Disrupting Effects of Single and Combined Emerging Pollutants on Thyroid Gland Function

  • Demetrio RaldúaEmail author
  • Patrick J. Babin
  • Carlos Barata
  • Benedicte Thienpont
Part of the The Handbook of Environmental Chemistry book series (HEC, volume 20)


Inadequate thyroid hormone (TH) production in mothers during the first months of pregnancy can produce irreversible neurological effects in the offspring. Even though the main cause of insufficient synthesis of TH is the lack of iodine in the diet, TH insufficiency can also be caused by the presence of some naturally occurring and synthetic chemicals disrupting the thyroid gland function. The identification of emerging pollutants that may interfere with mammalian thyroid gland function is still in progress. The goal of this chapter is to review the potential of the zebrafish eleutheroembryos, a vertebrate model used in toxicology and by pharmaceutical companies in drug discovery, as a predictive model for screening emerging pollutants and drugs having a direct effect on the mammalian thyroid gland function.


Goitrogens Thyroid follicle Thyroid gland Thyroid gland function disruptor Thyroid hormone Zebrafish 



Average pixel intensity


Benzophenone 2




Central nervous system




External granule layer


Ethylene thiourea




Iodine deficiency


Intrafollicular T4 content






Mode of action


Sodium-iodide symporter


No observed effect concentration










Thyroid gland function disruptor


Thyroid hormones


Thyroxine immunofluorescence quantitative disruption test




Thyroid-stimulating hormone (thyrotropin)



This work has been supported by the Spanish Ministry of Science and Innovation (CTM2011-30471-C02-01 and PA1002979) and the Generalitat de Catalunya (2010 BE1 00623) to D.R. and C.B. B.T. was supported by a fellowship of the Spanish Government (AP2006-01324). This work was supported by a Conseil Régional d’Aquitaine grant (200881301031/TOD project) to P.J.B.


