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Maternal Hypothyroxinemia-Induced Neurodevelopmental Impairments in the Progeny

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Abstract

Maternal hypothyroxinemia can induce neurodevelopmental impairments in the developing fetus. We here review recent studies on the epidemiology and molecular mechanisms associated with this important public health issue. In 2011, the American Thyroid Association defined maternal hypothyroxinemia as low serum free thyroxine (FT4) levels (<5th or <10th percentile) existing in conjunction with normal serum free triiodothyronine (FT3) or thyroid stimulating hormone (TSH) levels during pregnancy. Compared to clinical or subclinical hypothyroidism, hypothyroxinemia is more commonly found in pregnant women. Hypothyroxinemia usually ensues in response to several factors, such as mild iodine deficiency, environmental endocrine disrupters, or certain thyroid diseases. Unequivocal evidence demonstrates that maternal hypothyroxinemia leads to negative effects on fetal brain development, increasing the risks for cognitive deficits and poor psychomotor development in resulting progeny. In support of this, rodent models provide direct evidence of neurodevelopmental damage induced by maternal hypothyroxinemia, including dendritic and axonal growth limitation, neural abnormal location, and synaptic function alteration. The neurodevelopmental impairments induced by hypothyroxinemia suggest an independent role of T4. Increasing evidence indicates that adequate thyroxine is required for the mothers in order to protect against the abnormal brain development in their progeny.

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References

  1. Morreale de Escobar G, Obregon MJ, Escobar del Rey F (2000) Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85:3975–3987

    CAS  PubMed  Google Scholar 

  2. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN et al (2011) Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21(10):1081–1125

    Article  PubMed  PubMed Central  Google Scholar 

  3. Finken MJ, van Eijsden M, Loomans EM, Vrijkotte TG, Rotteveel J (2013) Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. J Clin Endocrinol Metab 98(4):1417–1426

    Article  CAS  PubMed  Google Scholar 

  4. Boelaert K, Franklyn JA (2005) Thyroid hormone in health and disease. J Endocrinol 187(1):1–15

    Article  CAS  PubMed  Google Scholar 

  5. Pinazo-Durán MD, Pons-Vázquez S, Gallego-Pinazo R, Galbis Estrada C, Zanón-Moreno V, Vila Bou V, Sanz Solana P (2011) Thyroid hormone deficiency disrupts rat eye neurodevelopment. Brain Res 1392:16–26

    Article  PubMed  CAS  Google Scholar 

  6. Williams GR (2008) Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol 20:784–794

    Article  CAS  PubMed  Google Scholar 

  7. Bernal J, Guadaño-Ferraz A, Morte B (2003) Perspectives in the study of thyroid hormone action on brain development and function. Thyroid 13(11):1005–1012

    Article  CAS  PubMed  Google Scholar 

  8. Cheng SY, Leonard JL, Davis PJ (2010) Molecular aspects of thyroid hormone actions. Endocr Rev 31:139–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen C, Zhou Z, Zhong M, Zhang Y, Li M, Zhang L, Qu M, Yang J, et al (2012) Thyroid hormone promotes neuronal differentiation of embryonic neural stem cells by inhibiting STAT3 signaling through TRα1. Stem Cells Dev 21:2667–2681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Patel J, Landers K, Li H, Mortimer RH, Richard K (2011) Thyroid hormones and fetal neurological development. J Endocrinol 209:1–8

    Article  CAS  PubMed  Google Scholar 

  11. König S, Moura Neto V (2002) Thyroid hormone actions on neural cells. Cell Mol Neurobiol 22(5–6):517–544

    Article  PubMed  Google Scholar 

  12. Ausó E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escoba G, Berbel P (2004) A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 145:4037–4047

    Article  PubMed  CAS  Google Scholar 

  13. Henrichs J, Ghassabian A, Peeters RP, Tiemeier H (2013) Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin Endocrinol (Oxf) 79:152–162

    Article  Google Scholar 

  14. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ (2006) Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 117:161–167

    Article  PubMed  Google Scholar 

  15. Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C, Teng X, Guo R et al (2010) Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clin Endocrinol (Oxf) 72:825–829

