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Hypothyroidism

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Title: 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 TRa

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
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
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