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TERATOGENESIS in INBRED STRAINS OP MICE Major Professor V* Y *R^ ^Inor/Professox^. ^ Director of the Department of ^Jology Deanl

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TERATOGENESIS in INBRED STRAINS OP MICE Major Professor V* Y *R^ ^Inor/Professox^. ^ Director of the Department of ^Jology Deanl TERATOGENESIS IN INBRED STRAINS OP MICE Major Professor V* y *r^ ^inor/Professox^. ^ • \ Director of the Department of ^Jology Deanl of the Graduate School TERATOGENESIS IN INBRED STRAINS OP MICE THESIS Presented to the Graduate Council of the North Texas State University In Partial Fulfillment of the Requirements For the Degree of MASTER OF ARTS By Robert A. Morgan, E. A. Denton, Texas Augustt 1966 TABLE OP CONTENTS Pag® LIST OP TABLES lv Chapter I. INTRODUCTION 1 History of Teratogenesis Statement of Problem II, MATERIALS AND METHODS 12 Selection of Mouse Strains Preparation of Thalidomide Experimental Procedure III. RESULTS 21 IV. HIS CUSS IOM 31 APPENDIX A k2 APPENDIX B 50 BIBLIOGRAPHY 56 ill Lic-p OF *A*-LES Table Pace I. Results of Administering Throe Dosage Levels of Thalidomide to Pour Wouse Strains 22 II. Results of Administering Distilled Water to Four Strains of Mice 23 III. Comparison of Per Cent Resorptions Due to Administration of Thalidomide to Pour Strains of Mice. • ...... 2k IV. Scale for Rating Mice According to Extent of Deformity 26 V. Effect of Thalidomide Administration on Mean Deformity Score 27 VI. Mean Differences in Abnormality Scores in Pour Strains of wj.Ce 28 VII. Analysis of Vsrience in Mean Number of Mice Per Litter Due to Level of Thalidomide .... 2*> VIII. Analysis of Variance in Mean Deformity Score Per Group Due to Level of Thalidomide .... 29 IX. Analysis of Variance Due to Route of Thalidomide Injection 30 iv CHAPTER I INTRODUCTION History of Teratogenesis The first experimental production of congenital ab- normalities in manna la was accomplished by Altmann (1), who utilised x-irradiatlon of the pregnant mother. Since this work, which was performed in the first decade of this century, various methods have been employed to bring about deformations in the offspring of treated mothers. The fol- lowing ia a review of some of the more Important work, and la by no means exhaustive. Diets deficient in the various vitamins have been proved teratogenic in laboratory anlmala. The earliest study with a vitamin deficient diet was conducted by Hale (26), who fed a aow a regimen lacking In vitamin A, with the resultant birth of a litter of eyeless offspring. Vitamin A deficiency has since been found to be teratogenic in the rat (li|) and the rabbit (39). Vfarkany and Nelson (8l, 82, 83, 8I4.) obtained malformations in the progeny of female rats fed a fciboflavin- deficlent diet. Other workers (21, 3k$ 53) have subsequently corroborated these findings and expanded upon them somewhat. The rat has been a popular animal for use in teratogenic studies of vitamin deficiencies, as diets lacking in folic acid (6I4.), pantothenic acid (55)» vitamin E (65), thiamin (5U), X •nd frltttaln D (80), have all caused congenital malform- ations in the rat. Niacin antagonists have been shown to causa developmental anomalies in the chick embryo (141, U2) and In the mouse '62). While moat of the above studies Involve diets deficient in aorae particular vitamin, excesses of vitamin A can alao cause gross deformities In the rat (85) and mouse (51). Actadnistratlon of various other amenta to the present fe- msle laboratory animal has* resulted In deformed offspring. 6-mercaptopurlne, a nucleic acid antagonist'(73)» and an ato dye, trypan blue (77) ars teratogenic in the rat (7l|» 75# 76) and In the mouae (33* 67* 66), while cortisone has been found to eauae cleft palate in the mouse (11, 22, 26, 29, 30, 31# 32# 63) snd the rabbit (20). In recent yeara, certain drugs used by humans have been shown to be teratogenic in laboratory animals, a sulfon- amide, aulphamoprine, causes skull abnormalities in mice and rats (13)* Acetazolamide (k5)» Ancoloxan (6), and phsnobarbltal (50) each cause developmental anomalies in rats. Tetracyclines have been statiatioally implicated as teratogenic in humans (9, 78) «nd definitely ahown to cause limb and beak deformities in chick embryos (2, 10). Even acetylsalicyllc acid, taken in large quantltiea, is teratogenic in the mouse and the rat (57)* In 1962 Somera (70) administered thalidomide, a tran- quilizer, to pregnant white rabbits. There were deformed fetuaei in three of the four litters delivered. This tranquilizer had already been strongly suspected tc be the eauaal agant of a rsssh of limb deformities in humans (lj.9, 60). Following Soners1 work, other experimenters produced skeletal deformities In mice (17# 25, 56), monkeys (16, I4.fi), rats (11, 37. 