Skip to main content
SpringerLink
Log in

Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signalling in the developing brain

  • Original Article
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

Persistent polyhalogenated organic pollutants are present worldwide and accumulate along the food chain. They interfere with human and animal health and are particularly harmful for pre- and perinatal neurodevelopment. The mechanisms behind the observed effects vary depending on the specific compound investigated. Co-planar polychlorinated biphenyls (PCBs) can act via the arylhydrocarbon receptor while many ortho-substituted PCBs disrupt intracellular Ca2+ homeostasis. A common mechanism for a wide variety of PCBs is interference with thyroid hormone (TH) signalling in developing brain, by changing intracellular TH availability or by interacting directly at the level of the TH receptors. Studies on gene expression in cortex and cerebellum revealed both hypothyroid- and hyperthyroid-like effects. However, since THdependent gene expression plays a crucial role in the coordination of neuronal proliferation, migration, synaptogenesis, myelination, etc., both reduced/delayed and increased/premature expression may result in permanent structural changes in neuronal communication networks, leading to lifelong deficits in cognitive performance, motor functions, and psychobehavior. In a similar way, PCBs are able to interfere with estrogen- and androgen-dependent brain development and in some studies neurobehavioral outcome was shown to be gender-specific. Other persistent organohalogens like polychlorinated dibenzo-p-dioxins (PCDDs) and polybrominated diphenyl ethers (PBDEs) also act as endocrine disrupters in the developing brain. Several of the mechanisms involved are similar to those of PCBs, but each group also works via own specific pathways. The fact that persistent organohalogens can amplify the neurotoxic effects of other environmental pollutants, such as heavy metals, further increases their risk for human and animal neurodevelopment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Grier JW. Ban of DDT and subsequent recovery of reproduction in bald eagles. Science. 1982;218(4578):1232–1235.

    PubMed  CAS  Google Scholar 

  2. Brouwer A, Ahlborg UG, Van den Berg M, Birnbaum LS, Boersma ER, Bosveld B, Denison MS, Gray LE, Hagmar L, Holene E, Huisman M, Jacobson SW, Jacobson JL, Koopman-Esseboom C, Koppe JG, Kulig BM, Morse DC, Muckle G, Peterson RE, Sauer PJJ, Seegal RF, Smits-van Prooije AE, Touwen BCL, Weisglas-Kuperus N, Winneke G. Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants. Eur J Pharmacol. 1995;293:1–40.

    PubMed  CAS  Google Scholar 

  3. Brouwer A, Morse DC, Lans MC, Schuur AG, Murk AJ, Klasson-Wehler E, Bergman A, Visser TJ. Interactions of persistent environmental organohalogens with the thyroid hormone system: mechanisms and possible consequences for Persistent organohalogens and brain development animal and human health. Toxicol Ind Health. 1998;14:59–84.

    PubMed  CAS  Google Scholar 

  4. Leatherland JF. Changes in thyroid hormone economy following consumption of environmentally contaminated great lakes fish. Toxicol Ind Health. 1998;14:41–57.

    PubMed  CAS  Google Scholar 

  5. Tanabe S. Contamination and toxic effects of persistent endocrine disrupters in marine mammals and birds. Mar Pollut Bull. 2002;45:69–77.

    PubMed  CAS  Google Scholar 

  6. Hansen LG. Stepping backward to improve assessment of PCB congener toxicities. Environ Health Perspect. 1998;106:S171–87.

    Google Scholar 

  7. Schecter AJ, Piskac AL. PCBs, dioxins, and dibenzofurans: measured levels and toxic equivalents in blood, milk and food from various countries. In: Robertson LW, Hansen LG, editors. PCBs, recent advances in environmental toxicology and health effects. The University Press of Kentucky, 2001. pp 161–8.

  8. Fisk AT, de Wit CA, Wayland M, Kuzyk ZZ, Burgess N, Letcher R, Braune B, Norstrom R, Blum SP, Sandau C, Lie E, Larsen HJS, Skaare JU, Muir DCG. An assessment of the toxicological significance of anthropogenic contaminants in Canadian arctic wildlife. Science Total Environ. 2005;351–2:57–93.

    Google Scholar 

  9. Fisher BE. Most unwanted. Environ Health Perspect. 1999;107:A18–23.

    PubMed  CAS  Google Scholar 

  10. Thomson C, Lundanes E, Becher G. Brominated flame retardants in archived serum samples from Norway: a study on temporal trends and the role of age. Environ Sci Technol. 2002;36:1414–18.

    Google Scholar 

  11. Law RJ, Alaee M, Allchin CR, Boon JP, Lebeuf M, Lepom P, Stern GA. Levels and trends of polybrominated diphenylethers and other brominated flame retardants in wildlife. Environ Int. 2003;29:757–70.

    PubMed  CAS  Google Scholar 

  12. Gill U, Chu I, Ryan JJ, Feeley M. Polybrominated diphenyl ethers: human tissue levels and toxicology. Rev Environ Contam Toxicol. 2004;182:55–96.

