Environmental Disrupters of Thyroid Hormone Action

ENVIRONMENTAL DISRUPTERS OF THYROID HORMONE ACTION

selective estrogen receptor modulators Natural or synthetic ligands that exhibit either estrogen agonist or antagonist activity among different cells and tissues. Most likely, this is due to the differential expression of cell- and tissue-specific factors, such as co-activator and corepressor proteins.

See Also the Following Articles Environmental Disruptors of Thyroid Hormone Action . Estrogen and Progesterone Receptors in Breast Cancer . Phytoestrogens . SERMs (Selective Estrogen Receptor Modulators) . Sexual Differentiation, Molecular and Hormone Dependent Events in . Sexual Differentiation of the Brain

Further Reading Colborn, T., vom Saal, F. S., and Soto, A. M. (1993). Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ. Health Perspect. 101, 378–384. Crain, D. A., Guilette, L. J., Jr., Rooney, A. A., and Pickford, D. B. (1997). Alterations in steroidogenesis in alligators (Alligator mississippiensis) exposed naturally and experimentally to environmental contaminants. Environ. Health Perspect. 105(5), 528 –533. Crews, D., Willingham, E., and Skipper, J. K. (2000). Endocrine disruptors: Present issues, future directions. Q. Rev. Biol. 75(3), 243–260. Kelce, W. R., Monosson, E., Gamcsik, M. P., Laws, S. C., and Gray, L. E., Jr. (1994). Environmental hormone disruptors: Evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites. Toxicol. Appl. Pharmacol. 126, 276–285. LeBlanc, G. A., and Bain, L. J. (1997). Chronic toxicity of environmental contaminants: Sentinels and biomarkers. Environ. Health Perspect. 105(1), 65–80. Markey, C. M., Luque, E. H., Munoz de Toro, M. M., Sonnenschein, C., and Soto, A. M. (2001). In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol. Reprod. 65, 1215–1223. McLachlan, J. (1980). “Estrogens in the Environment: Developments in Toxicology and Environmental Science,” Vol. 5. Elsevier/North Holland, New York. National Research Council (1999). “Hormonally Active Agents in the Environment.” National Academy Press, Washington, DC. Sassoon, D. (1999). Wnt genes and endocrine disruption of the female reproductive tract: A genetic approach. Mol. Cell. Endocrinol. 158, 1 –5. Sheehan, D. M., Willingham, E., Gaylor, D., Bergeron, J. M., and Crews, D. (1999). No threshold dose for estradiol-induced sex reversal of turtle embryos: How little is too much? Environ. Health Perspect. 107, 155 –159. Silva, E., Rajapakse, N., and Kortenkamp, A. (2002). Something from “nothing”—Eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ. Sci. Technol. 36, 1751– 1756. Sonnenschein, C., and Soto, A. M. (1999). “The Society of Cells: Cancer and Control of Cell Proliferation” Springer Verlag, New York.

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Sonnenschein, C., and Soto, A. M. (1998). An updated review of environmental estrogen and androgen mimics and antagonists. J. Steroid Biochem. Mol. Biol. 65, 143 –150. vom Saal, F. S., and Timms, B. G. (1999). The role of natural and man-made estrogens in prostate development. In “Endocrine Disruptors: Effects on Male and Female Reproductive Systems” (R. K. Naz, ed.), pp. 307– 328. CRC Press, Boca Raton, FL. Zoeller, R. T., Dowling, L. S., Herzig, T. A., Iannacone, E. A., Gauger, K. J., and Bansal, R. (2002). Thyroid hormone, brain development, and the environment. Environ. Health Perspect. 110(3), 355–361. Encyclopedia of Hormones. Copyright 2003, Elsevier Science (USA). All rights reserved.

Environmental Disrupters of Thyroid Hormone Action FRANC¸ OISE BRUCKER -DAVIS Hoˆpital l’Archet 1, Nice, France I. II. III. IV. V. VI.

