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Aspirin Induced Polydactyly in Rats Mediated by Inhibition of Prostaglandin Synthesis

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Culture Techniques
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Aspirin Induced Polydactyly in Rats Mediated by Inhibition of Prostaglandin Synthesis W. J. Scott* and K. L. Klein * Department of Pediatrics, University of Cincinnati, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA Some years ago we were intrigued by the observation that offspring of pregnant rats treated with anticancer drugs, such as cytosine arabino-side, frequently had preaxial Polydactyly of the hindlimbs (SCOTT et al., 1975). How could a drug which reduced cell proliferation and killed embryonic cells lead to a tissue excess deformity such as Polydactyly? Based on additional studies using the cancer chemotherapeutic drugs cy-tosine arabinoside, 5-fluorodeoxyuridine, cyclophosphamide, and 6-mer-captopurine (SCOTT et al., 1977, 1980), the following sequence of e-vents was hypothesized for the pathogenesis of preaxial Polydactyly of the hindlimbs. Initially, each of these drugs kills cells throughout the mesoderm of the hindlimb buds. This in turn leads to a delay in the normal episode of physiological cell death in the preaxial apical ectoder-mal ridge (AER). MILAIRE (personal communication) has suggested that the delayed involution of the preaxial AER is caused by an excess of apical ectodermal maintenance factor (AEMF) released from dying meso-dermal cells. The AER then is active well past its normal duration, which in turn may be responsible for the final event in the pathogenesis of preaxial Polydactyly, an absence of the normal episode of cell death in the preaxial mesoderm termed the foyer primaire preaxial ('fpp') by MI-LAIRE (1976). The 'fpp' is thought to be instrumental in controlling preaxial digit formation in mammals. We next wanted to examine the pathogenesis of Polydactyly by a drug which presumably did not kill embryonic cells. Aspirin was chosen be-cause KIMMEL et al. (1971) showed that high doses produce Polydactyly and there were no reports demonstrating a cytotoxic effect on embryonic cells. In a recent study (KLEIN et al., 1981 a), we confirmed the results of KIMMEL et al. and interestingly, observed that aspirin-induced Polydac-tyly was distinctly asymmetrical in that defects of the right hindlimb were 3-4 times more common than defects of the left. To our sur-prise, we also found that teratogenic doses of aspirin (625 mg/kg, 9:00 AM d. 11, p.o.) were also cytotoxic to mesodermal cells in the hindlimb bud and that this cytotoxicity exhibited a unique pattern in that only cells in the preaxial mesoderm were affected. We are aware of no other cytotoxic agent which acts on such a local population of cells. In addi-tion to preaxial mesodermal cell death, aspirin treatment also causes a delayed involution of the preaxial AER and absence of cell death in the 'fpp'. Figure 1 shows the unique pattern of preaxial mesodermal cell death, the absence of cell death in the postaxial mesoderm, the normal episode of cell death in the postaxial AER, and absence of cell death in the preaxial AER. Culture Techniques © 1981 Walter de Gruyter & Co., Berlin • New York
© 2019 Walter de Gruyter GmbH, Berlin/Munich/Boston

Aspirin Induced Polydactyly in Rats Mediated by Inhibition of Prostaglandin Synthesis W. J. Scott* and K. L. Klein * Department of Pediatrics, University of Cincinnati, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA Some years ago we were intrigued by the observation that offspring of pregnant rats treated with anticancer drugs, such as cytosine arabino-side, frequently had preaxial Polydactyly of the hindlimbs (SCOTT et al., 1975). How could a drug which reduced cell proliferation and killed embryonic cells lead to a tissue excess deformity such as Polydactyly? Based on additional studies using the cancer chemotherapeutic drugs cy-tosine arabinoside, 5-fluorodeoxyuridine, cyclophosphamide, and 6-mer-captopurine (SCOTT et al., 1977, 1980), the following sequence of e-vents was hypothesized for the pathogenesis of preaxial Polydactyly of the hindlimbs. Initially, each of these drugs kills cells throughout the mesoderm of the hindlimb buds. This in turn leads to a delay in the normal episode of physiological cell death in the preaxial apical ectoder-mal ridge (AER). MILAIRE (personal communication) has suggested that the delayed involution of the preaxial AER is caused by an excess of apical ectodermal maintenance factor (AEMF) released from dying meso-dermal cells. The AER then is active well past its normal duration, which in turn may be responsible for the final event in the pathogenesis of preaxial Polydactyly, an absence of the normal episode of cell death in the preaxial mesoderm termed the foyer primaire preaxial ('fpp') by MI-LAIRE (1976). The 'fpp' is thought to be instrumental in controlling preaxial digit formation in mammals. We next wanted to examine the pathogenesis of Polydactyly by a drug which presumably did not kill embryonic cells. Aspirin was chosen be-cause KIMMEL et al. (1971) showed that high doses produce Polydactyly and there were no reports demonstrating a cytotoxic effect on embryonic cells. In a recent study (KLEIN et al., 1981 a), we confirmed the results of KIMMEL et al. and interestingly, observed that aspirin-induced Polydac-tyly was distinctly asymmetrical in that defects of the right hindlimb were 3-4 times more common than defects of the left. To our sur-prise, we also found that teratogenic doses of aspirin (625 mg/kg, 9:00 AM d. 11, p.o.) were also cytotoxic to mesodermal cells in the hindlimb bud and that this cytotoxicity exhibited a unique pattern in that only cells in the preaxial mesoderm were affected. We are aware of no other cytotoxic agent which acts on such a local population of cells. In addi-tion to preaxial mesodermal cell death, aspirin treatment also causes a delayed involution of the preaxial AER and absence of cell death in the 'fpp'. Figure 1 shows the unique pattern of preaxial mesodermal cell death, the absence of cell death in the postaxial mesoderm, the normal episode of cell death in the postaxial AER, and absence of cell death in the preaxial AER. Culture Techniques © 1981 Walter de Gruyter & Co., Berlin • New York
© 2019 Walter de Gruyter GmbH, Berlin/Munich/Boston