    Google Scholar 

  13. De Roode DF, van den Brink NW. Uptake of injected PCBs from the yolk by the developing chicken embryo. Chemosphere. 2002;48:195–9.

    PubMed  Google Scholar 

  14. Maervoet J, Beck V, Roelens SA, Covaci A, Voorspoels S, Geuns JMC, Darras VM, Schepens P. Uptake and tissuespecific distribution of selected polychlorinated biphenyls in developing chicken embryos. Environ Toxicol Chem. 2005;24:597–602.

    PubMed  CAS  Google Scholar 

  15. Bandeira SM. Cytochrome P450 enzymes as biomarkers of PCB exposure and modulators of toxicity. In: Robertson LW, Hansen LG, editors. PCBs, recent advances in environmental toxicology and health effects. The University Press of Kentucky, 2001. pp 185–92.

  16. Kodavanti PRS, Shin D-S, Tilson HA, Harry GJ. Comparative effects of two polychlorinated biphenyl congeners on calcium homeostasis in rat cerebellar granule cells. Toxicol Appl Pharmacol. 1993;123:97–106.

    PubMed  CAS  Google Scholar 

  17. Shain W, Bush B, Seegal R. Neurotoxicity of polychlorinated biphenyls: structure-activity relationship of individual congeners. Toxicol Appl Pharmacol. 1991;111:33–42.

    PubMed  CAS  Google Scholar 

  18. Kodavanti PRS, Tilson HA. Structure-activity relationships of potentially neurotoxic PCB congeners in the rat. Neurotoxicology. 1997;18:425–41.

    PubMed  CAS  Google Scholar 

  19. Kodavanti PRS. Intracellular signaling and developmental neurotoxicity. In: Zawia NH, editor. Molecular neurotoxicology environmental agents and transcription-transduction coupling. Boca Raton: CRC Press, 2004. pp 151–82.

    Google Scholar 

  20. Seegal RF, Bush B, Brosch KO. Sub-chronic exposure of the rat to Aroclor 1254 selectively alters central dopaminergic function. Neurotoxicol. 1991;12:55–66.

    CAS  Google Scholar 

  21. Seegal RF, Bush B, Brosch KO. Comparison of effects of Aroclors 1016 and 1260 on non-human primate catecholamine function. Toxicology. 1991;66:145–63.

    PubMed  CAS  Google Scholar 

  22. van Haaren F, van Hest A, Heinsbroek RPW. Behavioral differences between male and female rats: effects of gonadal hormones on learning and memory. Neurosci Biobehav Rev. 1990;14:23–33.

    PubMed  Google Scholar 

  23. Williams CL, Barnett AM, Meck WH. Organizational effects of early gonadal secretions on sexual differentiation of spatial memory. Behav Neurosci. 1990;104:84–97.

    PubMed  CAS  Google Scholar 

  24. Tsutsui K. Biosynthesis and organizing action of neurosteroids in the developing Purkinje cell. Cerebellum. 2006;5:89–96.

    PubMed  CAS  Google Scholar 

  25. Bernal J. Thyroid hormones and brain development. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, editors. Hormones, brain and behavior, Vol 4. USA: Elsevier Science, 2002. pp 543–87.

    Google Scholar 

  26. Howdeshell KL. A model of the development of the brain as a construct of the thyroid system. Environ Health Perspect. 2002;110(Suppl. 3):337–48.

    PubMed  CAS  Google Scholar 

  27. Anderson GW, Schoonover CM, Jones SA. Control of thyroid hormone action in the developing rat brain. Thyroid. 2003;13:1039–56.

    PubMed  CAS  Google Scholar 

  28. Gould JC, Cooper KR, Scanes CG. Effects of polycholorinated biphenyl mixtures and three specific congeners on growth and circulating growth-related hormones. Gen Comp Endocrinol. 1997;106:221–30.

    PubMed  CAS  Google Scholar 

  29. Gould JC, Cooper KR, Scanes CG. Effects of polychlorinated biphenyls on thyroid hormones and liver type I monodeiodinase in the chick embryo. Ecotoxicol Environ Safety. 1999;43:195–203.

    PubMed  CAS  Google Scholar 

  30. McNabb FMA, Fox GA. Avian thyroid development in chemically contaminated environments: is there evidence of alterations in thyroid function and development? Evol Dev. 2003;5:76–82.

    PubMed  CAS  Google Scholar 

  31. Morse DC, Klasson-Wehler E, Wesseling W, Koeman JH, Brouwer A. Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254). Toxicol Appl Pharmacol. 1996;136:269–79.

    PubMed  CAS  Google Scholar 

  32. Roelens SA, Beck V, Maervoet J, Aerts G, Reyns GE, Schepens P, Darras VM. The dioxin-like PCB 77 but not the ortho-substituted PCB 153 interferes with chicken embryo thyroid hormone homeostasis and delays hatching. Gen Comp Endocrinol. 2005;143:1–9.

    PubMed  CAS  Google Scholar 

  33. Beck V, Roelens SA, Darras VM. Exposure to PCB 77 induces tissue-dependent changes in iodothyronine deiodinase activity patterns in the embryonic chicken. Gen Comp Endocrinol. 2006;148:327–35.

