Thyroid Hormones and
Development
Growth Vs. Maturation
Growth refers to increase in the size of a
tissue, organ or organism.
Maturation refers to emergence of a
characteristic through growth or
differentiation.
V
X
XV
Thyroxine - independent
XVIII
XX
XXI
Thyroxine - dependent
•apoptosis of tail tissues
XXII
•mitosis, protein synthesis in limbs
•CNS neurogenesis, apoptosis
XXIII
Shepherd, G.M. (1974) The Synaptic Organization of the Brain
From www.1911encyclopedia.org/C/CR/CRETINISM.htm
A description from 1855:
“ I see a head of unusual form and size, a squat and
bloated figure, a stupid look, bleared hollow and heavy
eyes, thick projecting eyelids, and a flat nose. His face is of
a leaden hue, his skin dirty, flabby, covered with tetters, and
his thick tongue hangs down over his moist livid lips. His
mouth, always open and full of saliva, shows teeth going to
decay. His chest is narrow, his back curved, his breath
asthmatic, his limbs short, misshapen, without power. The
knees are thick and inclined inward, the feet flat. The large
head drops listlessly on the breast; the abdomen is like a
bag.”
35 years old, China
15-20 years old,
Congo-Kinshasa
Causes of Hypothyroidism
1. Dietary deficiency (iodine)
2. Pituitary defect
3. Enzyme deficiency
4. Thyroid autoimmunity
5. Exposure to 131I
Table 1 Different experimental model methods for the induction of congenital hypothyroidism.
I
Models
Surgical
Method
Extirpation of thyroid
gland
Species
Rat
Sheep
Rabbits
References
Tsujio et al. 2008 [13]
Chen et al. 2007 [14]
Zimmermann et al. 2009 [15]
II
Radioactive
Application of iodine
Radioisotope 131I
Rat
Mice
Usenko et al. 1999 [16]
Usenko et al. 1999 [18]
Torlak et al. 2007 [17]
III
Substance reduction
Dietetic reduction of
iodine
Rat
MacLanahan et al. 2008 [20]
Wijk et al. 2009 [21]
IV
Administration of
substances
Application of
Rat
- Propylthiouracil (PTU) Mice
- Methylimidazole (MMI) Rabbits
Kawada et al. 1988 [23]
Gilbert et al. 2004 [24]
Isaia et al. 2008 [25]
Darbra et al. 2003 [47]
Hasebe et al. 2008 [26]
Bruce et al. 2004 [27]
Moriyama et al. 2007 [28]
V
Genetic
Genom manipulation
Amendola et al. 2005 [29]
Johnson et al. 2007 [30]
Mustapha et al. 2009 [31]
Mice and
Rats
G. S. Argumedo1, C. R. Sanz1, H. J. Olguín2 (2012) Experimental Models of Developmental
Hypothyroidism. Horm Metab Res ,44, 79-85.
Table 2 Congenital hypothyroidism models: advantages and disadvantages.
Model
Advantages
I
Surgical
Success in elimination of thyroid hormone in blood
Disadvantages
It is an invasive model. Difficult
to complete extirpation of the
gland to avoid induction
immune response due to
remnants, which produce
antibodies against the tissue
itself. Another disadvantage is
the removal of parathyroid
gland is related with calcium
metabolism together with
thyroids
Special permission is needed
for handling radioactive
isotopes and specific skill for
the same objective. The
consequence of removing
parathyroid and parafollicular
cells of the thyroid is also a
disadvantage
It is an expensive diet that is
not easy to get
References
Tsujio et al. 2008 [13]
Chen et al. 2007 [14]
Zimmermann et al. 2009 [15]
Kawada et al. 1988 [23]
Gilbert et al. 2004 [24]
Isaia et al. 2008 [25]
Darbra et al. 2003 [47]
Hasebe et al. 2008 [26]
Bruce et al. 2004 [27]
Moriyama et al. 2007 [28]
II
Radioactive
Damage of thyroid gland with small dose of radioactive iodine
giving rise to congenital hypothyroidism in the descendants
III
Substance reduction
The rats witness progressive reduction of iodine without
undergoing special handling
IV
Supply of substances Reproduces many characteristics of CH. The fetus is directly
affected no matter the condition of the thyroid of the mother; the
rats do not require additional handling. So, the cost does not
increase. Treatment is relatively simple to apply. Due to their
hydrophilic nature, they can mix up well in solution. Reduction
of congenital hypothyroidism with small amount of medicine in
the order of micrograms
In any methods used, doctors
can have errors in
administration and dosage,
and/or processing. Besides,
skin and tissue of mouth can
be permeable to substances
V
Genetic
Transgenic animals are
Amendola et al. 2005 [29]
expensive and not easy to get Johnson et al. 2007 [30]
Mustapha et al. 2009 [31]
Provokes hypothyroidism through specific damage to the
genes, thereby genetically manipulating the animals to obtain
an organism expressing the deficiency to study
Usenko et al. 1999 [16]
Usenko et al. 1999 [18]
Torlak et al. 2007 [17]
MacLanahan et al. 2008 [20]
Wijk et al. 2009 [21]
G. S. Argumedo1, C. R. Sanz1, H. J. Olguín2 (2012) Experimental Models of Developmental
Hypothyroidism. Horm Metab Res ,44, 79-85.
