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Cited by 13Thyroid Disorders and TreatmentsAttention Deficit Hyperactivity DisorderPrenatal Substance Exposure Effects

Hyperactive behavioral phenotypes and an altered brain monoaminergic state in male offspring mice with perinatal hypothyroidism

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Umezu, Toyoshi, Kita, Taizo, Morita, Masatoshi·2019·Toxicology Reports
DOI 10.1016/j.toxrep.2019.10.005PMC PMC6816216
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Abstract

Thyroid hormone (TH) is essential for normal brain development. TH insufficiency during early stages of development may increase the risk for attention deficit/hyperactivity disorder, in which malfunction of brain monoaminergic systems is likely involved. However, little is known about the effects of perinatal hypothyroidism on behaviors and brain monoaminergic systems in offspring mice. The present study examined in mice (1) whether perinatal hypothyroidism causes hyperactive behavioral phenotypes, (2) how perinatal hypothyroidism influences brain monoaminergic systems, and (3) whether hyperactive behavioral phenotypes are associated with the state of brain monoaminergic systems. When dams were exposed to propylthiouracil, offspring mice developed hypothyroidism during the perinatal period. Offspring mice with perinatal hypothyroidism exhibited hyperactive behavioral phenotypes such as hyper-ambulatory activity and an increased response rate in the two-way active avoidance test in a male-specific manner. Significant decreases in dopamine (DA) and serotonin turnover were observed in the striatum (ST), nucleus accumbens, hypothalamus, and hippocampus in male mice with perinatal hypothyroidism. A significant correlation between ambulatory activity and DA turnover in the ST and an augmented ambulatory response to the DA reuptake inhibitor bupropion suggested that DA in the ST was involved in the hyper-ambulatory activity in mice with perinatal hypothyroidism.

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  • Dopamine turnover rates are reduced in the NAc of TRβ -/- mice and in mice with perinatal hypothyroidism.

    “Whereas dopamine turnover rates are reduced in the NAc of TRβ -/- mice (35) and in mice with perinatal hypothyroidism (36)”

    From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [36]