    PubMed  CAS  Google Scholar 

  34. Campos-Barros A, Meinhold H, Walzog B, Behne D. Effects of selenium and iodine deficiency on thyroid hormone concentrations in the central nervous system of the rat. Eur J Endocrinol. 1997;136:316–23.

    PubMed  CAS  Google Scholar 

  35. Koibuchi N, Chin WW. Thyroid hormone action and brain development. Trends Endocrinol Metab. 2000;11:123–8.

    PubMed  CAS  Google Scholar 

  36. Li GH, Post J, Koibuchi N, Sajdel-Sulkowska EM. Impact of thyroid hormone deficiency on the developing CNS: cerebellar glial and neuronal protein expression in rat neonates exposed to antithyroid drug propylthiouracil. Cerebellum. 2004;3:100–06.

    PubMed  CAS  Google Scholar 

  37. Verhoelst CHJ, Darras VM, Zandieh Doulabi B, Reyns G, Kühn ER, Van der Geyten S. Type I iodothyronine deiodinase in euthyroid and hypothyroid chicken cerebellum. Mol Cell Endocrinol. 2004;214:97–105.

    PubMed  CAS  Google Scholar 

  38. Nicholson JL, Altman J. The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. Brain Res. 1972;44:13–23.

    PubMed  CAS  Google Scholar 

  39. Rabie A, Legrand J. Effects of thyroid hormone and undernourishment on the amount of synaptosomal fraction in the cerebellum of the young rat. Brain Res. 1973;61:267–78.

    PubMed  CAS  Google Scholar 

  40. Cheek AO, Kow K, Chen J, McLachlan JA. Potential mechanisms of thyroid disruption in humans: Interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environ Health Perspect. 1999;107:273–8.

    PubMed  CAS  Google Scholar 

  41. Miyazaki W, Iwasaki T, Takeshita A, Kuroda Y, Koibuchi N. Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism. J Biol Chem. 2004;279:18195–202.

    PubMed  CAS  Google Scholar 

  42. Koibuchi N, Iwasaki T. Regulation of brain development by thyroid hormone and its modulation by environmental chemicals. Endocr J. 2006;53:295–303.

    PubMed  CAS  Google Scholar 

  43. Zoeller RT, Dowling AL, Vas AA. Developmental exposure to polychlorinated biphenyls exerts thyroid hormone-like effects on the expression of RC3/neurogranin and myelin basic protein messenger ribonucleic acids in the developing rat brain. Endocrinology. 2000;141:181–9.

    PubMed  CAS  Google Scholar 

  44. Gauger KJ, Kato Y, Haraguchi K, Lehmler H-J, Robertson LW, Bansal R, Zoeller RT. Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors. Environ Health Perspect. 2004;112:516–23.

    PubMed  CAS  Google Scholar 

  45. Bansal R, You S-H, Herzig CTA, Zoeller RT. Maternal thyroid hormone increases HES expression in the fetal rat brain: an effect mimicked by exposure to a mixture of polychlorinated biphenyls (PCBs). Dev Brain Res. 2005;156:13–22.

    CAS  Google Scholar 

  46. You S-H, Gauger KJ, Bansal R, Zoeller RT. 4-Hydroxy-PCB106 acts as a direct thyroid hormone receptor agonist in rat GH3 cells. Mol Cell Endocrinol. 2006;257–58:26–34.

    Google Scholar 

  47. Fritsche E, Cline JE, Nguyen N-H, Scanlan TS, Abel J. Polychlorinated biphenyls disturb differentiation of normal human neural progenitor cells: clue for involvement of thyroid hormone receptors. Environ Health Perspect. 2005;113:871–6.

    PubMed  CAS  Google Scholar 

  48. Zoeller RT, Dowling ALS, Herzig CTA, Iannacone EA, Gauger KJ, Bansal R. Thyroid hormone, brain development, and the environment. Environ Health Perspect. 2002;110(Suppl. 3):355–61.

    PubMed  CAS  Google Scholar 

  49. Harada M. Intrauterine poisoning. Bull Inst Constit Med. 1976;25:38–61.

    Google Scholar 

  50. Chen YCJ, Hsu CC. Effects of prenatal exposure to PCBs on the neurological function of children: a neuropsychological and neurophysiological study. Dev Med Child Neurol. 1994;36:312–20.

    PubMed  CAS  Google Scholar 

  51. Chen YCJ, Yu ML, Rogan WJ, Gladen BC, Hsu CC. A 6-year follow-up of behavior and activity disorders in the Taiwan Yucheng children. Am J Public Health. 1994;84:415–21.

    PubMed  CAS  Google Scholar 

  52. Rogan WJ, Gladen BC. PCBs, DDE, and child development at 18 and 24 months. Ann Epidemiol. 1991;1:407–13.

    PubMed  CAS  Google Scholar 

  53. Jacobson JL, Jacobson SW, Humphrey HEB. Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J Pediatr. 1990;116:38–45.

    PubMed  CAS  Google Scholar 

  54. Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med. 1996;335:783–9.