    Article  CAS  Google Scholar 

  16. Opazo MC, Gianini A, Pancetti F, Azkcona G, Alarcón L, Lizana R, Noches V, Gonzalez PA et al (2008) Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 149(10):5097–5106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wei W, Wang Y, Wang Y, Dong J, Min H, Song B, Teng W, Xi Q et al (2013) Developmental hypothyroxinemia induced by maternal mild iodine deficiency delays hippocampal axonal growth in the rat offspring. J Neuroendocrinol 25:852–862

    Article  CAS  PubMed  Google Scholar 

  18. Wang Y, Wang Y, Dong J, Wei W, Song B, Min H, Teng W, Chen J (2014) Developmental hypothyroxinemia and hypothyroidism limit dendritic growth of cerebellar purkinje cells in rat offspring: involvement of MAP2 and stathmin. Neuropathol Appl Neurobiol 40:398–415

    Article  CAS  PubMed  Google Scholar 

  19. Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM et al (2010) Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 95(9):4227–4234

    Article  CAS  PubMed  Google Scholar 

  20. Suárez-Rodríguez M, Azcona-San Julián C, Alzina de Aguilar V (2012) Hypothyroxinemia during pregnancy: the effect on neurodevelopment in the child. Int J Dev Neurosci 30(6):435–438

    Article  PubMed  CAS  Google Scholar 

  21. Moleti M, Lo Presti VP, Mattina F, Mancuso A, De Vivo A, Giorgianni G, Di Bella B, Trimarchi F et al (2009) Gestational thyroid function abnormalities in conditions of mild iodine deficiency: early screening versus continuous monitoring of maternal thyroid status. Eur J Endocrinol 160(4):611–617

    Article  CAS  PubMed  Google Scholar 

  22. de Escobar GM, Ares S, Berbel P, Obregón MJ, del Rey FE (2008) The changing role of maternal thyroid hormone in fetal brain development. Semin Perinatol 32(6):380–386

    Article  PubMed  Google Scholar 

  23. Krassas GE, Poppe K, Glinoer D (2010) Thyroid function and human reproductive health. Endocr Rev 31(5):702–755

    Article  CAS  PubMed  Google Scholar 

  24. Poppe K, Glinoer D (2003) Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 9:149–161

    Article  PubMed  Google Scholar 

  25. Hu X, Teng X, Zheng H, Shan Z, Li J, Jin T, Xiong C, Zhang H et al (2014) Iron deficiency without anemia causes maternal hypothyroxinemia in pregnant rats. Nutr Res 34(7):604–612

    Article  CAS  PubMed  Google Scholar 

  26. Vermiglio F, Lo Presti VP, Moleti M, Sidoti M, Tortorella G, Scaffidi G, Castagna MG, Mattina F et al (2004) Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate ID: a possible novel ID disorder in developed countries. J Clin Endocrinol Metab 89:6054–6060

    Article  CAS  PubMed  Google Scholar 

  27. Zimmermann MB (2009) Iodine deficiency. Endocr Rev 30:376–408

    Article  CAS  PubMed  Google Scholar 

  28. Zimmermann MB, Andersson M (2012) Update on iodine status worldwide. Curr Opin Endocrinol Diabetes Obes 19:382–387

    Article  CAS  PubMed  Google Scholar 

  29. Pearce EN, Andersson M, Zimmermann MB (2013) Global iodine nutrition: where do we stand in 2013? Thyroid 23:523–528

    Article  CAS  PubMed  Google Scholar 

  30. Saira S, Khattak RM, Rehman AU, Khan AA, Khattak MNK (2014) Prevalence of goiter and iodine status in 6–12 years school children and pregnant women of district Charsadda, Pakistan. Acta Endocrinol (Buc) 10:65–75

    Article  CAS  Google Scholar 

  31. Andersson M, Karumbunathan V, Zimmermann MB (2012) Global iodine status in 2011 and trends over the past decade. J Nutr 142:744–750

    Article  CAS  PubMed  Google Scholar 

  32. Walker SP, Wachs TD, Gardner JM, Lozoff B, Wasserman GA, Pollitt E, Carter JA (2007) Child development: risk factors for adverse outcomes in developing countries. Lancet 369:145–157

