Hypothyroidism

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 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

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  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

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 deficits

Hypothyroidism and Development

From Zoeller and Rovet, 2004

Experimental Evidence Hypothyroid rat dams during pregnancy and the effects on their offspring



I. II. III. IV.

General effects Effects on oligodendrocytes Changes in phosphorylation of protein kinases Effects on HDACs, gene repression

Hypothyroidism  Female

rats made hypothyroid (Tx) prior to mating; offspring were cross-fostered to nonhypothyroid 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  Decreased

animals demonstrate:

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)

 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 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  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 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 coimmunoprecipitate d by TR  Hr coimmunoprecipitate s with HDACs • Hr expression is controlled by TRα

From Potter et al 2002

TH and Hairless  In cerebellum

forebrain

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 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

exposure

of HES expression may be a mediating factor of PCB

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 longterm 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  



Early Neonatal TH loss 



visuospatial

Late Neonatal TH loss  



Visual processing Motor and visuomotor abilities

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