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  1. [1]Ahmed O.M. El-Gareib A.W. El-Bakry A.M. Ei-Tawab S.M.A. Ahmed R.G. Thyroid hormones states and brain development interactions Int. J. Dev. Neurosci. 26 2008 147 209 18031969
  2. [2]Bárez-López S. Guadaño-Ferraz A. Thyroid hormone availability and action during brain development in rodents Front. Cell. Neurosci. 11 2017 240 28855863 PMC5557746
  3. [4]Bernal J. Thyroid hormone receptors in brain development and function Nat. Clin. Pract. Endocrinol. Metab. 3 2007 249 259 17315033
  4. [5]Brucker-Davis F. Effects of environmental synthetic chemicals on thyroid function Thyroid 8 1998 827 856 9777756
  5. [6]Brunner D. Buhot M.C. Hen R. Hofer M. Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice Behav. Neurosci. 113 1999 587 601 10443785
  6. [7]Davies W. Sex differences in attention deficit hyperactivity disorder: candidate genetic and endocrine mechanisms Front. Neuroendocrinol. 35 2014 331 346 24680800
  7. [8]Davis P.J. Lin H.Y. Mousa S.A. Luidens M.K. Hercbergs A.A. Wehling M. Davis F.B. Overlapping nongenomic and genomic actions of thyroid hormone and steroids Steroids 76 2011 829 833 21354437
  8. [9]de Cock M. Maas Y.G.H. van de Bor M. Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review Acta Paediatr. 101 2012 811 818 22458970
  9. [11]Faraone S.V. Khan S.A. Candidate gene studies of attention-deficit/hyperactivity disorder J. Clin. Psychiatry 67 Suppl. 8 2006 13 20 https://www.psychiatrist.com/jcp/article/Pages/2006/v67s08/v67s0803.aspx 16961425
  10. [12]Gainetdinov R.R. Jones S.R. Fumagalli F. Wightman R.M. Caron M.G. Re-evaluation of the role of the dopamine transporter in dopamine system homeostasis Brain Res. Brain Res. Rev. 26 1998 148 153 9651511
  11. [13]Gainetdinov R.R. Wetsel W.C. Jones S.R. Levin E.D. Jaber M. Caron M.G. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity Science 283 1999 397 401 9888856
  12. [14]Gizer I.R. Ficks C. Waldman I.D. Candidate gene studies of ADHD: a meta-analytic review Hum. Genet. 126 2009 51 90 19506906
  13. [15]Hauser P. Zametkin A.J. Martinez P. Vitiello B. Matochik J.A. Mixson A.J. Weintraub B.D. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone N. Engl. J. Med. 328 1993 997 1001 8450877
  14. [17]Howdeshell K.L. A model of the development of the brain as a construct of the thyroid system Environ. Health Perspect. 110 Suppl. 3 2002 337 348 PMC1241181 12060827
  15. [18]Jardi F. Laurent M.R. Kim N. Khalil R. De Bundel D. Van Eeckhaut A. Van Helleputte L. Deboel L. Dubois V. Schollaert D. Decallonne B. Carmeliet G. Van den Bosch L. D’Hooge R. Claessens F. Vanderschueren D. Testosterone boosts physical activity in male mice via dopaminergic pathways Sci. Rep. 8 2018 957 29343749 PMC5772634
  16. [19]Kuribara H. Haraguchi H. Tadokoro S. Comparisons between discrete lever-press and shuttle avoidance response in mice: acquisition processes and effects of psychoactive drugs Jpn. J. Pharmacol. 38 1985 141 151 4032855
  17. [20]Kuribara H. Dopamine D-1 receptor antagonist SCH-23390 retards methamphetamine sensitization in both combined administration and early posttreatment schedules in mice Pharmacol. Biochem. Behav. 52 1995 759 763 8587917
  18. [21]Leo D. Gainetdinov R.R. Transgenic mouse models for ADHD Cell Tissue Res. 354 2013 259 271 23681253 PMC3785710
  19. [22]Li D.W. Sham P.C. Owen M.J. He L. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD) Hum. Mol. Genet. 15 2006 2276 2284 16774975
  20. [24]Modesto T. Tiemeier H. Peeters R.P. Jaddoe V.W.V. Hofman A. Verhulst F.C. Ghassabian A. Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit/hyperactivity disorder symptoms in children JAMA Pediatr. 169 2015 838 845 26146876
  21. [25]Negishi T. Kawasaki K. Sekiguchi S. Ishii Y. Kyuwa S. Kuroda Y. Yoshikawa Y. Attention-deficit and hyperactive neurobehavioural characteristics induced by perinatal hypothyroidism in rats Behav. Brain Res. 159 2005 323 331 15817195
  22. [26]Niederkofler V. Tedi E. Asher T.E. Dymecki S.M. Functional interplay between dopaminergic and serotonergic neuronal systems during development and adulthood ACS Chem. Neurosci. 6 2015 1055 1070 25747116 PMC4791184
  23. [27]Ookubo M. Sadamatsu M. Yoshimura A. Suzuki S. Kato N. Kojima H. Yamada N. Kanai H. Aberrant monoaminergic system in thyroid hormone receptor-β deficient mice as a model of attention-deficit/hyperactivity disorder Int. J. Neuropsychopharmacol. 18 2015 1 9 PMC4540106 25612897
