Hypothyroidism

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Hypothyroidism

• Fetal Brain Development

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Thyroid Hormone Action
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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
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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
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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

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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

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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

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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

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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

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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

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Hypothyroidism and Development
From Zoeller and Rovet, 2004
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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

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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
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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

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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

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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

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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
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Oligodendrocyte Accumulation

• Anterior commisure (AC) is reduced in hypothyroid
  state
• Reduction of cell number
• Similar in Corpus collosum (CC)

From Schnoover et al 2004
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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

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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
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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

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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

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TH and Hairless

• Hr is able to be co-immunoprecipitated by TR
• Hr co-immunoprecipitates with HDACs
• Hr expression is controlled by TRa

From Potter et al 2002
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TH and Hairless

• In situ hybridization demonstrates hr and hdac
  expression overlaps in neonatal rat brain

cerebellum
forebrain
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TH and Hairless

• Expression of hr is regulated during development
  by TH
• Expression occurs rapidly following treatment
  with TH

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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

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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
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Activation of HES
From Bansal et al 2005
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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
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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

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Whats 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