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Hypothyroidism Fetal Brain Development Thyroid Hormone Action Thyroid Hormone Action Thyroid Hormone Action Hypothyroidism and Development Fetal and neonatal ... – PowerPoint PPT presentation

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Title: Hypothyroidism

  • Fetal Brain Development

Thyroid Hormone Action
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
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
Hypothyroidism and Development
  • Fetal and neonatal hypothyroidism has been
    correlated with neurological deficits
  • Severity of deficits are related to severity of
  • 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

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

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

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

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

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

Hypothyroidism and Development
From Zoeller and Rovet, 2004
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

  • 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
  • Gender difference on learning
  • Females more sensitive to TH insufficiency than
    males in terms of learning

From Friedhoff et al, 2000
Oligodendrocyte Accumulation
  • Hypothyroidal animals demonstrate
  • Decreased number of myelinated axons in
  • 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

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

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

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

From Schnoover et al 2004
Phosphorylation of ERK in Hippocampus
  • Congenital hypothyroidism
  • Shown previously that ERK phosphorylation and LTP
    were decreased in the hippocampus of Tx adult
  • Hypothyroidal neonatal rats were analyzed for ERK
    phosphorylation in the hippocampus

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
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

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
  • 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

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

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

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

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
  • 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
Activation of HES
From Bansal et al 2005
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
  • 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
  • TH is required for a number of neuropsychological
  • Type of deficit dependent on timing of TH
  • 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

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
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