  24. [28]Oppenheimer J.H. Schwartz H.L. Molecular basis of thyroid hormone-dependent brain development Endocr. Rev. 18 1997 462 475 9267760
  25. [29]Perez-Castillo A. Bernal J. Ferreiro B. Pans T. The early ontogenesis of thyroid hormone receptor in the rat fetus Endocrinology 117 1985 2457 2461 2998737
  26. [30]Pitychoutis P.M. Belmer A. Moutkine I. Adrien J. Maroteaux L. Mice lacking the serotonin Htr(2B) receptor gene present an antipsychotic-sensitive schizophrenic-like phenotype Neuropsychopharmacology 40 2015 2764 2773 25936642 PMC4864652
  27. [32]Refetoff S. Resistance to thyroid hormone: an historical overview Thyroid 4 1994 345 349 7833674
  28. [33]Siesser W.B. Zhao J. Miller L.R. Cheng S.Y. McDonald M.P. Transgenic mice expressing a human mutant beta1 thyroid receptor are hyperactive, impulsive, and inattentive Genes Brain Behav. 5 2006 282 297 16594981
  29. [34]Sinclair D. Purves-Tyson T.D. Allen K.M. Weickert C.S. Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain Psychopharmacology 231 2014 1581 1599 24481565 PMC3967083
  30. [35]Umezu T. Evaluation of the effects of plant-derived essential oils on central nervous system function using discrete shuttle-type conditioned avoidance response in mice Phytother. Res. 26 2012 884 891 22086772
  31. [37]Umezu T. Shibata Y. Brain regions and monoaminergic neurotransmitters that are involved in mouse ambulatory activity promoted by bupropion Toxicol. Rep. 3 2016 552 562 28959579 PMC5615937
  32. [38]van den Buuse M. Ruimschotel E. Martin S. Risbrough V.B. Halberstadt A.L. Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT1A receptor knockout mice: implications for schizophrenia Neuropharmacology 61 2011 209 216 21501627 PMC3866100
  33. [39]Vermiglio F. Lo Presti V.P. Moleti M. Sidoti M. Tortorella G. Scaffidi G. Castagna M.G. Mattina F. Violi M.A. Crisa A. Artemisia A. Trimarchi F. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries J. Clin. Endocrinol. Metab. 89 2004 6054 6060 15579758
  34. [40]Wilcoxon J.S. Nadolski G.J. Samarut J. Chassande O. Redei E.E. Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor alpha Behav. Brain Res. 177 2007 109 116 17129617 PMC1819397
  35. [41]Wood A.C. Neale M.C. Twin studies and their implications for molecular genetic studies: endophenotypes integrate quantitative and molecular genetics in ADHD research J. Am. Acad. Child Adolesc. Psychiatry 49 2010 874 883 20732624 PMC3148177
  36. [42]Xu M. Moratalla R. Gold L.H. Hiroi N. Koob G.F. Graybiel A.M. Tonegawa S. Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses Cell 79 1994 729 742 7954836
  37. [43]Zhu Y.S. Yen P.M. Chin W.W. Pfaff D.W. Estrogen and thyroid hormone interaction on regulation of gene expression Proc. Natl. Acad. Sci. U. S. A. 93 1996 12587 12592 8901626 PMC38036
  38. [44]Zhuang X. Oosting R.S. Jones S.R. Gainetdinov R.R. Miller G.W. Caron M.G. Hen R. Hyperactivity and impaired response habituation in hyperdopaminergic mice Proc. Natl. Acad. Sci. U. S. A. 98 2001 1982 1987 11172062 PMC29368
  39. [45]Zoeller R.T. Crofton K.M. Mode of action: developmental thyroid hormone insufficiency—neurological abnormalities resulting from exposure to propylthiouracil Crit. Rev. Toxicol. 35 2005 771 781 16417044

Cited by

Sorted by citations

Authors
Umezu, T., Kita, T., & Morita, M.
Affiliations
  • National Institute for Environmental Studies (JP)
  • Kyushu Nutrition Welfare University (JP)
  • Ehime University (JP)
Corresponding author
Umezu, Toyoshi
ORCID
Umezu, Toyoshi
Venue
Toxicology Reports
Publisher
Elsevier BV
Published
2019
Volume
6
Pages
1031-1039
ISSN
2214-7500 (ISSN-L)
DOI
10.1016/j.toxrep.2019.10.005
PMC
PMC6816216
OpenAlex
W2980040098
Cited by
13
References
5
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Toxicology Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
Keywords
perinatal hypothyroidism, hyperactivity, attention deficit hyperactivity disorder, monoaminergic systems, dopamine turnover, serotonin turnover, striatum, nucleus accumbens, hypothalamus, hippocampus, propylthiouracil, bupropion, active avoidance, ambulatory activity, male offspring, thyroid hormones, brain development

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