehs.nih.gov) which obvi- circulating serum TH and TSH, thus altering both the pitu- ously lacked endocrine expertise in the report on Developmental itary setpoint of the negative feedback regulation and at the Toxicity of Bisphenol A to declare bisphenol A as not relevant same time increasing TH elimination, again a situation requir- with respect to disruption of the thyroid hormone axis is difficult ing adequate iodine supply for compensatorily increased TH to reconcile with published scientific data and met with major synthesis and secretion. For several of the ED effects on TH glu- surprise in the concerned scientific community. Obviously, more curonidation and thus, elimination have been described [55–58]. and especially also, interdisciplinary research is needed to ade- Induction of conjugating enzymes such as sulfotransferases quately address issues of endocrine disruption in general and might involve the xenobiotic receptor constitutive androstane especially during development. receptor (CAR, NR1I3), which acts as chemosensor and its acti- Especially, agents such as several pesticides, the plas- vation leads to decreased serumT4 and T3 levels and elevated ticizer bisphenol A, the UV screens 4-MBC or Octyl- TSH. methoxycinnamate (OMC), which is worldwide one of the most More detailed information on interference of ED has been frequently used chemical UV-filters in sunscreens to protect the accumulated for inhibition of Dio1 and thus, T3 produc- skin against the noxious influence of UV radiation and several tion. Several classes of ED are potent Dio1 inhibitors, e.g. other ED agents need to be examined in more detail with respect (iso-)flavonids, polyphenols, aromatic and polycyclic phenolic to their mechanism of action in the endocrine and especially the ring systems. Many of these agents act as competitive inhibitors thyroid hormone system, their distribution and exposure levels, and their Ki values reach equimolar ranges to the Km of T4 environmental persistence or accumulation in the food chain or rT3 [59–61,32,34]. Apparently the Dio1 active site not only [32,36,5,69]. accommodates several iodothyronines substrates (e.g., T4, rT3, T3-sulfate) but also various ED acting as competitors of TH Acknowledgements in this reaction. Whether this inhibition of TH deiodination exerts major effects on TH homeostasis, T3 formation and feed- This work was supported by EU grant EKV1-CT-2002-00128 back regulation of the thyroid axis remains to characterized in “Multi-Organic Risk Assessment of Selected Endocrine Dis- Author's personal copy

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