ANIMAL MODEL OF HUMAN DISEASE
Cretinism
Animal Model: Neonatal roidism in the Rat
Hvpothv-
Contributed by: Wayne S. Schwark, DVM, PhD, Department of Physiology, Biochemistry, and Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Human D
Cretinism is characterized by a profound and permanent retardation in the development of the central nervous system (CNS) due to deficiency of thyroid hormone during fetal or early neonatal life. The condition occurs in sporadic and endemic forms, and the incidence of endemic cretinism has decreased markedly since the advent of iodine supplementation of the diet. However, in certain underdeveloped regions, cretinism-induced states of mental retardation may still occur in up to 5-% of the population.' A major problem in the management of cretinism, particularly the sporadic type, relates to the difficulty in establishing a diagnosis of neonatal hy-pothyroidism. Since there appears to be a critical period for the effect of thvroid hormone on the development of the CNS, delay in the initiation of replacement therapy with thvroid hormone results in a less favorable prognosis for normal mental development. 2 Ai*ml Mod
Although a variety of animal species may be used in the study of cretinism, several characteristics of the rat make it more desirable for studies of this nature. Rats have a short gestation period, and the litter size produced is relativelyr large. Importantlv, the pups are born with an immature CNS which is vulnerable to deficiencv of thyroid hormone. Several procedures mav be used to induce neonatal hypothyroidism in the rat. In general, surgical thyroidectomy is too difficult to perform routinelv in newrborn rat pups. Treatment of neonatal animals with 1311, shich is concentrated in the thvroid gland, leads to a discrete radiodestruction of thyroid tissue (Figure 1 ).34 Chronic administration of goitrogens (e.g., propvlthiouracil) starting at birth has also been employed.5' Using the latter two procedures, we have found that the morPublication sponsored b- the Registry of Comparatise Patholog- of the Armed Forces Institute of
Pathology and supported by Public Health Senrice Grant RR 00301 from the Division of Research Resources. US Department of Health. Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology. Inc Research supported in part by Grant NS111:37 from the National Institutes of Health.
473
474
American Journal of Pathology
SCHWARK
tality rate of rats with neonatal hypothyroidism is variable but may approach 50%. Reducing the litter size to a maximum of 8 animals favors survival of the thyroid-deficient animals.
A'k
'p~~~~~~~~ ,I%
,
~~~~~~~WdL
IL w V3 4F Ix Figure 1A-Cross section of neck in thyroid gland region of a 45-day-old rat which was treated with 200 uCi of 1311 at 1 day of age. Tracheal lumen is at upper left. The thyroid gland region is occupied mainly by connective tissue except for a few remnants of thyroid follicles (encircled area). The parathyroid gland (PT) appears to be unaffected. (H&E, x 120) B-Cross section of the neck in area of the thyroid gland of a 45-day-old control rat. Tracheal cartilage is at the upper right. Large numbers of intact thyroid follicles are present. (H&E, x 120) ,
Vol. 87, No. 2 May 1977
CRETINISM
475
Fgrem 2-Comparison of normal rat (upper) with a littermate which was treated with 200 MCi of 1311 at 1 day of age (lower). Both animals are 45 days old.
Neonatal hypothvroidism in the rat is manifested bv a variety of phvsical abnormalities (Figure 2). There is a marked impairment of grow..th and a delay in the appearance of maturational landmarks such as opening of the eve and elongation of the snout. The hair coat is sparse and dry and a bilaterallv svmmetrical alopecia is occasionally observ*ed. The animals appear listless and are relatively immobile. Some rats exhibit a highstepping gait, w%hile others may showv tremors of the head and limbs. The appearance of innately organized behavioral patterns such as the startle response to sound or the righting reflex is delaved.7 Widespread histopathologic abnormalities h ave been observ%ed in the CNS of rats subjected to neonatal hypothyroidism. These include reduced numbers and dilation of capillaries in the cerebral cortex, decreased size and increased density of cortical neurons, shorter and less frequently branched basal dendrites, and alterations in the patterns of svnaptogenesis in the cerebellar cortex.5'8' There is a retardation of mvelination in various regions of the brain."0 Cragg observed abnormal membranous bodies in the visual cortex of hypothyroid rats which were similar to those seen in Tav-Sachs disease in man.11 Compwarison With Human Diseas Certain features of neonatal
hypothyroidism in the rat, such as the marked stunting of body and brain growth and the dull, apathetic behavior are reminiscent of human cretinism. Rosman studied the brain of an
476
SCHWARK
American Journal of Pathology