    PubMed  CAS  Google Scholar 

  55. Koopman-Esseboom C, Weisglas-Kuperus N, de Ridder MAJ, Van der Paauw CG, Tuinstra LGMTh, Sauer PJJ. Effects of polychlorinated biphenyl/dioxin exposure and feeding type on infants’ mental and psychomotor development. Pediatrics. 1996;97:700–06.

    PubMed  CAS  Google Scholar 

  56. Winneke G, Bucholski A, Heinzow B, Kramer U, Schmidt E, Walkowiak J, Wiener JA, Steingruber HJ. Developmental neurotoxicity of polychlorinated biphenyls PCBs: cognitive and psychomotor functions in 7-month-old children. Toxicol Lett. 1998;102–3:423–8.

    Google Scholar 

  57. Winneke G. Health risks of developmental low-level exposure to environmental PCBs in children. Int J Neuropsychopharmacol. 2000;3(Suppl. 1):S53.

    Google Scholar 

  58. Korrick SA. Polychlorinated biphenyls (PCBs) and neurodevelopment in general population samples. In: Robertson LW, Hansen LG, editors. PCBs, recent advances in environmental toxicology and health effects. The University Press of Kentucky, 2001. pp 143–54.

  59. Jacobson JL, Jacobson SW. Developmental effects of PCBs in the fish eater cohort studies. In: Robertson LW, Hansen LG, editors. PCBs, recent advances in environmental toxicology and health effects. The University Press of Kentucky, 2001. pp 127–36.

  60. Schantz SL. Neurotoxic food contaminants: polychlorinated biphenyls (PDB’s) and related compounds. In: Niesink RJ, Jaspers RMA, Kornet LMW, van Ree JM, Tilson HA, editors. Introduction in neuro-behavioral toxicology: food and environment. New York: CRC Press, 1999. pp 253–82.

    Google Scholar 

  61. Tilson HA, Jacobson JL, Rogan WJ. Polychlorinated biphenyls and the developing nervous system: cross-species comparisons. Neurotoxicol Teratol. 1990;12:239–48.

    PubMed  CAS  Google Scholar 

  62. Schantz SL, Widholm JJ. Effects of PCB exposure on neurobehavioral function in animal models. In: Robertson LW, Hansen LG, editors. PCBs, recent advances in environmental toxicology and health effects. The University Press of Kentucky, 2001. pp 221–40.

  63. Kimura-Kuroda J, Nagata I, Kuroda Y. Hydroxylated metabolites of polychlorinated biphenyls inhibit thyroidhormone-dependent extension of cerebellar Purkinje cell dendrites. Develop Brain Res. 2005;154:259–63.

    CAS  Google Scholar 

  64. Gravel C, Hawkes R. Neuronal maturation in the normal and hypothyroid rat cerebellar cortex studied with monoclonal antibody MIT-23. J Comp Neurol. 1987;258:447–62.

    PubMed  CAS  Google Scholar 

  65. Bouvet J, Usson Y, Legrand J. Morphometric analysis of the cerebellar Purkinje cell in the developing normal and hypothyroid chick. Int J Dev Neurosci. 1987;5:345–55.

    PubMed  CAS  Google Scholar 

  66. Kimura-Kuroda J, Nagata I, Negishi-Kato M, Kuroda Y. Thyroid hormone-dependent development of mouse cerebellar Purkinje cells in vitro. Brain Res Dev Brain Res. 2002;137:55–65.

    PubMed  CAS  Google Scholar 

  67. Heuer H, Mason CA. Thyroid hormone induces cerebellar Purkinje cell dendritic development via the thyroid hormone receptor alpha1. J Neurosci. 2003;23:10604–12.

    PubMed  CAS  Google Scholar 

  68. Takasuga T, Senthilkumar K, Watanabe K, Takemori H, Shda T, Kuroda Y. Ultratrace analysis of polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OHPCBs) in human serum and cerebrospinal fluid (CSF) samples. Organohalog Compd. 2004;66:2529–34.

    Google Scholar 

  69. Roegge CS, Morris JR, Villareal S, Wang VC, Powers BE, Klintsova AY, Greenough WT, Pessa IN, Schantz SL. Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg. Neurotoxicol Teratol. 2006;28:74–85.

    PubMed  CAS  Google Scholar 

  70. Howell BW, Hawkes R, Soriano P, Cooper JA. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature. 1997;389(6652):668–9.

    Google Scholar 

  71. Howell BW, Gertler FB, Cooper JA. Mouse disabled (Mdab1): a Src binding protein implicated in neuronal development. EMBO J. 1997;16:121–32.

    PubMed  CAS  Google Scholar 

  72. Luque JM. Integrin and the Reelin-Dab1 pathway: a sticky affair? Brain Res Dev Brain Res. 2004;152:269–71.

    PubMed  CAS  Google Scholar 

  73. Jones PL, Jones FS. Tenascin-C in development and disease: gene regulation and cell function. Matrix Biol. 2000;19:581–96.