  1. 1.
    Berbel P, Bernal J (2010) Hypthyroxinemia: a subclinical condition affecting neurodevelopment. Exp Rev Endocrinol Metab 5:563–575CrossRefGoogle Scholar
  2. 2.
    Zoeller RT, Tyl RW, Tan SW (2007) Current and potential rodent screens and tests for thyroid toxicants. Crit Rev Toxicol 37:55–95CrossRefGoogle Scholar
  3. 3.
    Nicholson JL, Altman J (1972) The effects of early hypo- and hyperthyroidism on the development of the rat cerebellar cortex. II. Synaptogenesis in the molecular layer. Brain Res 44:25–36CrossRefGoogle Scholar
  4. 4.
    Xiao Q, Nikodem VM (1998) Apoptosis in the developing cerebellum of the thyroid hormone deficient rat. Front Biosci 3:A52–A57Google Scholar
  5. 5.
    Brown V (2003) Disrupting a delicate balance: environmental effects on the thyroid. Environ Health Perspect 111:A642–A649CrossRefGoogle Scholar
  6. 6.
    de Escobar G, Obregon M, del Rey F (2000) Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85:3975–3987CrossRefGoogle Scholar
  7. 7.
    Kopp P, Pesce L, Solis-S JC (2008) Pendred syndrome and iodide transport in the thyroid. Trends Endocrinol Metab 19:260–268CrossRefGoogle Scholar
  8. 8.
    Bizhanova A, Kopp P (2009) The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology 150:1084–1090CrossRefGoogle Scholar
  9. 9.
    Dedieu A, Gaillard JC, Pourcher T, Darrouzet E, Armengaud J (2011) Revisiting iodination sites in thyroglobulin with an organ-oriented shotgun strategy. J Biol Chem 286:259–269CrossRefGoogle Scholar
  10. 10.
    Alvino CG, Acquaviva AM, Memoli Catanzano AM, Tassi V (1995) Evidence that thyroglobulin has an associated protein kinase activity correlated with the presence of an adenosine triphosphate binding site. Endocrinology 136:3179–3185CrossRefGoogle Scholar
  11. 11.
    Eastman CJ, Zimmermann MB (2009) The iodine deficiency disorders.
  12. 12.
    WHO/UNICEF/ICCIDD (1991) Global prevalence of iodine deficiency disorders. Micronutrient Deficiency Information System Working Paper No. 1. Geneva, WHOGoogle Scholar
  13. 13.
    Gaitan E (1990) Goitrogens in food and water. Annu Rev Nutr 10:21–39CrossRefGoogle Scholar
  14. 14.
    Brucker-Davis F (1993) Effects of environmental synthetic chemicals on thyroid function. Thyroid 8:827–856CrossRefGoogle Scholar
  15. 15.
    Gaitan E, Cooksey RC, Legan J, Cruse JM, Lindsay RH, Hill J (1993) Antithyroid and goitrogenic effects of coal-water extracts from iodine-sufficient goiter areas. Thyroid 3:49–53CrossRefGoogle Scholar
  16. 16.
    Cunha GCP (2005) Evaluation of mechanisms inducing thyroid toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes. Arch Toxicol 79:390–405CrossRefGoogle Scholar
  17. 17.
    Mastorakos G, Karoutsou EI, Mizamtsidi M, Creatsas G (2007) The menace of endocrine disruptors on thyroid hormone physiology and their impact on intrauterine development. Endocrine 31:219–237CrossRefGoogle Scholar
  18. 18.
    De Groef B, Decallonne BR, Van der Geyten S, Darras VM, Bouillon R (2006) Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Eur J Endocrinol 155:17–25CrossRefGoogle Scholar
  19. 19.
    Giuliani C, Noguchi Y, Harii N, Napolitano G, Tatone D, Bucci I et al (2008) The flavonoid quercetin regulates growth and gene expression in rat FRTL-5 thyroid cells. Endocrinology 149:84–92CrossRefGoogle Scholar
  20. 20.
    Doerge DR, Sheehan DM (2002) Goitrogenic and estrogenic activity of soy isoflavones. Environ Health Perspect 110:349–353CrossRefGoogle Scholar
  21. 21.
    Steinmaus C, Miller M, Howd R (2007) Impact of smoking and thiocyanate on perchlorate and thyroid hormone associations in the 2001–2002 national health and nutrition examination survey. Environ Health Perspect 115:1333–1338CrossRefGoogle Scholar
  22. 22.
    Vanderver GB (2007) Cigarette smoking and iodine as hypothyroxinemic stressors in US women of childbearing age: a NHANES III analysis. Thyroid 17:741–746CrossRefGoogle Scholar
  23. 23.
    Zimmermann MB (2009) Iodine deficiency. Endocr Rev 30:376–408CrossRefGoogle Scholar
