Hypothyroidism

1. Hypothyroidism Fetal Brain Development

2. Thyroid Hormone Action

3. Thyroid Hormone Action T4 has the highest levels in the body T3 has the highest affinity for thyroid receptors T4 can be metabolized into T3

4. Thyroid Hormone Action From Forrest et al 2002 Thyroid receptor sits on promotor in absence of ligand (corepressor complex) Ligand binding causes recruitment of the coactivator complex and gene transcription

5. Hypothyroidism and Development • Fetal and neonatal hypothyroidism has been correlated with neurological deficits • Severity of deficits are related to severity of hypothyroidism • Females may be more sensitive to TH and hypothyroidism than males (shown via gene array data, animal models) • Studies show that TH has different actions in the brain at different developmental times • Majority of specific neurodevelopmental events affected by TH are poorly understood

6. Timing of TH Action • Fetal thyroid gland is not functional until 12th week of gestation • Fetus dependent entirely on maternal source of thyroid hormone (1st trimester) • Reduced maternal supply of TH can occur by maternal hypothyroidism or premature birth • Fetal thyroid gland increases its role in development during gestation • TH insufficiency late in development by decreased fetal TH production is referred to as congenital hypothyroidism

7. Maternal Hypothyroidism • Nearly 3% of pregnant women have low-normal circulating T4 • Most low-normal hypothyroidism is undiagnosed and/or untreated • Fetuses exposed to thyroid hormone insufficiency as mother does not produce enough T4 for both her and her fetus • Severity of fetal thyroid hormone insufficiency is dependent on severity of maternal hypothyroidism

8. Maternal Hypothyroidism • Offspring are often found to have reduced perceptual and motor abilities, short attention spans, developmental delays, variable reaction times to visual stimuli • Effect of low TH at specific times results in different developmental deficits • Before 16 weeks: visual attention abilities • After 16 weeks: fine and graphomotor skills, reading abilities

9. Premature Birth • Premature birth causes a loss of TH from maternal sources before fetal gland is operational • Provide another model of fetal TH insufficiency • Low-risk premies (50%) show reduced visuospatial and fine motor skills, selective attention and memory abilities, and reduced math competency

10. Congenital Hypothyroidism • Takes place later in development than maternal hypothyroidism or premature birth hypothyroidism • Children exhibit IQ levels 6 points below expectation as well as visuospatial, motor, language, memory and attention deficits • Newborn screening for congenital hypothyroidism has allowed treatment, reducing severity of deficits

11. Hypothyroidism and Development From Zoeller and Rovet, 2004

12. Experimental Evidence • Hypothyroid rat dams during pregnancy and the effects on their offspring • General effects • Effects on oligodendrocytes • Changes in phosphorylation of protein kinases • Effects on HDACs, gene repression

13. Hypothyroidism • Female rats made hypothyroid (Tx) prior to mating; offspring were cross-fostered to non-hypothyroid dams at birth • On PND 80: • Offspring exhibited learning deficits (via maze learning), “hyperactivity” (increased open-field exploration), less cautious during emotionality testing • Gender difference on learning • Females more sensitive to TH insufficiency than males in terms of learning From Friedhoff et al, 2000

14. Oligodendrocyte Accumulation • Hypothyroidal animals demonstrate: • Decreased number of myelinated axons in commissures • HOWEVER, no difference in the total number of axons; suggests hypothyroidism interferes with myelination of the axons • Decreased thickness of myelin sheath surrounding those axons that are myelinated

15. Oligodendrocyte Accumulation • TH Actions on oligodendrocytes: • Initiation of oligodendrocyte maturation • In absence of TH, precursor O-2A cells proliferate indefinitely; in presence of TH, O-2A cells terminate cell division, mature • Enhance oligodendrocyte survival • Protection from apoptosis (shown in vitro) • Regulate myelin production in developing oligodendrocyte via MBP (myelin basic protein) • MBP levels are reduced in hypothyroid states

16. Oligodendrocyte Accumulation • Cortical areas of mammalian brain hemispheres are reciprocally connected via intrahemispheric commissures • Critical for information transfer in higher brain function • Arise embryonically in rat and develop post-natally • TH is required for normal commissure development

