Thyroid Hormones andDevelopment

Growth Vs. Maturation

Growth refers to increase in the size of atissue, organ or organism.

Maturation refers to emergence of acharacteristic through growth ordifferentiation.

V

X

XV

XX

XXI

XXII

XXIII

XVIII

Thyroxine - independent

Thyroxine - dependent•apoptosis of tail tissues

•mitosis, protein synthesis in limbs

•CNS neurogenesis, apoptosis

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

3. Enzyme deficiency

2. Pituitary defect

4. Thyroid autoimmunity

1. Dietary deficiency (iodine)

5. Exposure to 131I

Table 1 Different experimental model methods for the induction of congenital hypothyroidism.

Models Method Species ReferencesI Surgical Extirpation of thyroid

glandRatSheepRabbits

Tsujio et al. 2008 [13] Chen et al. 2007 [14] Zimmermann et al. 2009 [15]

II Radioactive Application of iodineRadioisotope 131I

RatMice

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- Propylthiouracil (PTU)- Methylimidazole (MMI)

RatMiceRabbits

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 Mice andRats

Amendola et al. 2005 [29] Johnson et al. 2007 [30] Mustapha et al. 2009 [31]

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 Disadvantages References

I Surgical Success in elimination of thyroid hormone in blood 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

Tsujio et al. 2008 [13] Chen et al. 2007 [14] Zimmermann et al. 2009 [15]

II Radioactive Damage of thyroid gland with small dose of radioactive iodine giving rise to congenital hypothyroidism in the descendants

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

Usenko et al. 1999 [16] Usenko et al. 1999 [18] Torlak et al. 2007 [17]

III Substance reduction The rats witness progressive reduction of iodine without undergoing special handling

It is an expensive diet that is not easy to get

MacLanahan et al. 2008 [20] Wijk et al. 2009 [21]

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

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 Provokes hypothyroidism through specific damage to the genes, thereby genetically manipulating the animals to obtain an organism expressing the deficiency to study

Transgenic animals are expensive and not easy to get

Amendola et al. 2005 [29] Johnson et al. 2007 [30] Mustapha et al. 2009 [31]

G. S. Argumedo1, C. R. Sanz1, H. J. Olguín2 (2012) Experimental Models of Developmental Hypothyroidism. Horm Metab Res ,44, 79-85.

tyrosine diiodothyroninetetraiodothyronine

(thyroxine, T4)

thyroid peroxidase

thyroid peroxidase

T4 T3de-iodination

by tissue

Thyroid Hormone SynthesisIodine sequestered in the thyroid glane by a Na-I pump, whose activitiy is controlled by TSH

Mechanisms of Hormone Actions

1. Nuclear (regulate gene transcription)

2. Ribosomal (regulate gene translation)

3. Regulate enzymatic activity

4. Alter membrane characteristics

protein synthesis

membrane receptors

Thyroid hormones appear to act directly via T3 receptors, but also indirectly by altering expression of genes for neurotrophinsor their receptors.

A. BDNF-labelled cells, TH-treated Insert from vDB.B. BDNF-labelled cells, control. Insert from vDBC. BDNF and Trk-B mRNA in P10 rats, MS/vDBD. BDNF labelled cells in P10 and adult (4-mo) rats treated with TH.

Legend:MS—Medial SeptumLS—Lateral SeptumDB—ventral Diagonal Band of Broca

Camboni, D., Roskoden, T. &Schwegler, H. (2003)

Effect of early thyroxinetreatment on brain-derivedneurotrophic factor mRNA expression and protein amount in the rat medial septum/diagonal band of Broca.

Neurosci. Lett., 350,141-144.

Tetra-iodothyronine (Thyroxine [T4])

De-iodinated by target tissue

Tri-iodothyronine (T3)

Cellular effectsGene 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

Stellate,Basket,Some granule

Basket

Stellate

External granulecell layer regenerates,abnormalparallelfibers

Some granule

Modified from: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

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 postnatalsecondary migration d. 15-30

microneurons: 4-15 days postnatalbasket cells: 4-7 days postnatalstellate cells: 8-15 days posnatal

Sensitive Period for Thyroid Hormones

birth to d. 10 to 12 in the ratfirst trimester through 6 mo. postnatally in humans

period of development normally associated with proliferationapopotosisrapid myelinationgrowth of neuronal processessynaptogenesisproliferation 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.

Timiras, P. (1988)Handbook ofHuman Growth and Development, Vol. 1., Part C, Pp. 59-82

A. ControlB. ControlC. HypothyroidD. HypothyroidE. Hypothyroid + thyroid therapyF. Hypothyroid + thyroid therapy

Cerebellum of hypothyroid rats

retarded, prolonged proliferation of granule cellsnormal number finally attained but is 25% below normal # on day 14shorter parallel fibers

thus, contacts with fewer Purkinje cellsgreater cell death during proliferationsecondary migration retarded

proliferation and growth of stellate and basket cells similarly retarded

retarded maturation of Purkinje cellsreduced numberreduced dendritic growth, fewer targets for parallel fibers

could be factor in greater death of granule cellsalong 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.

Rat SomatosensoryCortex

From Wise, Fleshman & Jones (1979) Neuroscience, 4, 1275-1297

Rat SomatosensoryCortex

From Wise, Fleshman & Jones (1979) Neuroscience, 4, 1275-1297

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 boardsmall, densely packed (fewer glia, less neuropildendrites shorter, fewer high-order branches(concentric ring analysis)

fewer dendritic spines# of potential synaptic contacts reduced by 85%

less spatial summation, neural integrationreliability of processing reducedrange of effective stimuli reduced

Neocortex of hypothyroid rats

axonsmyelination greatly reduced

slower conduction velocitywith 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 arrestedmuch like that of the athyroid tadpole

Gross Characteristics of a “Cretinoid” Rat

face foreshortened (brachycephaly)lethargichair is thinlearning & memory impairedbrain wt. reducedgrowth 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 intolerancedeafnessdelayed somatic maturation as indicated by

delayed eye, ear, vaginal openingdelayed endochondral ossification

Behavior of a “Cretinoid” Rat

fits of activity when stimulated, susceptible to seizuresstartle response, righting reflex, placing responses all retardedpersistence of mass-action wriggling to noxious stimulusdeficits 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.