Thyroid Hormone Synthesis
Iodine sequestered in the thyroid glane by a Na-I pump,
whose activitiy is controlled by TSH
thyroid
peroxidase
tyrosine
T4
thyroid
peroxidase
diiodothyronine
de-iodination
by tissue
tetraiodothyronine
(thyroxine, T4)
T3
Mechanisms of Hormone Actions
1.
2.
3.
4.
Nuclear (regulate gene transcription)
protein synthesis
Ribosomal (regulate gene translation)
Regulate enzymatic activity
membrane receptors
Alter membrane characteristics
Thyroid hormones appear to act directly via T3 receptors, but
also indirectly by altering expression of genes for neurotrophins
or their receptors.
Legend:
MS—Medial Septum
LS—Lateral Septum
DB—ventral Diagonal
Band of Broca
Camboni, D., Roskoden, T. &
Schwegler, H. (2003)
Effect of early thyroxine
treatment on brain-derived
neurotrophic factor mRNA
expression and protein amount
in the rat medial septum/
diagonal band of Broca.
Neurosci. Lett., 350,
141-144.
A. BDNF-labelled cells, TH-treated Insert from vDB.
B. BDNF-labelled cells, control. Insert from vDB
C. BDNF and Trk-B mRNA in P10 rats, MS/vDB
D. BDNF labelled cells in P10 and adult (4-mo) rats treated with TH.
Tetra-iodothyronine (Thyroxine [T4])
De-iodinated by
target tissue
Tri-iodothyronine (T3)
Cellular effects
Gene transcription/translation
Cellular metabolism
Shepherd, G.M. (1974) The Synaptic Organization of the Brain
Altman, J. & Bayer, S.A. (1988)
Handbook of Human Growth and
Development, Vol. 1, Part A, Pp.1-26
Modified from:
Altman, J. & Bayer, S.A. (1988)
Handbook of Human Growth and
Development, Vol. 1, Part A, Pp.1-26
Stellate,
Basket,
Some granule
Basket
Stellate
External granule
cell layer regenerates,
abnormal
parallel
fibers
Some
granule
Altman, J. & Bayer, S.A. (1988)
Handbook of Human Growth and
Development, Vol. 1, Part A, Pp.1-26
Altman, J. & Bayer, S.A. (1988)
Handbook of Human Growth and
Development, Vol. 1, Part A, Pp.1-26
In rats, proliferation after birth accounts for
50% of forebrain cells (mostly glia)
80% of olfactory bulb
97% of cerebellum
granule cells : birth-15 days postnatal
secondary migration d. 15-30
microneurons: 4-15 days postnatal
basket cells: 4-7 days postnatal
stellate cells: 8-15 days posnatal
Sensitive Period for Thyroid Hormones
birth to d. 10 to 12 in the rat
first trimester through 6 mo. postnatally in humans
period of development normally associated with
proliferation
apopotosis
rapid myelination
growth of neuronal processes
synaptogenesis
proliferation in cerebellum
(prolonged by hypothyroidism)
Thyroid hormones can exert direct effects on gene
expression and protein synthesis, but also indirect
effects via receptor-activated second messenger
systems. Among the products affected during sensitive
period for thyroid hormones are neurotrophins and their
receptors
NGF, NT family, BDNF, Trk receptors, P75 receptor are
all modulated by TH during the sensitive period
Escobar, M. de, Ruiz-Marcos, A.