  24. 24.
    Laurberg P, Nøhr SB, Pedersen KM, Fuglsang E (2004) Iodine nutrition in breast-fed infants is impaired by maternal smoking. J Clin Endocrinol Metab 89:181–187CrossRefGoogle Scholar
  25. 25.
    Gasparoni A, Autelli M, Ravagni-Probizer MF, Bartoli A, Regazzi-Bonora M, Chirico G, Rondini G (1998) Effect of passive smoking on thyroid function in infants. Eur J Endocrinol 138:379–382CrossRefGoogle Scholar
  26. 26.
    Sarne D (2010) Effects of the environment, chemicals and drugs on thyroid function.
  27. 27.
    Crofton K (2008) Thyroid disrupting chemicals: mechanisms and mixtures. Int J Androl 31:209–223CrossRefGoogle Scholar
  28. 28.
    Flippin JL, Hedge JM, DeVito MJ, LeBlanc GA, Crofton KM (2009) Predictive modeling of a mixture of thyroid hormone disrupting chemicals that affect production and clearance of thyroxine. Int J Toxicol 28:368–381CrossRefGoogle Scholar
  29. 29.
    Crofton KM, Craft ES, Hedge JM, Gennings C, Simmons JE, Carchman RA, Carter WH Jr, DeVito MJ (2005) Thyroid-hormone-disrupting chemicals: evidence for dose-dependent additivity or synergism. Environ Health Perspect 113:1549–1554CrossRefGoogle Scholar
  30. 30.
    Parng C, Seng WL, Semino C, McGrath P (2002) Zebrafish: a preclinical model for drug screening. Assay Drug Dev Technol 1:41–48CrossRefGoogle Scholar
  31. 31.
    Ton C, Lin Y, Willett C (2006) Zebrafish as a model for developmental neurotoxicity testing. Birth Defects Res A Clin Mol Teratol 76:553–567CrossRefGoogle Scholar
  32. 32.
    Love DR, Pichler FB, Dodd A, Copp BR, Greenwood DR (2004) Technology for high-throughput screens: the present and future using zebrafish. Curr Opin Biotechnol 15:564–571CrossRefGoogle Scholar
  33. 33.
    McGrath P, Li CQ (2008) Zebrafish: a predictive model for assessing drug-induced toxicity. Drug Discov Today 13:394–401CrossRefGoogle Scholar
  34. 34.
    Goldsmith P (2004) Zebrafish as a pharmacological tool: the how, why and when. Curr Opin Pharmacol 4:504–512CrossRefGoogle Scholar
  35. 35.
    Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 4:35–44CrossRefGoogle Scholar
  36. 36.
    Berghmans S, Butler P, Goldsmith P, Waldron G, Gardner I, Golder Z et al (2008) Zebrafish based assays for the assessment of cardiac, visual and gut function-potential safety screens for early drug discovery. J Pharmacol Toxicol Methods 58:59–68CrossRefGoogle Scholar
  37. 37.
    Strähle U, Schloz S, Geisler R, Greiner P, Hollert H, Rastegar S et al (2011) Zebrafish embryos as an alternative to animal experiments – a commentary on the definition of the onset of protected life stages in animal welfare regulations. Reprod Toxicol. doi: 10.1016/j.reprotox.2011.06.121
  38. 38.
    Porazzi P, Calebiro D, Benato F, Tiso N, Persani L (2009) Thyroid gland development and function in the zebrafish model. Mol Cell Endocrinol 312:14–23CrossRefGoogle Scholar
  39. 39.
    Alt B, Reibe S, Feitosa N, Elsalani O, Wendl T, Rohr KB (2006) Analysis of origin and growth of the thyroid gland in zebrafish. Dev Dyn 235:1872–1883CrossRefGoogle Scholar
  40. 40.
    Alt B, Elsalani O, Schrumpf P, Haufs N, Lawson N, Schwabe G et al (2006) Arteries define the position of the thyroid gland during its developmental relocalisation. Development 133:3797–3804CrossRefGoogle Scholar
  41. 41.
    Opitz R, Maquet E, Zoenen M, Dadhich R, Costagliola S (2011) TSH receptor function is required for normal thyroid differentiation in zebrafish. Mol Endocrinol 25:1579–1599Google Scholar
  42. 42.
    Dohan O, De la Vieja A, Carrasco N (2000) Molecular study of the sodium-iodide symporter (NIS): a new field in thyroidology. Trends Endocrinol Metab 11:99–105CrossRefGoogle Scholar
  43. 43.
    Raldúa D, Andrè M, Babin PJ (2008) Clofibrate and gemfibrozil induce an embryonic malabsorption syndrome in zebrafish. Toxicol Appl Pharmacol 228:301–314CrossRefGoogle Scholar
  44. 44.