17. Oligodendrocyte Accumulation • MBP levels are reduced in hypothyroid animals compared to control • T3 treatment showed no effect on MBP mRNA levels From Schnoover et al 2004

18. Oligodendrocyte Accumulation • Anterior commisure (AC) is reduced in hypothyroid state • Reduction of cell number • Similar in Corpus collosum (CC) From Schnoover et al 2004

19. Phosphorylation of ERK in Hippocampus • Congenital hypothyroidism • Shown previously that ERK phosphorylation and LTP were decreased in the hippocampus of Tx adult rats • Hypothyroidal neonatal rats were analyzed for ERK phosphorylation in the hippocampus

20. Phosphorylation of ERK in Hippocampus • Hypothyroidism increased pERK1/2 • Hypothyroidism decreased p38/MAPK • Changes occurred in the absence of a change in the phosphorylation state of JNK From Calloni et al 2005

21. Phosphorylation of ERK in Hippocampus • Changes in phosphorylation of ERK and p38 in hypothyroidism may mediate changes in the hippocampus common to hypothyroidism such as: • synaptic transmission • migration of dentate granule cells • decreases in cell number • Reduction of dendritic arbors of dendrites and pyramidal cells

22. TH and Hairless • Hairless (hr) is a direct target of TH in the developing brain • Originally identified in mice with congenital hair loss • Analogous phenotype in humans • Hr mutant mice show altered neuronal morphology, inner ear defects, abnormal retinal cytoarchitecture • Hr (protein) interacts with unliganded TR to enhance transcriptional repression • Binds to TR via two independent domains and has multiple repression domains • Known to associate with histone deacetylases (HDACs), suggesting hr and TR form repression complex with HDAC

23. TH and Hairless • Hr is able to be co-immunoprecipitated by TR • Hr co-immunoprecipitates with HDACs • Hr expression is controlled by TRα From Potter et al 2002

24. TH and Hairless • In situ hybridization demonstrates hr and hdac expression overlaps in neonatal rat brain cerebellum forebrain

25. TH and Hairless • Expression of hr is regulated during development by TH • Expression occurs rapidly following treatment with TH

26. Why do we care? • PCBs in environment • Polychlorinated biphenyls bioaccumulate through the food chain and are found in high concentrations in samples of human tissues • Children exposed to PCBs in utero exhibit neuropsychological deficits such as a lower full-scale IQ, reduced visual recognition memory, attention deficits, and motor deficits • Developmental deficits overlap with those following developmental TH insufficiency

27. Activation of HES • Maternal thyroid status affects the expression of HES1 and HES5 (TH-responsive genes; bHLH regulated by Notch receptor) • Inhibits neurogenesis while favoring gliogenesis • Therefore, TH may have role in fate specification of cells in early cortex by enhancing HES activation • PCBs mimic affects of elevated T4 on HES1/5 • Possible that PCB exposure exerts effects on brain development by interfering with TH action • dysregulation of HES expression may be a mediating factor of PCB exposure From Bansal et al 2005

28. Activation of HES From Bansal et al 2005

29. ADHD and Hypothyroidism • Children born to mothers from iodine-deficient area have a higher incidence of ADHD • Syndrome previously reported to be associated with resistance to TH by receptor mutations • Study performed in Northeastern Sicily to identify long-term effects of maternal hypothyroxinemia • Two groups (one normal iodine intake (11#), one low iodine intake (16#)); age-matched mothers and their children • TSH levels remained normal in mothers, while all 11 identified ADHD children were born to mothers in iodine deficient area From Vermiglio et al 2004

30. Summary • TH is required for a number of neuropsychological abilities • Type of deficit dependent on timing of TH deficiency • General: • Prenatal TH loss • Visual processing • Motor and visuomotor abilities • Early Neonatal TH loss • visuospatial • Late Neonatal TH loss • Sensorimotor • Language • Late Late TH loss • Language • Fine motor skills • Auditory processing • Attention • Memory skills

31. What’s Next? • Though the morphological changes due to hypothyroidism in fetal brain development are well-described, underlying molecular mechanisms have yet to be fully understood • Potential sex differences in TH action in developing brain may provide insight into some of the mechanisms • Determine better ways to identify and treat fetal hypothyroidism