    PubMed  CAS  Google Scholar 

  74. Irintchev A, Rollenhagen A, Troncoso E, Kiss JZ, Schachner M. Structural and functional aberrations in the cerebral cortex of tenascin-C deficient mice. Cereb Cortex. 2005;15:950–62.

    PubMed  Google Scholar 

  75. Roelens SA, Beck V, Clerens S, Van den Bergh G, Arckens L, Darras VM, Van der Geyten S. Neurotoxicity of polychlorinated biphenyls (PCBs) by disturbance of thyroid hormone-regulated genes. Ann NY Acad Sci. 2005;1040:454–6.

    PubMed  CAS  Google Scholar 

  76. Quinn CC, Gray GE, Hockfield S. A family of proteins implicated in axon guidance and outgrowth. J Neurobiol. 1999;41:158–64.

    PubMed  CAS  Google Scholar 

  77. Charrier E, Reibel S, Rogemond V, Aguera M, Thomasset N, Honnorat J. Collapsin response mediator proteins (CRMPs): involvement in nervous system development and adult neurodegenerative disorders. Mol Neurobiol. 2003;28:51–64.

    PubMed  CAS  Google Scholar 

  78. Dowling ALS, Martz GU, Leonard JL, Zoeller RT. Acute changes in maternal thyroid hormone induce rapid and transient changes in gene expression in fetal rat brain. J Neurosci. 2000;20:2255–65.

    PubMed  CAS  Google Scholar 

  79. Dowling AL, Zoeller RT. Thyroid hormone of maternal origin regulates the expression of RC3/neurogranin mRNA in the fetal rat brain. Brain Res Mol Brain Res. 2000;82:126–32.

    PubMed  CAS  Google Scholar 

  80. Munoz A, Rodriguez-Pena A, Perez-Castillo A, Ferreiro B, Sutcliffe JG, Bernal J. Effects of neonatal hypothyroidism on rat brain gene expression. Mol Endocrinol. 1991;5:273–80.

    PubMed  CAS  Google Scholar 

  81. Iñiguez MA, Rodriguez-Peña A, Ibarrola N, Aguilera M, Muñoz A, Bernal J. Thyroid hormone regulation of RC3, a brain-specific gene encoding a protein kinase-C substrate. Endocrinology. 1993;133:467–73.

    PubMed  Google Scholar 

  82. Piosik PA, van Groeningen M, Baas F. Effect of thyroid hormone deficiency on RC3/neurogranin mRNA expression in the prenatal and adult caprine brain. Brain Res Mol Brain Res. 1996;42:227–35.

    PubMed  CAS  Google Scholar 

  83. Figueiredo BC, Almazan G, Ma Y, Tetzlaff W, Miller FD, Cuello AC. Gene expression in the developing cerebellum during perinatal hypo- and hyperthyroidism. Brain Res Mol Brain Res. 1993;17:258–68.

    PubMed  CAS  Google Scholar 

  84. Dowling ALS, Iannacone EA, Zoeller RT. Maternal hypothyroidism selectively affects the expression of neuroendocrine-specific protein A messenger ribonucleic acid in the proliferative zone of the fetal rat brain cortex. Endocrinology. 2001;142:390–9.

    PubMed  CAS  Google Scholar 

  85. Alvarez-Dolado M, Cuadrado A, Navarro-Yubero C, Sonderegger P, Furley AJ, Bernal J, Munõz A. Regulation of the LA cell adhesion molecule by thyroid hormone in the developing brain. Mol Cell Neurosci. 2000;16:499–514.

    PubMed  CAS  Google Scholar 

  86. Nguon K, Baxter MG, Sajdel-Sulkowska EM. Perinatal exposure to polychlorinated biphenyls differentially affects cerebellar development and motor functions in male and female rat neonates. Cerebellum. 2005;4:112–22.

    PubMed  CAS  Google Scholar 

  87. Granholm AC. Effects of thyroid hormone deficiency on glial constituents in developing cerebellum of the rat. Exp Brain Res. 1985;59:451–6.

    PubMed  CAS  Google Scholar 

  88. Martinez-Galan JR, Pedraza P, Santacana M, Escobar del Ray F, Morreale de Escobar G, Ruiz-Marcos A. Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism. J Clin Invest. 1997;99:2701–09.

    PubMed  CAS  Google Scholar 

  89. Connor K, Ramamoorthy K, Moore M, Mustain M, Chen I, Safe S, Zacharewski T, Gillesby B, Joyeux A, Balaguer P. Hydroxylated polychlorinated biphenyls (PCBs) as estrogens and antiestrogens: structure-activity relationships. Toxicol Appl Pharmacol. 1997;145:111–23.

    PubMed  CAS  Google Scholar 

  90. Bonefeld-Jorgensen EC, Andersen HR, Rasmussen TH, Vinggaard AM. Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity. Toxicology. 2001;158:141–53.

    PubMed  CAS  Google Scholar 

  91. Tavolari S, Bucci L, Tomasi V, Guarnieri T. Selected polychlorobiphenyls congeners bind to estrogen receptor alpha in human umbilical vascular endothelial (HUVE) cells modulating angiogenesis. Toxicology. 2006;218:67–74.