    Walpita CN, Van der Geyten S, Rurangwa E, Darras VM (2007) The effect of 3,5,3’-triiodothyronine supplementation on zebrafish (Danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors. Gen Comp Endocrinol 152:206–214CrossRefGoogle Scholar
  45. 45.
    Wendl T, Lun K, Mione M, Favor J, Brand M, Wilson SW et al (2002) Pax2.1 is required for development of thyroid follicles in zebrafish. Development 129:3751–3760Google Scholar
  46. 46.
    Raldúa D, Babin PJ (2009) Simple, rapid zebrafish larva bioassay for assessing the potential of chemical pollutants and drugs to disrupt thyroid gland function. Environ Sci Technol 43:6844–6850CrossRefGoogle Scholar
  47. 47.
    Thienpont B, Tingaud-Sequeira A, Prats E, Barata C, Babin PJ, Raldúa D (2011) Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis. Environ Sci Technol 45:7525–7532Google Scholar
  48. 48.
    Pitsiavas V, Semerdely P, Li M, Boyages SC (1997) Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both BB/W rat and the Wistar rat. Eur J Endocrinol 137:89–98CrossRefGoogle Scholar
  49. 49.
    Martino E, Bartalena L, Bogazzi F, Braverman LE (2001) The effects of amiodarone on the thyroid. Endocr Rev 22:240–254CrossRefGoogle Scholar
  50. 50.
    Cunha GC, van Ravenzwaay B (2005) Evaluation of mechanisms inducing thyroid toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes. Arch Toxicol 79:390–405CrossRefGoogle Scholar
  51. 51.
    MacKenzie DS, Jones RA, Miller TC (2009) Thyrotropin in teleost fish. Gen Comp Endocrinol 161:83–89CrossRefGoogle Scholar
  52. 52.
    Charles JM, Cunny HC, Wilson RD, Bus JS (1996) Comparative studies on 2,4- dichlorophenoxyacetic acid, amine and ester in rats. Fundam Appl Toxicol 33:161–165CrossRefGoogle Scholar
  53. 53.
    Santini F, Vitti P, Mammoli C, Rosellini V, Pelosini C, Marsili A et al (2003) In vitro assay of thyroid disruptors affecting TSH-stimulated adenylate cyclase activity. J Endocrinol Invest 26:950–955Google Scholar
  54. 54.
    Rossi M, Dimida A, Dell’anno MT, Trincavelli ML, Agretti P, Giorgi F et al (2007) The thyroid disruptor 1,1,1-trichloro-2,2-bis(p-chloropheyl)ethane appears to be an uncompetitive inverse agonist for the thyrotropin receptor. J Pharmacol Exp Ther 320:465–474CrossRefGoogle Scholar
  55. 55.
    Pandey AK, George KC, Mohamed MP (1995) Effect of DDT on the thyroid gland of the mullet Liza parsia (Hamilton-Buchanan). J Mar Biol Assoc India 37:287–290Google Scholar
  56. 56.
    Bleau H, Daniel C, Chevalier G, van Tra H, Hontela A (1996) Effects of acute exposure to mercuric chloride and methylmercury on plasma cortisol, T3, T4, glucose, and liver glycogen in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol 34:221–235CrossRefGoogle Scholar
  57. 57.
    Kirubagaran R, Joy KP (1994) Effects of short-term exposure to methylmercury chloride and its withdrawal on serum levels of thyroid hormones in the catfish Clarias batrachus (L). Bull Environ Contam Toxicol 63:166–170Google Scholar
  58. 58.
    Nishida M, Muraoka K, Nishikawa K, Takagi T, Kawada J (1989) Differential effects of methylmercuric chloride and mercuric chloride on the histochemistry of rat thyroid peroxidase and thyroid peroxidase activity of isolated pig thyroid cells. J Histochem Cytochem 37:723–727CrossRefGoogle Scholar
  59. 59.
    Stoker TE, Guidici DL, Cooper RL (2002) The effects of atrazine metabolites on puberty and thyroid function in male Wistar rat. Toxicol Sci 67:198–206CrossRefGoogle Scholar
  60. 60.
    Flatt T, Moroz LL, Tatar M, Heyland A (2006) Comparing thyroid and insect hormone signalling. Integr Comp Biol 46:777–794CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011 2011

Authors and Affiliations

  • Demetrio Raldúa
    • 1
    Email author
  • Patrick J. Babin
    • 2
  • Carlos Barata
    • 1
  • Benedicte Thienpont
    • 1
  1. 1.Institute of Environmental Assessment and Water Research (IDÆA-CSIC)BarcelonaSpain
  2. 2.University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576TalenceFrance

Personalised recommendations