    Article  PubMed  Google Scholar 

  33. Kerac M, Postels DG, Mallewa M, Jalloh AA, Voskuijl WP, Groce N, Gladstone M, Molyneux E (2014) The interaction of malnutrition and neurological disability in Africa. Semin Pediatr Neurol 21:42–49

    Article  PubMed  Google Scholar 

  34. Clifton VL, Hodyl NA, Fogarty PA, Torpy DJ, Roberts R, Nettelbeck T, Ma G, Hetzel B (2013) The impact of iodine supplementation and bread fortification on urinary iodine concentrations in a mildly iodine deficient population of pregnant women in South Australia. Nutr J 12:32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bath SC, Rayman MP (2013) Iodine deficiency in the UK: an overlooked cause of impaired neurodevelopment? Proc Nutr Soc 72:226–235

    Article  CAS  PubMed  Google Scholar 

  36. Gowachirapant S, Melse-Boonstra A, Winichagoon P, Zimmermann MB (2014) Overweight increases risk of first trimester hypothyroxinaemia in iodine-deficient pregnant women. Matern Child Nutr 10:61–71

    Article  PubMed  Google Scholar 

  37. World Health Organization/UNICEF/ICCIDD (2007) Assessment of ID disorders and monitoring their elimination: a guide for programme managers, 3rd edn. World Health Organization, Geneva, Available from http://whqlibdoc.who.int/publications/2007/9789241595827_eng.pdf

    Google Scholar 

  38. Román GC (2007) Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. J Neurol Sci 262(1–2):15–26

    Article  PubMed  CAS  Google Scholar 

  39. Ozpinar A, Kelestimur F, Songur Y, Can O, Valentin L, Caldwell K, Arikan E, Unsal I et al (2014) Iodine status in Turkish populations and exposure to iodide uptake inhibitors. PLoS One 9(2):e88206

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Rogan WJ, Paulson JA, Baum C, Brock-Utne AC, Brumberg HL, Campbell CC, Lanphear BP, Lowry JA et al (2014) Iodine deficiency, pollutant chemicals, and the thyroid: new information on an old problem. Pediatrics 133:1163–1166

    Article  PubMed  Google Scholar 

  41. Tonacchera M, Viacava P, Fanelli G, Agretti P, De Marco G, De Servi M, Di Cosmo C, Chiovato L et al (2004) The sodium-iodide symporter protein is always present at a low expression and confined to the cell membrane in nonfunctioning nonadenomatous nodules of toxic nodular goitre. Clin Endocrinol (Oxf) 61(1):40–45

    Article  CAS  Google Scholar 

  42. Kirk AB (2006) Environmental perchlorate: why it matters. Anal Chim Acta 567(1):4–12

    Article  CAS  PubMed  Google Scholar 

  43. Lumen A, Mattie DR, Fisher JW (2013) Evaluation of perturbations in serum thyroid hormones during human pregnancy due to dietary iodide and perchlorate exposure using a biologically based dose–response model. Toxicol Sci 133(2):320–341

    Article  CAS  PubMed  Google Scholar 

  44. Melse-Boonstra A, Mackenzie I (2013) Iodine deficiency, thyroid function and hearing deficit: a review. Nutr Res Rev 26(2):110–117

    Article  CAS  PubMed  Google Scholar 

  45. Conde-Agudelo A, Romero R (2009) Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and metaanalysis. Am J Obstet Gynecol 200(6):595–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Román GC, Ghassabian A, Bongers-Schokking JJ, Jaddoe VW, Hofman A, de Rijke YB, Verhulst FC, Tiemeier H (2013) Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol 74(5):733–742

    Article  PubMed  CAS  Google Scholar 

  47. Hynes KL, Otahal P, Hay I, Burgess JR (2013) Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. J Clin Endocrinol Metab 98:1954–1962

    Article  CAS  PubMed  Google Scholar 

  48. Bath SC, Steer CD, Golding J, Emmett P, Rayman MP (2013) Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet 382:331–337