    PubMed  CAS  Google Scholar 

  92. Sperry TS, Thomas P. Identification of two nuclear androgen receptors in kelp bass (Paralabrax clathratus) and their binding affinities for xenobiotics: comparison with Atlantic croaker (Micropogonias undulates) androgen receptors. Biol Reprod. 1999;61:1152–61.

    PubMed  CAS  Google Scholar 

  93. Portigal CL, Cowell SP, Fedoruk MN, Butler CM, Rennie PS, Nelson CC. Polychlorinated biphenyls interfere with androgen-induced transcriptional activation and hormone binding. Toxicol Appl Pharmacol. 2002;179:185–94.

    PubMed  CAS  Google Scholar 

  94. Schrader TJ, Cooke GM. Effects of Aroclors and individual PCB congeners on activation of the human androgen receptor in vitro. Reprod Toxicol. 2003;17:15–23.

    PubMed  CAS  Google Scholar 

  95. Salama J, Chakraborty TR, Ng L, Gore AC. Effects of polychlorinated biphenyls on estrogen receptor-beta expression in the anteroventral periventricular nucleus. Environ Health Perspect. 2003;111:1278–82.

    PubMed  CAS  Google Scholar 

  96. Colciago A, Negri-Cesi P, Pravettoni A, Mornati O, Casati L, Celotti F. Prenatal Aroclor 1254 exposure and brain sexual differentiation: effect on the expression of testosterone metabolising enzymes and androgen receptors in the hypothalamus of male and female rats. Reprod Toxicol. 2006;22:738–45.

    PubMed  CAS  Google Scholar 

  97. Daniel JM. Effects of oestrogen on cognition: what have we learned from basic research? J Neuroendocrinol. 2006;18:787–95.

    PubMed  CAS  Google Scholar 

  98. Mannella P, Brinton RD. Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphylated Akt and extracellular signalregulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. J Neurosci. 2006;26:9439–47.

    PubMed  CAS  Google Scholar 

  99. Brannval K, Bogdanovic N, Korhonen L, Lindholm D. 19-nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain. Eur J Neursci. 2005;21:871–8.

    Google Scholar 

  100. Knickmeyer RC, Baron-Cohen S. Fetal testosterone and sex differences. Early Hum Dev. 2006;82:755–60.

    CAS  Google Scholar 

  101. Kodavanti PRS, Shafer TJ, Ward TR, Mundy WR, Freudenrich T, Harry GJ, Tilson HA. Differential effects of PCB congeners on phosphoinositide hydrolysis and protein kinase C translocation in rat cerebellar granule cells. Brain Res. 1994;662:75–82.

    PubMed  CAS  Google Scholar 

  102. Yang JH, Kodavanti PR. Possible molecular targets of halogenated aromatic hydrocarbons in neuronal cells. Biochem Biophys Res Commun. 2001;280:1372–7.

    PubMed  CAS  Google Scholar 

  103. Kodavanti PRS, Derr-Yellin EC, Mundy WR, Shafer TJ, Herr DW, Barone Jr S, Choksi NY, MacPhail RC, Tilson HA. Repeated exposure of adult rats to Aroclor 1254 causes brain region-specific changes in intracellular CA2+ buffering and protein kinase C activity in the absence of changes in tyrosine hydroxylase. Toxicol Appl Pharmacol. 1998;153:186–98.

    PubMed  CAS  Google Scholar 

  104. Basha MR, Braddy MS, Zawia NH, Kodavanti PR. Ontogenetic alterations in prototypical transcription factors in the rat cerebellum and hippocampus following perinatal exposure to a commercial PCB mixture. Neurotoxicology. 2006;27:118–24.

    PubMed  CAS  Google Scholar 

  105. Mariussen E, Myhre O, Reistad T, Fonnum F. The polychlorinated biphenyl mixture Aroclor 1254 induces death of rat cerebellar granule cells: the involvement of the N-methyl-D-aspartate receptor and reactive oxygen species. Toxicol Appl Pharmacol. 2002;179:137–44.

    PubMed  CAS  Google Scholar 

  106. Morse DC, Seegal RF, Borsch KO, Brouwer A. Long-term alterations in regional brain serotonin metabolism following maternal polychlorinated biphenyl exposure in the rat. Neurotoxicology. 1996;17:631–8.

    PubMed  CAS  Google Scholar 

  107. Birnbaum LS, Tuomisto J. Non-carcinogenic effects of TCDD in animals. Food Addit Contam. 2000;17:275–88.

    PubMed  CAS  Google Scholar 

  108. Boersma ER, Lanting CI. Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins. Consequences for longterm neurological and cognitive development of the child lactation. Adv Exp Med Biol. 2000;478:271–87.

    PubMed  CAS  Google Scholar 

  109. Kakeyama M, Tohyama C. Developmental neurotoxicity of dioxin and its related compounds. Ind Health. 2003;41:215–30.

    PubMed  CAS  Google Scholar 

  110. Jones MK, Weisenburger WP, Sipes IG, Russel DH. Circadian alterations in prolactin, corticosterone, and thyroid hormone levels and down-regulation of prolactin receptor activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol. 1987;87:337–50.