INTRODUCTION NATURAL ENVIRONMENTAL THYROID DISRUPTERS SYNTHETIC ENVIRONMENTAL THYROID DISRUPTERS MECHANISMS OF THYROID DISRUPTION FACTORS PREDISPOSING TO THYROID DISRUPTION CLINICAL IMPACT OF THYROID DISRUPTERS

The thyroid gland is easily disturbed by numerous external factors, both natural and synthetic. Endemic environmental goitrogenesis, the enlargement of the thyroid gland, has long been associated with diets deficient in iodine or with diets rich in goitrogenic substances (phytogoitrogens). In addition to goiter development, thyroid hormone imbalance and/or exposure to thyroid-toxic chemicals during pregnancy can have devastating effects on fetal brain development, as illustrated by the endemic cretinism observed in areas where native diets are iodine deficient.

I. INTRODUCTION The goiter, or enlarged thyroid gland, has long been recognized to be the result of a dietary deficiency of iodine-containing foods. The question of environmental thyroid disruption, however, has been recently assessed in the more global context of the impact of environmental synthetic chemicals on endocrine system function. Many synthetic chemicals have been found to have deleterious effects on the thyroid, both in vitro and in vivo in fauna, laboratory animals,

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ENVIRONMENTAL DISRUPTERS OF THYROID HORMONE ACTION

and humans. The clinical significance of exposure to environmental chemicals and contaminants with respect to normal thyroid development and function is currently under investigation. It is important to determine whether, beyond their goitrogenic effects, these chemicals may also have an effect on thyroid tumorigenesis and cognitive functions.

II. NATURAL ENVIRONMENTAL THYROID DISRUPTERS The primary natural thyroid disrupters, excluding dietary iodine deficiency, are goitrogens found in food or water supplies as a result of bacterial contamination or mineral compound decomposition (Table 1). Goitrogenic substances are also found in many vegetables: thiocyanates and isothiocyanates in Cruciferae; goitrin in turnips; cyanogenic glucosides in cassava or sweet potatoes; disulfides in onion and garlic; and flavonoids in millet, sorghum, and beans. In addition, degradation of humic substances, i.e., soil decomposition of plant and animal tissues, leads to the production of resorcinol, a phenol derivative with potent antithyroid effects. Distinguishing between natural mineral compounds (such as coals or shales) and synthetic contamination is sometimes fuzzy, because mineral compound decomposition and industrial manufacturing processes may produce similar chemical products.

III. SYNTHETIC ENVIRONMENTAL THYROID DISRUPTERS The twentieth century witnessed vast developments in the chemical industry, particularly following the end TABLE 1

Chemicals with Thyroid-Disrupting Properties Family

Sulfurated organics Flavonoids Phenol derivatives Pyridines and hydroxypyridines Phthalate esters and metabolites Polyhalogenated hydrocarbons Polycyclic aromatic hydrocarbons Pesticides Chlorinated Others Heavy metals, inorganics a

of the Second World War. Thousands of new compounds are now produced annually for both agricultural and industrial purposes. Few if any of the routinely manufactured chemicals have been tested for their endocrine effects, and in cases in which tests have been made, the test doses are not relevant to endocrine systems or to levels of probable environmental exposure. Synthetic chemicals are used to make every imaginable type of product: computers, automobiles, toys, clothing, food containers, cosmetics, and perfumes. The chemicals, as the manufactured products are discarded and break down, are eventually released into the environment and are found in water, soils, and foodstuffs, including vegetables, fruits, diary products, meats, and fish. Evidence of the ubiquity of contaminating chemicals is supported by their presence in urine, adipose tissue, and even amniotic fluid. They are found in most cord blood samples, proof of human in utero transplacental contamination. Additionally, early postnatal exposure can occur through maternal breast milk, potentially impeding the well-known benefits of breast-feeding. Some compounds, such as pesticides, are released intentionally into the environment and are designed to be toxic. Others, such as plastics and industrial compounds, until recently were considered benign. They are released unintentionally as a result of pollution. A number of synthetic chemicals are persistent, in some cases by design, and are able to travel long distances under the influence of winds and water currents. They also bioconcentrate and biomagnify in live organisms as they move up the food chain.