    Article  CAS  PubMed  Google Scholar 

  49. Berbel P, Mestre JL, Santamaría A, Palazón I, Franco A, Graells M, González-Torga A, de Escobar GM (2009) Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 19:511–519

    Article  CAS  PubMed  Google Scholar 

  50. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM et al (1999) Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 50:149–155

    Article  CAS  Google Scholar 

  51. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL (2003) Maternal hypothyroxinemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 59:282–288

    Article  Google Scholar 

  52. Skeaff SA (2011) Iodine deficency in pregnancy: the effect on neurodevelopment in the child. Nutrients 3:265–273

    Article  PubMed  PubMed Central  Google Scholar 

  53. Costeira MJ, Oliveira P, Santos NC, Ares S, Saenz-Rico B, de Escobar GM, Palha JA (2011) Psychomotor development of children from an iodine-deficient region. J Pediatr 159:447–453

    Article  PubMed  Google Scholar 

  54. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de Muinck Keizer-Schrama SM, Hofman A, Ross HA et al (2013) Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J Clin Endocrinol Metab 98(11):4382–4390

    Article  CAS  PubMed  Google Scholar 

  55. Ares S, Escobar-Morreale HF, Quero J, Durán S, Presas MJ, Herruzo R, Morreale de Escobar G (1997) Neonatal hypothyroxinemia: effects of iodine intake and premature birth. J Clin Endocrinol Metab 82(6):1704–1712

    PubMed  Google Scholar 

  56. van Wassenaer AG, Kok JH (2004) Hypothyroxinaemia and thyroid function after preterm birth. Semin Neonatol 9(1):3–11

    Article  PubMed  Google Scholar 

  57. Williams FL, Hume R (2008) Perinatal factors affecting thyroid hormone status in extreme preterm infants. Semin Perinatol 32:398–402

    Article  PubMed  Google Scholar 

  58. Williams FL, Mires GJ, Barnett C, Ogston SA, van Toor H, Visser TJ, Hume R, Scottish Preterm Thyroid Group (2005) Transient hypothyroxinemia in preterm infants: the role of cord sera thyroid hormone levels adjusted for prenatal and intrapartum factors. J Clin Endocrinol Metab 90:4599–4606

    Article  CAS  PubMed  Google Scholar 

  59. Hong T, Paneth N (2008) Maternal and infant thyroid disorders and cerebral palsy. Semin Perinatol 32(6):438–445

    Article  PubMed  Google Scholar 

  60. Rovet J, Simic N (2008) The role of transient hypothyroxinemia of prematurity in development of visual abilities. Semin Perinatol 32(6):431–437

    Article  PubMed  Google Scholar 

  61. Allen MC (2008) Neurodevelopmental outcomes of preterm infants. Curr Opin Neurol 21(2):123–128

    Article  PubMed  Google Scholar 

  62. Reuss ML, Paneth N, Pinto-Martin JA, Lorenz JM, Susser M (1996) The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N Engl J Med 334(13):821–827

    Article  CAS  PubMed  Google Scholar 

  63. Hamm MP, Cherry NM, Martin JW, Bamforth F, Burstyn I (2009) The impact of isolated maternal hypothyroxinemia on perinatal morbidity. J Obstet Gynaecol Can 31(11):1015–1021

    Article  PubMed  Google Scholar 

  64. Storey NM, Gentile S, Ullah H, Russo A, Muessel M, Erxleben C, Armstrong DL (2006) Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone. Proc Natl Acad Sci U S A 103:5197–5201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wiesner RJ, Kurowski TT, Zak R (1992) Regulation by thyroid hormone of nuclear and mitochondrial genes encoding subunits of cytochrome-c oxidase in rat liver and skeletal muscle. Mol Endocrinol 6:1458–1467

    CAS  PubMed  Google Scholar 

  66. Zamoner A, Pessoa-Pureur R (2011) Nongenomic actions of thyroid hormones: every why has a wherefore. Immunol Endocr Metab Agents Med Chem 11:165–178

    Article  CAS  Google Scholar 

  67. Berbel P, Navarro D, Román GC (2014) An evo-devo approach to thyroid hormones and cerebral cortex development: etiological implications for autism. Front Endocrinol 5:146. doi:10.3389/fendo.2014.00146