    PubMed  CAS  Google Scholar 

  111. Raasmaja A, Viluksela M, Rozman KK. Decreased liver type I 5′-deiodinase and increased brown adipose tissue type II 5′-deiodinase activity in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated long-evans rats. Toxicology. 1996;114:199–205.

    PubMed  CAS  Google Scholar 

  112. Johnson E, Shorter C, Bestervelt L, Patterson D, Needham L, Piper W, Lucier G, Nolan C. Serum hormone levels in humans with low serum concentrations of 2,3,7,8-TCDD. Toxicol Ind Health. 2001;17:105–12.

    PubMed  CAS  Google Scholar 

  113. Chaffin CL, Trewin AL, Watanabe G, Taya K, Hutz RJ. Alterations to the pituitary-gonadal axis in the peripubertal female rat exposed to in utero and through lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biol Reprod. 1997;56:1498–502.

    PubMed  CAS  Google Scholar 

  114. Grochowalski A, Pieklo R, Gasinska A, Chrzaszcz R, Gregoraszczuk EL. Accumulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in porcine preovulatory follicles after in vitro exposure to TCDD: effects on steroid secretion and cell proliferation. Cytobios. 2000;102(399):21–31.

    PubMed  CAS  Google Scholar 

  115. Petersen SL, Curran MA, Marconi SA, Carpenter CD, Lubbers LS, McAbee MD. Distribution of mRNAs encoding the arylhydrocarbon receptor, arylhydrocarbon receptor nuclear translocator, and arylhydrocarbon receptor nuclear translocator-2 in the rat brain and brainstem. J Comp Neurol. 2000;427:428–39.

    PubMed  CAS  Google Scholar 

  116. Williamson MA, Gasiewicz TA, Opanashuk LA. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity. Toxicol Sci. 2005;83:340–8.

    PubMed  CAS  Google Scholar 

  117. Kuramoto N, Baba K, Gion K, Sugiyama C, Taniura H, Yoneda Y. Xenobiotic response element binding enriched in both nuclear and microsomal fractions of rat cerebellum. J Neurochem. 2003;85:264–73.

    Article  PubMed  CAS  Google Scholar 

  118. Nayyar T, Zawia NH, Hood DB. Transplacental effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the temporal modulation of Sp1 DNA binding in the developing cerebral cortex and cerebellum. Exp Toxicol Pathol. 2002;53:461–8.

    PubMed  CAS  Google Scholar 

  119. Fujita H, Samejima H, Kitagawa N, Misuhashi T, Washio T, Yonemoto J, Tomita M, Takahashi T, Kosaki K. Genomewide screening of dioxin-responsive genes in fetal brain: bioinformatic and experimental approaches. Congenit Anom. 2006;46:135–43.

    CAS  Google Scholar 

  120. Chang SF, Sun YY, Yang LY, Hu SY, Tsai SY, Lee WS, Lee YH. Bcl-2 gene family expression in the brain of rat offspring after gestational and lactational dioxin exposure. Ann NY Acad Sci. 2005;1042:471–80.

    PubMed  CAS  Google Scholar 

  121. Henshel DS, Martin JW, Norstrom R, Whitehead P, Steeves JD, Cheng KM. Morphometric abnormalities in brains of great blue heron hatchlings exposed in the wild to PCDDs. Environ Health Perspect. 1995;103(Suppl. 4):61–6.

    PubMed  CAS  Google Scholar 

  122. Henshel DS, Martin JW, DeWitt JC. Brain asymmetry as a potential biomarker for developmental TCDD intoxication: a dose-response study. Environ Health Perspect. 1997;105:718–25.

    PubMed  CAS  Google Scholar 

  123. Stanton B, DeWitt J, Henshel D, Watkins S, Lasley B. Fatty acid metabolism in neonatal chickens (Gallus domesticus) treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3’,4,4’,5-pentachlorobiphenyl (PCB-126) in ovo. Comp Biochem Physiol C. 2003;136:73–84.

    Google Scholar 

  124. Peterson RE, Theobald HM, Kimmel GL. Developmental and reproductive toxicity of dioxins and related compounds: cross-species comparisons. Crit Rev Toxicol. 1993;23:283–335.

    PubMed  CAS  Google Scholar 

  125. Ton C, Lin Y, Willett C. Zebrafish as a model for developmental neurotoxicity testing. Birth Defects Res A. 2006;76:553–67.

    CAS  Google Scholar 

  126. Hill A, Howard CV, Strahle U, Cossins A. Neurodevelopmental defects in zebrafish (Danio rerio) at environmentally relevant dioxin (TCDD) concentrations. Toxicol Sci. 2003;76:392–9.

    PubMed  CAS  Google Scholar 

  127. Darnerud PO. Toxic effects of brominated flame retardants in man and wildlife. Environ Int. 2003;29:841–53.

    PubMed  CAS  Google Scholar 

  128. Marsh G, Bergman A, Bladh L-G, Gillner M, Jakobsson E. Synthesis of p-hydroxybromodiphenyl ethers and binding to the thyroid receptor. Organohalogen Compds. 1998;37:305–08.