18-month-old human cretin and found changes, including decreased brain size, sparse suibcortical white matter and neuronal changes in the cerebral cortex and cerebellum, which were not unlike those observed in rats made hypothyroid in early life.10 Davenport and Dorcey reported that early postnatal thyroid deficiency in rats caused permanent deficits in learning capacity which may be related to the deranged mental development in the human cretin.12 It is of interest that there seems to be a critical period for action of thyroid hormone on development of the CNS in the rat comparable to that observed in man, since thyroid hormone replacement therapy initiated in the early life of cretinous rats more readily corrects the induced abnormalities of the CNS than does treatment that is delayed until later in life.4'13 Usefulness of the Model
Experimental cretinism in the rat represents one of the few available animal models of a state of mental deficiency in man.'1 The model can be used to determine neurochemical abnormalities in order to elucidate the pathogenesis of the defective brain development in this condition.4'67"3 This information may suggest improved methods for the prevention and treatment of this and other types of mental retardation in man. References 1. Stanbthrv JB, Ermans AM, Hetzel BS, Pretell EA, Querido A: Endemic goitre and cretinism: Public health significance and prevention. WHO Chron 28:220-228, 1974 2. Smith DW, Blizzard RM, Wilkins L: The mental prognosis in hypothvroidism of infancy and childhood: A review of 128 cases. Pediatrics 19:1011-1022, 1957 .3. Goldberg RC, Chaikoff IL: A simplified procedure for thvroidectomy of the new-
born rat without concomitant parathyroidectomy. Endocrinology 45:64-70, 1949 Metabolic control mechanisms in mammalian svstems: Regulation of key glvcolytic enzymes in developing brain during experimental cretinism. J Neurochem 19:1171-1182, 1972 Nicholson JL, Altman J: The effects of early hypo- and hyperthyroidism on the development of the rat cerebellar cortex. II. Synaptogenesis in the molecular laver. Brain Res 44:25-36, 1972 Schwark WS, Keesev RR: Thyroid hormone control of serotonin in developing rat brain. Res Commun Chem Pathol Pharmacol 10:37-50, 1975 Schwark WS: Regulation of Carbohydrate Metabolism in the Central Nervous Svstem. PhD thesis, Ottawa University, 1970 Eavrs JT: The vascularity of the cerebral cortex in normal and cretinous rats. J Anat 88:164-173, 1954 Eavrs JT: The cerebral cortex of normal and hypothyroid rats. Acta Anat 25:160-183, 1955 Rosman NP: The neuropathology of congenital hypothyroidism, Adv Exp Med Biol 30:337-366, 1972 Cragg BG: Synapses and membranous bodies in experimental hvpothvroidism. Brain Res 18:297-307, 1970 Davenport JW, Dorcev TP: Hypothyroidism: Learning deficit induced in rats by earlv exposure to thiouracil. Horm Behav 3:97-112, 1972 Rastogi RB, Singhal RL: Thyroid hormone control of 5-hydroxytrvptamine metabolism in developing rat brain. J Pharmacol Exp Ther 191:72-81, 1974
4. Schwark WS, Singhal RL, Ling GM:
5. 6. 7. 8. 9.
10. 11. 12.
13.
Cretinism
Animal Model: Neonatal roidism in the Rat
Hvpothv-
Contributed by: Wayne S. Schwark, DVM, PhD, Department of Physiology, Biochemistry, and Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Human D
Cretinism is characterized by a profound and permanent retardation in the development of the central nervous system (CNS) due to deficiency of thyroid hormone during fetal or early neonatal life. The condition occurs in sporadic and endemic forms, and the incidence of endemic cretinism has decreased markedly since the advent of iodine supplementation of the diet. However, in certain underdeveloped regions, cretinism-induced states of mental retardation may still occur in up to 5-% of the population.' A major problem in the management of cretinism, particularly the sporadic type, relates to the difficulty in establishing a diagnosis of neonatal hy-pothyroidism. Since there appears to be a critical period for the effect of thvroid hormone on the development of the CNS, delay in the initiation of replacement therapy with thvroid hormone results in a less favorable prognosis for normal mental development. 2 Ai*ml Mod
Although a variety of animal species may be used in the study of cretinism, several characteristics of the rat make it more desirable for studies of this nature. Rats have a short gestation period, and the litter size produced is relativelyr large. Importantlv, the pups are born with an immature CNS which is vulnerable to deficiencv of thyroid hormone. Several procedures mav be used to induce neonatal hypothyroidism in the rat. In general, surgical thyroidectomy is too difficult to perform routinelv in newrborn rat pups. Treatment of neonatal animals with 1311, shich is concentrated in the thvroid gland, leads to a discrete radiodestruction of thyroid tissue (Figure 1 ).34 Chronic administration of goitrogens (e.g., propvlthiouracil) starting at birth has also been employed.5' Using the latter two procedures, we have found that the morPublication sponsored b- the Registry of Comparatise Patholog- of the Armed Forces Institute of
Pathology and supported by Public Health Senrice Grant RR 00301 from the Division of Research Resources. US Department of Health. Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology. Inc Research supported in part by Grant NS111:37 from the National Institutes of Health.
473
474
American Journal of Pathology
SCHWARK
tality rate of rats with neonatal hypothyroidism is variable but may approach 50%. Reducing the litter size to a maximum of 8 animals favors survival of the thyroid-deficient animals.