Namea

Natural or syntheticb

Thiocyanate, isothiocyanate, goitrin, disulfides Glycosides, aglycones Resorcinol, DNP, pyrogallol — — PCB, PBB, dioxin Benzopyrene, methylcolanthrene, dimethylbenzanthracene

N N N, N, N, S N,

DDT and others Amides, benzonitriles, carbamates, organophosphates, pyrethroid, pyridinoxy, thiocarbamates, thiourea, triazine, triazole Hg, Pb, I, Cd, perchlorate

S S

S S S S

N

Abbreviations: DNP, dinitrophenol; DDT, dichlorodiphenyldichloroethane; PCB, polychlorinated biphenyl; PBB, polybrominated biphenyl; Hg, mercury; Pb, lead; I, iodine; Li, lithium; Cd, cadmium. b N, Naturally occurring even though it may be used for industrial or other anthropological purpose; S, synthetic.

ENVIRONMENTAL DISRUPTERS OF THYROID HORMONE ACTION

Importantly, animal and human species have been exposed to these chemicals for less than a century. This extremely short period of time with respect to the evolution of species has not allowed for adaptation. Indeed, differences in how humans and animals handle man-made compounds and natural compounds involve detoxification and metabolism pathways and binding affinities for protein carriers. Many synthetic chemicals have thyroid system effects (see Table 1). Interestingly, some chemicals, e.g., dichlorodiphenyldichloroethane (DDT) and polychlorinated biphenyls (PCBs) or their metabolites, also have estrogenic and antiandrogenic activities. Field studies in fauna have supported evidence of environmental thyroid disruption in salmon and birds from the Great Lakes and in the Florida panther. However, no specific correlation has been established between these observations and a given chemical, because environmental exposure has been to a mixture of chemicals. On the other hand, experimental studies in laboratory rodents and birds, for example, have shown specific thyroid system effects of many compounds, either alone or in mixtures.

IV. MECHANISMS OF THYROID DISRUPTION Chemicals may disrupt the thyroid economy at virtually all stages, as shown in Table 2. This complicates the screening of chemicals for their impact on the thyroid gland. Disruption is primarily at the level of thyroid gland morphology and thyroid hormone metabolism. An effect at one stage of thyroid function or development also induces compensatory mechanisms at other stages. For example,

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increased glucuronidation of thyroxine (T4) by PCBs results in increased thyroid gland production of thyroid hormones to keep up with the elimination. The effects of some chemicals may be profound: the antithyroperoxidase (antiTPO) activity of resorcinol is 26 times the activity of propylthiouracil, one of the main medications for treating thyroid overactivity. Many halogenated compounds compete with natural hormones for binding to protein carriers (transthyretin, and to a lesser degree thyroxine-binding globulin), although the clinical consequences are unclear. Preliminary data suggest a possible effect of PCBs on thyroid hormone regulated genes.

V. FACTORS PREDISPOSING TO THYROID DISRUPTION The nature of thyroid system disruption by environmental chemicals depends on the chemical and on the exposed individual. Among the factors linked to the chemical are its persistence and environmental concentrations, as well as its ability to cross the placenta and the blood –brain barrier and whether it is eliminated in breast milk. Chemical structure occasionally indicates a possible thyroid effect. For example, DDT, PCBs, and thyroid hormones have similar structures; compounds with structures unrelated to thyroid hormone structure are less predictable (Fig. 1). In addition, the compounding effects of iodine deficiency and/or the presence of co-contaminants are important. Inherent differences in individuals and species exposed to chemicals dictate thyroid effects. For example, compared to humans, rats are more susceptible to goiter; there are also differences based

TABLE 2 Mechanisms of Thyroid Disruption Level of disruption Thyroid hormone synthesis Iodine uptake a AntiTPO action Inhibition of thyroid hormone secretion Transport of thyroid hormone Metabolism Deiodinase, glucuronyltransferase, sulfatase Central effect Autoimmunity b Tumorigenesis Genomic effect a

Examples of chemicals Iodine, thiocyanate, sulfurated agents, aldrin, perchlorate Thiourea, triazole, phenols, phtalate Iodine, PCBs? Polyhalogenated, chlorinated pesticides; phenol, phthalate

þþþ þþ þ þþþ

Pesticides, heavy metals, polyhalogenated pesticides, polycyclic aromatics, polyhalogenated PCBs, pentachlorophenols Lead, dinitrophenol, PCBs?, pentachlorophenol? PBBs?, methylcholanthrene, furan? Iodine isotopes, acetochlor PCBs?