& Escobar del Rey, F. (1983)
Congenital Hypothyrodism,
pp. 85-126
Coulombe, P., Ruel, R. & Dussault, J.H. (1981) Union Med. Can., 110, 658-651.
Legrand, J. (1979) Trends in Neuroscience, 2, 234-236.
A.
B.
C.
D.
E.
Control
Control
Hypothyroid
Hypothyroid
Hypothyroid +
thyroid therapy
F. Hypothyroid +
thyroid therapy
Timiras, P. (1988)
Handbook ofHuman Growth and Development, Vol. 1., Part C, Pp. 59-82
Cerebellum of hypothyroid rats
retarded, prolonged proliferation of granule cells
normal number finally attained
but is 25% below normal # on day 14
shorter parallel fibers
thus, contacts with fewer Purkinje cells
greater cell death during proliferation
secondary migration retarded
proliferation and growth of stellate and basket cells similarly
retarded
retarded maturation of Purkinje cells
reduced number
reduced dendritic growth, fewer targets for parallel fibers
could be factor in greater death of granule cells
along with shorter parallel fibers (“ripple effects”)
Rat Somatosensory Cortex
From Wise, Fleshman & Jones (1979) Neuroscience, 4, 1275-1297
Aghajanian, G.K. & Bloom, F.E. (1967)
Brain Research, 6, 716-727.
From Wise, Fleshman & Jones (1979)
Neuroscience, 4, 1275-1297
Rat Somatosensory
Cortex
From Wise, Fleshman & Jones (1979) Neuroscience, 4, 1275-1297
Rat Somatosensory
Cortex
Escobar, M. de, Ruiz-Marcos, A. & Escobar del Rey, F. (1983)
Congenital Hypothyroidism, pp. 85-126
Neocortex of hypothyroid rats
pyramidal cells--largest in cortex--draw on board
small, densely packed (fewer glia, less neuropil
dendrites shorter, fewer high-order branches
(concentric ring analysis)
fewer dendritic spines
# of potential synaptic contacts reduced by 85%
less spatial summation, neural integration
reliability of processing reduced
range of effective stimuli reduced
Neocortex of hypothyroid rats
axons
myelination greatly reduced
slower conduction velocity
with low metabolic rate, accounts for sluggishness
note that these are same features that distinguish the
mature from the immature brain
thus, it is as though development is arrested
much like that of the athyroid tadpole
Gross Characteristics of
a “Cretinoid” Rat
face foreshortened (brachycephaly)
lethargic
hair is thin
learning & memory impaired
brain wt. reduced
growth retarded after 12 to 15 d. of age
(after several mo. in humans)
apparent by 18 mo, but by then too late
O2 consumption (metabolism) lowered, cold intolerance
deafness
delayed somatic maturation as indicated by
delayed eye, ear, vaginal opening
delayed endochondral ossification
Behavior of a “Cretinoid” Rat
fits of activity when stimulated, susceptible to seizures
startle response, righting reflex, placing responses all retarded
persistence of mass-action wriggling to noxious stimulus
deficits in both learning and memory
Human Behavioral Phenotype
The mental capacity varies within narrow limits; an intelligent
adult cretin may reach the intellectual development of a child
3-4 years of age, though more often the standard attained is
even below this. The child cretin learns neither to walk nor talk
at the usual time. Often it is unable even to sit without support.
Some years later a certain power of movement is acquired,
but the gait is waddling and clumsy. Speech is long delayed,
or in bad cases may be almost entirely lacking. The voice is
usually harsh and unpleasant. Of the senses smell and taste
are but slightly developed, more or less deafness is generally
present, and only the sight is fairly normal. In the adult the
genital organs remain undeveloped. If the cretin is untreated
he rarely has a long life, thirty years being an exceptional age.
Death results from some intercurrent disease.