Thyroid Hormones and Development. Growth Vs. Maturation Growth refers to increase in the size of a...
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Transcript of Thyroid Hormones and Development. Growth Vs. Maturation Growth refers to increase in the size of a...
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
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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.