þþþ

AntiTPO, Antithyroperoxidase. Independently of effect through hormonal effects.

b

Frequency

þ /2 þ? þ /2 þ /2?

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ENVIRONMENTAL DISRUPTERS OF THYROID HORMONE ACTION

FIGURE 1 Comparison of the chemical structure of thyroxine (T4) with the structures of selected pesticides and industrial and natural chemicals with documented thyroid activity. DDT, Dichlorodiphenyldichloroethane; TCB, tetrachlorobiphenyl; PTU, propylthiouracil.

on sex (women are more susceptible than men) genetic susceptibility and endogenous thyroid status (borderline state of dysthyroidism). Diets rich in goitrogenic substances play an obvious role. Most importantly, the effect on fetal thyroid economy will depend on the timing of exposure and on maternal thyroid status.

VI. CLINICAL IMPACT OF THYROID DISRUPTERS Although the deleterious effects of natural thyroid disrupters are well documented, much less is known regarding the effects of synthetic chemicals. The potential effects are different in individual adults (“activational phenotype”) and fetuses (“developmental phenotype”). However, it is fair to say that there is currently no consensus on the real impact of synthetic thyroid disrupters in humans. In adults, the potential risks of chemical exposure are goiter, thyroid cancer, and autoimmune thyroid disease. There are some scanty reports of thyroid abnormalities observed in the context of occupational exposure to pesticides or industrial chemicals. Those suggest at best a minor effect on genetically predisposed individuals, for both the occurrence of goiter and/or autoimmune thyroid disease. The main interest of these studies is that they involve mainly men, who are supposedly less likely than women to develop thyroid diseases.

In fetuses, the potential phenotype involves cognitive functions and behavior. Several studies have found neurological impairments linked to in utero exposure to synthetic chemicals such as PCBs or dioxins. However, even though those compounds have welldocumented experimental thyroid effects, it is not clear whether the observed neurocognitive effects in the children are linked to those thyroid effects or to more direct neurotoxic effects. Thus, the impact of chemical thyroid disruption following environmental exposure is largely unknown in human adults and fetuses, mainly because of methodological difficulties. There are no comprehensive data on human exposure and the number of potential chemical culprits is large. Consequently, analysis is limited to the resultant effects of a mixture of chemicals. In addition, thyroid disruption may be only one of the toxicity pathways of chemicals, because many compounds express different properties (direct neurotoxicity, estrogenicity, etc.).

Glossary endemic cretinism Mental retardation, associated with various neurological phenotypes, due to the deleterious effect of iodine deficiency on fetal brain development. This pathology occurs in areas where normal diets are iodine deficient, in the absence of an efficient program of iodination. endocrine disrupter Exogenous agent that interferes with the production, release, transport, metabolism, binding,

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EPHRINS AND THEIR RECEPTORS

action, or elimination of the natural hormones that are responsible for maintenance of homeostasis and regulation of developmental processes. Disrupters can directly affect an exposed individual and can affect fetuses through in utero exposure. goiter Thyroid gland enlargement, the most common thyroid abnormality, is present in about 200 million people worldwide. polyhalogenated hydrocarbons Synthetic chemicals, chlorinated or brominated, such as polychlorinated biphenyls, dioxin, or polybrominated biphenyls.

See Also the Following Articles Environmental Disruptors of Sex Hormone Action . Iodine . Thyroid and Reproduction . Thyroid Hormone Receptor, TSH and TSH Receptor Mutations . Thyroid Stimulating Hormone (TSH) . Thyrotropin-Releasing Hormone (TRH)

the Great Lakes and a hypothesis on the causal role of environmental contaminants. J. Wildlife Dis. 22, 60–70. Porterfield, S. P. (1994). Vulnerability of the developing brain to thyroid abnormalities: Environmental insults to the thyroid system. Environ. Health Pespect. 102, 125–130. Schantz, S. L., Seo, B.-W., Moshtaghian, J., and Amin, S. (1997). Developmental exposure topolychlorinated biphenyl or dioxin. Do changes in thyroid function mediate effects on spatial learning? Am. Zool. 37, 399– 408. Steenland, K., Cedillo, L., Tucker, J., Hines, C., Sorensen, K., Deddens, J., and Cruz, V. (1997). Thyroid hormones and cytogenic outcomes in backpack sprayers using ethylenebis (dithiocarbamate) (EBDC) fungicides in Mexico. Environ. Health Perspect. 105, 1126–1130. Encyclopedia of Hormones. Copyright 2003, Elsevier Science (USA). All rights reserved.