    Article  Google Scholar 

  68. Chatonnet F, Flamant F, Morte B (2014) A temporary compendium of thyroid hormone target genes in brain. Biochim Biophys Acta. doi:10.1016/j.bbagrm.2014.05.023

    PubMed  Google Scholar 

  69. Morte B, Díez D, Ausó E, Belinchón MM, Gil-Ibáñez P, Grijota-Martínez C, Navarro D, de Escobar GM et al (2010) Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway. Endocrinology 151:810–820

    Article  CAS  PubMed  Google Scholar 

  70. Siegrist-Kaiser CA, Juge-Aubry C, Tranter MP, Ekenbarger DM, Leonard JL (1990) Thyroxine-dependent modulation of actin polymerization in cultured astrocytes. A novel, extranuclear action of thyroid hormone. J Biol Chem 265:5296–5302

    CAS  PubMed  Google Scholar 

  71. Leonard JL, Farwell AP (1997) TH-regulated actin polymerization in brain. Thyroid 7:147–151

    Article  CAS  PubMed  Google Scholar 

  72. Davis PJ, Shih A, Lin HY, Martino LJ, Davis FB (2000) Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR. J Biol Chem 275:38032–38039

    Article  CAS  PubMed  Google Scholar 

  73. Visser WE, Friesema EC, Visser TJ (2011) Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol 25(1):1–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schwartz CE, Stevenson RE (2007) The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. Best Pract Res Clin Endocrinol Metab 21:307–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Babu S, Sinha RA, Mohan V, Rao G, Pal A, Pathak A, Singh M, Godbole MM (2011) Effect of hypothyroxinemia on thyroid hormone responsiveness and action during rat postnatal neocortical development. Exp Neurol 228(1):91–98

    Article  CAS  PubMed  Google Scholar 

  76. Chan S, Kilby MD (2000) Thyroid hormone and central nervous system development. J Endocrinol 165(1):1–8

    Article  CAS  PubMed  Google Scholar 

  77. Heuer H, Mason CA (2003) Thyroid hormone induces cerebellar Purkinje cell dendritic development via the thyroid hormone receptor α1. J Neurosci 23(33):10604–10612

    CAS  PubMed  Google Scholar 

  78. Gao FB, Apperly J, Raff M (1998) Cell-intrinsic timers and thyroid hormone regulate the probability of cell-cycle withdrawal and differentiation of oligodendrocyte precursor cells. Dev Biol 197:54–66

    Article  CAS  PubMed  Google Scholar 

  79. Billon N, Tokumoto Y, Forrest D, Raff M (2001) Role of thyroid hormone receptors in timing oligodendrocyte differentiation. Dev Biol 235(1):110–120

    Article  CAS  PubMed  Google Scholar 

  80. Billon N, Jolicoeur C, Tokumoto Y, Vennström B, Raff M (2002) Normal timing of oligodendrocyte development depends on thyroid hormone receptor alpha 1 (TRα1). EMBO J 21(23):6452–6460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tsunekawa K, Murakami M (2014) Thyroid disease caused by receptor abnormality. Rinsho Byori 62(1):60–66

    CAS  PubMed  Google Scholar 

  82. Shi C, Meng Q, Wood DW (2014) Analysis of the roles of mutations in thyroid hormone receptor-β by a bacterial biosensor system. J Mol Endocrinol 52(1):55–66

    Article  CAS  PubMed  Google Scholar 

  83. Glinoer D (2001) Pregnancy and iodine. Thyroid 11:471–481

    Article  CAS  PubMed  Google Scholar 

  84. Moleti M, Trimarchi F, Vermiglio F (2014) Thyroid physiology in pregnancy. Endocr Pract 20(6):589–596

    Article  PubMed  Google Scholar 

  85. Patel J, Landers K, Li H, Mortimer RH, Richard K (2011) Delivery of maternal thyroid hormones to the fetus. Trends Endocrinol Metab 22:164–170