    CAS  Google Scholar 

  129. Hallgren S, Darnerud PO. Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and chlorinated paraffins (CPs) in rats – testing interactions and mechanisms for thyroid hormone effects. Toxicology. 2002;177:227–43.

    PubMed  CAS  Google Scholar 

  130. Bahn AK, Mills JL, Synder PJ, Gann PH, Houten L, Bialik O, Hollmann L, Utiger RD. Hypothyroidism in workers exposed to polybrominated biphenyls. N Engl J Med. 1980;302:31–33.

    PubMed  CAS  Google Scholar 

  131. Byrne JJ, Carbone JP, Hanson EA. Hypothyroidism and abnormalities in the kinetics of thyroid hormone metabolism in rats treated chronically with polychlorinated biphenyl and polybrominated biphenyl. Endocrinology. 1987;12:520–7.

    Article  Google Scholar 

  132. Zhou T, Taylor MM, DeVito MJ, Crofton KM. Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption. Toxicol Sci. 2002;66:105–16.

    PubMed  CAS  Google Scholar 

  133. Fowles JR, Fairbrother A, Baecher-Steppan L, Kerkvliet NI. Immunologic and endocrine effects of the flame-retardant pentabromodiphenyl ether (PBDE-71) in C57BL/6J mice. Toxicology. 1994;86:49–61.

    PubMed  CAS  Google Scholar 

  134. Darnerud PO, Sinjari T. Effects of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) on thyroxine and TSH blood levels in rats and mice. Organohalogen Compds. 1996;29:316–19.

    CAS  Google Scholar 

  135. Meerts IATM, Letcher RJ, Hoving S, Marsh G, Bergman A, Lemmen JG, van der Burg B, Brouwer A. In vitro estrogenicity of polybrominated bisphenol A compounds. Environ Health Perspect. 2001;109:399–407.

    PubMed  CAS  Google Scholar 

  136. Chen G, Bunce NJ. Polybrominated diphenyl ethers as Ah receptor agonists and antagonists. Toxicol Sci. 2003;76:310–20.

    PubMed  CAS  Google Scholar 

  137. Peters AK, Nijmeijer S, Gradin K, Backlund M, Bergman A, Poellinger L, Denison MS, Van den Berg M. Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway. Toxicol Sci. 2006;92:133–42.

    PubMed  CAS  Google Scholar 

  138. Eriksson P, Jakobsson E, Fredriksson A. Brominated flame retardants: a novel class of developmental neurotoxicants in our environment? Environ Health Perspect. 2001;109:903–08.

    PubMed  CAS  Google Scholar 

  139. Eriksson P, Viberg H, Jakobsson E, Örn U, Fredriksson A. A brominated flame retardant, 2,2’,4,4’,5-pentabromodiphenyl ether: uptake, retention, and induction of neurobehavioral alterations in mice during a critical phase of neonatal brain development. Toxicol Sci. 2002;67:98–103.

    PubMed  CAS  Google Scholar 

  140. Viberg H, Fredriksson A, Jakobsson E, Örn U, Eriksson P. Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. Toxicol Sci. 2003;76:112–20.

    PubMed  CAS  Google Scholar 

  141. Siddiqi MA. Polybrominated diphenyl ethers (PBDEs): new pollutants – old diseases. Clin Med Res. 2003;1:281–90.

    PubMed  CAS  Google Scholar 

  142. Branchi I, Capone F, Vitalone A, Madia F, Santucci D, Alleva E, Costa LG. Early developmental exposure to BDE 99 or Aroclor 1254 affects neurobehavioural profile: Interference from the administration route. Neurotoxicology. 2005;26:183–92.

    PubMed  CAS  Google Scholar 

  143. Kodavanti PRS, Ward TR, Ludewig G, Robertson LW, Birnbaum LS. Polybrominated diphenyl ether (PBDE) effects in rat neuronal cultures: 14C-PBDE accumulation, biological effects, and structure-activity relationships. Toxicol Sci. 2005;88:181–92. Persistent organohalogens and brain development

    PubMed  CAS  Google Scholar 

  144. Kodavanti PRS, Ward TR. Differential effects of commercial polybrominated diphenyl ether and polychlorinated biphenyl mixtures on intracellular signalling in rat brain in vitro. Toxicol Sci. 2005;85:952–62.

    PubMed  CAS  Google Scholar 

  145. Madia F, Giordano G, Fattori V, Vitalone A, Branchi I, Capone F, Costa LG. Differential in vitro neurotoxicity of the flame retardant PBDE-99 and of the PCB Aroclor 1254 in human astrocytoma cells. Toxicol Lett. 2004;154:11–21.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Comparative Endocrinology, Zoological Institute, Naamsestraat 61, B-3000, Leuven, Belgium

    V. M. Darras

Authors
  1. V. M. Darras
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. M. Darras.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Darras, V.M. Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signalling in the developing brain. Cerebellum 7, 26–37 (2008). https://doi.org/10.1007/s12311-008-0004-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-008-0004-5

Key words

Search

Navigation