58), rabbits (1^, 72, 87), and the chick (3, 5, 6, 15, 19, 36, 52, 66). Thalidomide has subsequently been found to produce abnormal growth in a marine red alga (72), but not in higher plants (59). Skeletal malformations due to ingestion of this tran- quilizer by the pregnant human have been reported in West Germany (U7, 61), England (38, W>, 69, 71), Scotland (22), Taiwan (88), Japan (28), Africa (86), and the Hetherlands (18). The drug was never placed on the American market; thus the United States had little direct contact with the trag«0y. nevertheless, the deformities due to thalidomide have had the effect of emphasizing the fact that congenital malformations do occur, and can be caused by seemingly harmleaa agents. With the above facts in mind, the Food and Drug Admin- istration has established 8 program so that all new drugs are now teated for effect on reproduction in the rat (35). Both male and female rats are fed a diet containing sub- toxic levels of the drug in question. These rats are mated, and the offspring assayed for abnormalities. This procedure haa three major shortcomings. The first is that the treated fiaele rats are permitted to give birth to a litter of younp:, tte Membera of whieh are then examined for abnormalitiee. thla method of teetinr completely neglects the fact that ptdmts oftm eat their dead or deformed offapring, thereby leavinn no evidence of malformed young. The second fault ia that, regardlass of the drug toeing tested, the pregnant rata in a uniform diet* Evidence of diet-teratogen inter- action plays • major rola In level of malformation (1*0, l|3, 79) makee thia procedure fall aooiatfhat abort of the ideal, the third fault la that the testing program, aa now estab- lished, neglecta the likelihood that genetica may be an important, if not the primary, factor in determining aua- ce»tibillty to varloua teratogenic agents {?). Statement of Problem In view of the fact that the program now being utilised to teat drugs for poeaible teratogenic effecta does not con- sider genetic variability among teator atocka, it ia impor- tant that a atudy te conducted to investigate the influence that genotype may have on auaceptibility to thalidomide teratogeneaia. The purpoae of this inveatigation ia to determine if differencea exist between four inbred atraina of *lee in auaceptibility to the drug thalidomide. CHAPTER BIELIO-RAFHY 1. Altmann, P., "nor.-enltsl Atresia of the Ear In Man and Animals," Annsla of Otcloay and Rhlnology, LXIV (1955)# P21P8557 2. Bevelander, Territ, H. Nakahara, and G. K. Holla, "Inhibition of Skeletal Formation in the Chick Em- bryo Following Administration of Tetracycline," Mature, CLKXXiv (1958), 728. 3. Boney, A. D.» "Abnormal Growth of Sporllngs of a Mar- ina Red Alga Induced by ThalidomideNature, CIIC (1963), 1068. It* Boone, M. A., Mary Hammond, and B. D. Earnett, "The Effect of Thalidomide on Chickens and Embryos," Poultry Science. XXXXIII (1%U), 1+73- 5* Boylen, Joseph, Helen Korne, and Vllllard Johnson, "Teratogenic Effects of Thalidomide and Related Substances," Lancet. II (1963), 552^557• 6. Cameron, J. M., "Thalidomide and Congenital Abnor- malities," Lancet, II (1962), 937. 7. Cargener, Norman, "Teratogeneala," Lancet. II (1963)* 6* Carter, M. P. and F. Wilson, "Ancoloxin and Foetal Abnormalities," British Medical Journal, VCCCIXXX (1962), 1609. 9. • , "Antibiotics and Con- genital Abnormalities,** Lancet. II (1963)» 1267. 10. , "Tetracycline and Con- enitai Abnormalities," British Medical Journal, fCCCI (1962), 729. 11. Christie, 0. A., "Thalidomide end Congenital Abnor- malities," Lancet, II (1962), 21»9. 12* Clark, Karin H., "Histological Investigation of Cor- tisone Induced Cleft Palate in Mice." Genetice, (1956), 79U-798. 13. Clegg, Hugh, "Teratc.enic Effects of Sulfonamides," British ypdlcal Journal, VCCCCXXVIII (1^65), IJ42. lit* Cohlan, Sidney Q., "ixcesslva Intake of Vitamin A as a Cause of Congenital Anomalies in the Rat," Science, CXVIII (1°S3), 15. De Bock, C. A. »nd .. Peters, "Effect of Thalidomide on Development ol t e Chick Embryo," Nature, CIC (1963)» 12014.-1206. 16. Delahunt, C. S. sni L. J. Lassen, "Thalidomide syn- drome In Monkeys," Science, CXXXXVI (1964), 1300-130$. 17. Di Paolo, Joseph, "Congenital Malformations in Strain A Mice," Journal of the American Medical Association, CLXXXIII U%M, TT9^TI?I~ 18. Dljkhuls, H. J., B. Bekker, and W. van Duyne, "Thalido- mide and Congenital Abnormalities," Lancet, I (1963), 1375. 19. Ehmann, B., "Teratogenic Effects o; Thalidomide," Lancet, I (1963),' 772. 20. Falnstat, Theodore, "Cortisone-Induced cleft Palate in Rabbits," Endocrinology, LV (1954)* 503. 21. Fenton, P. F. and G. R. Covgill, "The Nutrition of the Mouse." Journal of nutrition. XXXIV (191*7), 273-283. 22* Fox, Theodore, "Congenital Abnormalities Due to Thal- idomide," Lancet,' II (1962), 986. 23. Fraser, F. C., H. Kslter, B. E. Walker, and T. D. Falnstat, "The Experimental Production of Cleft Palate with Cor- tisone «md other Hormones," Journal of Cellular and Comparative Physiology, ajuuIIX (J, •~~mm 2k' Giroud, A., H. Tuchmann-Dupleias, and L. Merceir-Parot, •Thalidomide and Congenital Abnormalities," Lancet, II (1962), 296-299. 25* Hagen, Odette, "Dru^s and Congenital Abnormalities," Lancet, I (1963), 501. 26* Rale, Fred, "Pigs Born Without Eyeball*,* Journal of Heredity, XXIV (1933), 105-106. 27* Jacoba, Richard M., "Histochemical Study of Morpho- genesis and Teratofrenesis of the Palate in Mouse Embryos," Anatomical Record, CIL (1961*), 691-690.
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