    Article  CAS  PubMed  Google Scholar 

  86. Puig-Domingo M, Vila L (2013) The implications of iodine and its supplementation during pregnancy in fetal brain development. Curr Clin Pharmacol 8(2):97–109

    Article  CAS  PubMed  Google Scholar 

  87. Pearce EN (2012) Effects of iodine deficiency in pregnancy. J Trace Elem Med Biol 26:131–133

    Article  CAS  PubMed  Google Scholar 

  88. Moleti M, Trimarchi F, Vermiglio F (2011) Doubts and concerns about isolated maternal hypothyroxinemia. J Thyroid Res 2011:463029

    Article  PubMed  PubMed Central  Google Scholar 

  89. Pedraza PE, Obregon MJ, Escobar-Morreale HF, del Rey FE, de Escobar GM (2006) Mechanisms of adaptation to iodine deficiency in rats: thyroid status is tissue specific. Its relevance for man. Endocrinology 147(5):2098–2108

    Article  CAS  PubMed  Google Scholar 

  90. Sharlin DS, Tighe D, Gilbert ME, Zoeller RT (2008) The balance between oligodendrocyte and astrocyte production in major white matter tracts in linearly related to serum total thyroxine. Endocrinology 149(5):2527–2536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sinha RA, Pathak A, Mohan V, Bandyopadhyay S, Rastogi L, Godbole MM (2008) Maternal thyroid hormone: a strong repressor of neuronal nitric oxide synthase in rat embryonic neocortex. Endocrinology 149(9):4396–4401

    Article  CAS  PubMed  Google Scholar 

  92. Lavado-Autric R, Ausó E, García-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G (2003) Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073–1082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gilbert ME, Ramos RL, McCloskey DP, Goodman JH (2014) Subcortical band heterotopia in rat offspring following maternal hypothyroxinemia: structural and functional characteristics. J Neuroendocrinol 26(8):528–541

    Article  CAS  PubMed  Google Scholar 

  94. Farwell AP, Dubord-Tomasetti SA, Pietrzykowski AZ, Stachelek SJ, Leonard JL (2005) Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3′,5′-triiodothyronine. Brain Res Dev Brain Res 154(1):121–135

    Article  CAS  PubMed  Google Scholar 

  95. Zamoner A, Funchal C, Jacques-Silva MC, Gottfried C, Barreto Silva FR, Pessoa-Pureur R (2007) Thyroid hormones reorganize the cytoskeleton of glial cells through Gfap phosphorylation and RhoA-dependent mechanisms. Cell Mol Neurobiol 27(7):845–865

    Article  CAS  PubMed  Google Scholar 

  96. Davis PJ, Leonard JL, Davis FB (2008) Mechanisms of nongenomic actions of thyroid hormone. Front Neuroendocrinol 29(2):211–218

    Article  CAS  PubMed  Google Scholar 

  97. Mitchison T, Kirschner M (1988) Cytoskeletal dynamics and nerve growth. Neuron 1(9):761–772

    Article  CAS  PubMed  Google Scholar 

  98. Wang Y, Wei W, Wang Y, Dong J, Song B, Min H, Teng W, Chen J (2013) Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway. Toxicol Appl Pharmacol 271:257–265

    Article  CAS  PubMed  Google Scholar 

  99. Wang Y, Wei W, Song B, Wang Y, Dong J, Min H, Chen J (2014) Developmental hypothyroxinemia caused by mild iodine deficiency leads to HFS-induced LTD in rat hippocampal CA1 region: involvement of AMPA receptor. Mol Neurobiol 50(2):348–357

    Article  CAS  PubMed  Google Scholar 

  100. Wei W, Wang Y, Dong J, Wang Y, Min H, Song B, Shan Z, Teng W et al (2014) Hypothyroxinemia induced by maternal mild iodine deficiency impairs hippocampal myelinated growth in lactational rats. Environ Toxicol. doi:10.1002/tox.21997

    Google Scholar 

  101. Brooks VB (1984) Cerebellar functions in motor control. Hum Neurobiol 2:251–260

    CAS  PubMed  Google Scholar 

  102. Wang Y, Wang Y, Dong J, Wei W, Song B, Min H, Yu Y, Lei X et al (2014) Developmental hypothyroxinemia and hypothyroidism reduce proliferation of cerebellar granule neuron precursors in rat offspring by downregulation of the sonic hedgehog signaling pathway. Mol Neurobiol 49:1143–1152