Ephrins and Their Receptors

Further Reading

MARTIN LACKMANN * AND ANDREW W. BOYD †

Bahn, A. K., Mills, J. L., Snyder, P. J., Gann, P. H., Houten, L., Bialik, O., Hollmann, L., and Utiger, U. D. (1980). Hypothyroidism in workers exposed to polybrominated biphenyls. N. Engl. J. Med. 302, 31–33. Brechner, R. J., Parkhurst, G. D., Humble, W. O., Brown, M. B., and Herman, W. H. (2000). Ammonium perchlorate contamination of Colorado river drinking water is associated with abnormal thyroid function in newborns in Arizona. J. Occup. Environ. Med. 42, 777–782. Brucker-Davis, F. (1998). Effects of environmental synthetic chemicals on thyroid function. Thyroid 8, 827– 856. Cheek, A. O., Kow, K., Chen, J., and MacLachlan, J. A. (1999). Potential mechanisms of thyroid disruption in humans: Interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environ. Health Perspect. 107, 273 –278. Gaitan, E. (1998). Environmental goitrogens. In “Contemporary Endocrinology: Diseases of the Thyroid” (L. D. Braverman, ed.), pp. 331–347. Humana Press, Totowa, NJ. Guillette, E. A., Meza, M. M., Aquilar, M. G., Soto, A. D., and Garcia, I. E. (1998). Ananthropological approach to the evaluation of preschool children exposed to pesticides in Mexico. Environ. Health Perspect. 106, 347–353. Hurley, P. M., Hill, R. N., and Whiting, R. J. (1998). Mode of carcinogenic action of pesticides including thyroid follicular cell tumors in rodents. Environ. Health Perspect. 106, 437–445. Jacobson, J. L., and Jacobson, S. W. (1996). Intellectual impairment in children exposed topolychlorinated biphenyls in utero. N. Engl. J. Med. 335, 783– 789. Koopman-Esseboom, C., Morse, D. C., Weisglas-Kuperus, N., Lutkeschipholt, I. J. J., Van der Pauw, C. G., Tuinstra, L. G., Brouwer, A., and Sauer, P. J. (1994). Effects of dioxins and polychlorinated biphenyls on thyroid function of pregnant women and their infants. Pediatr. Res. 36, 468–473. McLachlan, J. A. (2001). Environmental signaling: What embryos and evolution teach us about endocrine disrupting chemicals. Endocr. Rev. 22, 319– 341. Moccia, R. D., Fox, G. A., and Britton, A. (1986). A quantitative assessment of thyroid histopathology of herring gulls from

p

Ludwig Institute for Cancer Research, Australia . Queensland Institute for Medical Research, Australia

†

I. INTRODUCTION II. MOLECULAR PROPERTIES OF EPHRINS AND Eph RECEPTORS III. SIGNALING FUNCTIONS OF EPHRINS AND Eph RECEPTORS IV. BIOLOGICAL ACTIVITIES OF EPHRINS AND Eph RECEPTORS V. SUMMARY

Ephrins are cell-surface-associated ligands for a family of ephrin receptors (Eph). Ephrins and Ephs act as guidance cues to facilitate and direct the movement of cells and cell layers during various developmental processes.

I. INTRODUCTION Ephrins are cell-surface-associated ligands for ephrin receptor (Eph) tyrosine kinases (RTKs), the largest subgroup of the RTK superfamily. In contrast to other cytokine receptors, Eph RTKs (Ephs) have been discovered in the past decade as orphan receptors mostly by homology (complementary DNA) cloning approaches. The founding family member, EphA1, was isolated in a low-stringency screen with a v-fps oncogene cDNA probe from an erythropoietinproducing hepatocellular (EPH) carcinoma cell line; EPH receptor-interacting proteins (i.e., ephrins) were isolated in a simultaneous effort by several laboratories to unravel Eph RTK function. Although several