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
 Fetaland neonatal hypothyroidism has been
correlated with neurological deficits
 Severityof 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
 Majorityof 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
hypothyroidism
 Maternal Hypothyroidism
 Nearly3% 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
 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
 Takesplace 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
 Hypothyroidism and
Development

From Zoeller and Rovet, 2004

 Experimental Evidence
 Hypothyroid rat dams during
pregnancy and the effects on
their offspring
I. General effects
II. Effects on oligodendrocytes
III. Changes in phosphorylation of
protein kinases
IV. Effects on HDACs, gene repression
 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
 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
 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)
 Regulatemyelin 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
commissures
• Critical for information transfer in
higher brain function
• Arise embryonically in rat and develop
post-natally
• 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 state
 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 rats
 Hypothyroidalneonatal 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 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
 TH and Hairless
 Hr is able to be co-
immunoprecipitate
d by TR
 Hr co-
immunoprecipitate
s with HDACs
• Hr expression is
controlled by TRα

From Potter et al 2002

 TH and Hairless
 Insitu
hybridization
cerebellum
demonstrates hr
and hdac
expression
forebrain overlaps in
neonatal rat brain
 TH and Hairless
 Expressionof 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)
 Inhibitsneurogenesis 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

 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 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

 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
 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