    Article  CAS  PubMed  Google Scholar 

  103. Harry GJ, Hooth MJ, Vallant M, Behl M, Travlos GS, Howard JL, Price CJ, McBride S et al (2014) Developmental neurotoxicity of 3,3′,4,4′-tetrachloroazobenzene with thyroxine deficit: sensitivity of glia and dentate granule neurons in the absence of behavioral changes. Toxics 2(3):496–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang L, Sun YN, Li YM, Lin LX, Ye Y, Yan YQ, Chen ZP (2011) Effect of different iodine nutrition on cerebellum Pcp-2 in rat offspring during lactation. Biol Trace Elem Res 143:1629–1639

    Article  CAS  PubMed  Google Scholar 

  105. Man EB (1972) Thyroid function in pregnancy and infancy. Maternal hypothyroxinemia and retardation of progeny. CRC Crit Rev Clin Lab Sci 3(2):203–225

    Article  CAS  PubMed  Google Scholar 

  106. Trentin AG (2006) Thyroid hormone and astrocyte morphogenesis. J Endocrinol 189(2):189–197

    Article  CAS  PubMed  Google Scholar 

  107. Vila L, Velasco I, González S, Morales F, Sánchez E, Torrejón S, Soldevila B, Stagnaro-Green A et al (2013) Controversies in endocrinology. On the need for universal thyroid screening in pregnant women. Eur J Endocrinol 170(1):R17–R30

    Article  PubMed  CAS  Google Scholar 

  108. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R et al (2012) Antenatal thyroid screening and childhood cognitive function. N Engl J Med 366(6):493–501

    Article  CAS  PubMed  Google Scholar 

  109. Trumpff C, De Schepper J, Tafforeau J, Van Oyen H, Vanderfaeillie J, Vandevijvere S (2013) Mild iodine deficiency in pregnancy in Europe and its consequences for cognitive and psychomotor development of children: a review. J Trace Elem Med Biol 27(3):174–183

    Article  CAS  PubMed  Google Scholar 

  110. Zhou SJ, Anderson AJ, Gibson RA, Makrides M (2013) Effect of iodine supplementation in pregnancy on child development and other clinical outcomes: a systematic review of randomized controlled trials. Am J Clin Nutr 98(5):1241–1254

    Article  CAS  PubMed  Google Scholar 

  111. Ferreir SM, Navarro AM, Magalhães PK, Maciel LM (2014) Iodine insufficiency in pregnant women from the State of São Paulo. Arq Bras Endocrinol Metabol 58:282–287

    Article  Google Scholar 

  112. Méndez-Villa L, Elton-Puente JE, Solís-S JC, Sampson-Zaldívar E, García-G C, Villalobos P, Colarossi A, García OP et al (2014) Iodine nutrition and thyroid function assessment in childbearing age women from Queretaro, Mexico. Nutr Hosp 29:204–211

    PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant numbers 81102126, 30800896), and Important Platform of Science and Technology for the Universities in Liaoning Province (grant number 16010).

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The authors declare that there are no conflicts of interest.

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    Authors and Affiliations

    1. Department of Occupational and Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110013, People’s Republic of China

      Hui Min, Jing Dong, Yi Wang, Yuan Wang & Jie Chen

    2. Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

      Hui Min, Jing Dong, Yi Wang, Yuan Wang, Weiping Teng & Jie Chen

    3. Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

      Qi Xi

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    1. Hui Min
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    2. Jing Dong
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    3. Yi Wang
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    4. Yuan Wang
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    Correspondence to Qi Xi or Jie Chen.

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    Hui Min and Jing Dong contributed equally to this work.

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    Min, H., Dong, J., Wang, Y. et al. Maternal Hypothyroxinemia-Induced Neurodevelopmental Impairments in the Progeny. Mol Neurobiol 53, 1613–1624 (2016). https://doi.org/10.1007/s12035-015-9101-x

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