A'k
'p~~~~~~~~ ,I%
,
~~~~~~~WdL
IL w V3 4F Ix Figure 1A-Cross section of neck in thyroid gland region of a 45-day-old rat which was treated with 200 uCi of 1311 at 1 day of age. Tracheal lumen is at upper left. The thyroid gland region is occupied mainly by connective tissue except for a few remnants of thyroid follicles (encircled area). The parathyroid gland (PT) appears to be unaffected. (H&E, x 120) B-Cross section of the neck in area of the thyroid gland of a 45-day-old control rat. Tracheal cartilage is at the upper right. Large numbers of intact thyroid follicles are present. (H&E, x 120) ,
Vol. 87, No. 2 May 1977
CRETINISM
475
Fgrem 2-Comparison of normal rat (upper) with a littermate which was treated with 200 MCi of 1311 at 1 day of age (lower). Both animals are 45 days old.
Neonatal hypothvroidism in the rat is manifested bv a variety of phvsical abnormalities (Figure 2). There is a marked impairment of grow..th and a delay in the appearance of maturational landmarks such as opening of the eve and elongation of the snout. The hair coat is sparse and dry and a bilaterallv svmmetrical alopecia is occasionally observ*ed. The animals appear listless and are relatively immobile. Some rats exhibit a highstepping gait, w%hile others may showv tremors of the head and limbs. The appearance of innately organized behavioral patterns such as the startle response to sound or the righting reflex is delaved.7 Widespread histopathologic abnormalities h ave been observ%ed in the CNS of rats subjected to neonatal hypothyroidism. These include reduced numbers and dilation of capillaries in the cerebral cortex, decreased size and increased density of cortical neurons, shorter and less frequently branched basal dendrites, and alterations in the patterns of svnaptogenesis in the cerebellar cortex.5'8' There is a retardation of mvelination in various regions of the brain."0 Cragg observed abnormal membranous bodies in the visual cortex of hypothyroid rats which were similar to those seen in Tav-Sachs disease in man.11 Compwarison With Human Diseas Certain features of neonatal
hypothyroidism in the rat, such as the marked stunting of body and brain growth and the dull, apathetic behavior are reminiscent of human cretinism. Rosman studied the brain of an
476
SCHWARK
American Journal of Pathology
18-month-old human cretin and found changes, including decreased brain size, sparse suibcortical white matter and neuronal changes in the cerebral cortex and cerebellum, which were not unlike those observed in rats made hypothyroid in early life.10 Davenport and Dorcey reported that early postnatal thyroid deficiency in rats caused permanent deficits in learning capacity which may be related to the deranged mental development in the human cretin.12 It is of interest that there seems to be a critical period for action of thyroid hormone on development of the CNS in the rat comparable to that observed in man, since thyroid hormone replacement therapy initiated in the early life of cretinous rats more readily corrects the induced abnormalities of the CNS than does treatment that is delayed until later in life.4'13 Usefulness of the Model
Experimental cretinism in the rat represents one of the few available animal models of a state of mental deficiency in man.'1 The model can be used to determine neurochemical abnormalities in order to elucidate the pathogenesis of the defective brain development in this condition.4'67"3 This information may suggest improved methods for the prevention and treatment of this and other types of mental retardation in man. References 1. Stanbthrv JB, Ermans AM, Hetzel BS, Pretell EA, Querido A: Endemic goitre and cretinism: Public health significance and prevention. WHO Chron 28:220-228, 1974 2. Smith DW, Blizzard RM, Wilkins L: The mental prognosis in hypothvroidism of infancy and childhood: A review of 128 cases. Pediatrics 19:1011-1022, 1957 .3. Goldberg RC, Chaikoff IL: A simplified procedure for thvroidectomy of the new-
born rat without concomitant parathyroidectomy. Endocrinology 45:64-70, 1949 Metabolic control mechanisms in mammalian svstems: Regulation of key glvcolytic enzymes in developing brain during experimental cretinism. J Neurochem 19:1171-1182, 1972 Nicholson JL, Altman J: The effects of early hypo- and hyperthyroidism on the development of the rat cerebellar cortex. II. Synaptogenesis in the molecular laver. Brain Res 44:25-36, 1972 Schwark WS, Keesev RR: Thyroid hormone control of serotonin in developing rat brain. Res Commun Chem Pathol Pharmacol 10:37-50, 1975 Schwark WS: Regulation of Carbohydrate Metabolism in the Central Nervous Svstem. PhD thesis, Ottawa University, 1970 Eavrs JT: The vascularity of the cerebral cortex in normal and cretinous rats. J Anat 88:164-173, 1954 Eavrs JT: The cerebral cortex of normal and hypothyroid rats. Acta Anat 25:160-183, 1955 Rosman NP: The neuropathology of congenital hypothyroidism, Adv Exp Med Biol 30:337-366, 1972 Cragg BG: Synapses and membranous bodies in experimental hvpothvroidism. Brain Res 18:297-307, 1970 Davenport JW, Dorcev TP: Hypothyroidism: Learning deficit induced in rats by earlv exposure to thiouracil. Horm Behav 3:97-112, 1972 Rastogi RB, Singhal RL: Thyroid hormone control of 5-hydroxytrvptamine metabolism in developing rat brain. J Pharmacol Exp Ther 191:72-81, 1974
4. Schwark WS, Singhal RL, Ling GM:
5. 6. 7. 8. 9.
10. 11. 12.
13.