Chapters in this book

  1. Frontmatter 1
  2. Dedication 5
  3. Preface 7
  4. Table of Contents 9
  5. Introduction 13
  6. I. Studies on Whole-Embryo Culture
  7. Differentiation of Embryonic Tissues in Whole-Embryo Cultures as Compared to the Development In Vivo 19
  8. The Differentiation Between Teratogenic Action on Mother, Fetal Membranes and Embryos Using the Whole-Embryo Culture Method 37
  9. Trypan Blue Teratogenesis in the Rat In Vitro 43
  10. Studies on Embryotoxic Effects of Thallium Using the Whole-Embryo Culture Technique 57
  11. Evaluation of Serum Teratogenic Activity Using Rat Embryo Cultures 67
  12. Regulation of Mouse Embryogenesis by Exogenous Growth Factors 83
  13. Preliminary Communication on the Feasibility of Culturing Whole Embryos in a Chemically Defined Medium 97
  14. In Vitro Development of the Heart Under Influence of Retinole Acid 101
  15. II. Studies on Organ Cultures
  16. A. Differentiation of the Skeleton (predominantly Extremities)
  17. Simulation of Limb Bud Skeletogenesis In Vitro 119
  18. Comparison of the Differentiation of Muscle and Connective Tissue of Mouse Limb Buds in Culture and In Vivo: A Morphological Study by Indirect Immunofluorescence 135
  19. Quantification of Collagen Types I and II in Mouse Limbs during Differentiation In Vitro and In Vivo 161
  20. Feasibility of Storing Embryonic Tissues for Subsequent Use in Organ Culture 171
  21. Limb Bud Organ Cultures from Mouse Embryos after Apparent Induction of Monooxygenases In Utero. Effects of Cyclophosphamide, Dimethylnitrosamine and Some Thalidomide Derivatives 175
  22. On the Significance of Ascorbate and of Cysteine on Differentiation of Limb Buds in Organ Culture 197
  23. Effects of Some "Indirectly" Alkylating Agents on Differentiation of Limb Buds in Organ Culture 207
  24. Comparison of Effects on Limb Development In Vivo and In Vitro Using Methyl(acetoxymethyl)nitrosamine 223
  25. Development of Limb Buds in Organ Culture: Examination of Hydroxyurea Enhancement of Bromodeoxyuridine Toxicity Using Image Analysis 237
  26. Biochemical Characterization of Mouse Hereditary Chondrodystrophies in Organ Culture 255
  27. Effect of Teratogens on Human Embryonic Skeletal Tissue In Vitro 269
  28. Aspirin Induced Polydactyly in Rats Mediated by Inhibition of Prostaglandin Synthesis 277
  29. B. Differentiation of other Organ Anlagen (kidneys, lungs, heart, prostate gland, haematopoetic system, and intestine)
  30. The Developing Kidney as a Model System for Normal and Impaired Organogenesis 291
  31. The Embryonic Lung as In Vitro Model for Testing Teratogenic Substances 301
  32. The Toxic Effects of Metal Dusts on Human Foetal Lungs In Vitro 319
  33. Effects of Substances Influencing Glycosaminoglycan Synthesis on Lung Development in Culture 331
  34. Effects of L-azetidine-2-carboxylic Acid and ß-D-xylosides on Lung Development In Vitro 341
  35. Interaction of Epithelium and Mesenchyme in the Induction of Foetal Rat and Mouse Prostate Glands by Androgens in Organ Culture 359
  36. In Vivo and In Vitro Assays of Trisomie Cells Isolated from the Fetal Organism or Rescued by Transfer to Non-Trisomic Hosts 371
  37. Effects of Gliadin-derived Peptides from Bread and Durum Wheat on Small Intestine Cultures from Rat Fetus and Coeliac Children 385
  38. III. Studies on Preimplantation Embryos
  39. Differential Adhesiveness as a Mechanism of Cell Allocation to Inner Cell.Mass and Trophectoderm in the Mouse Blastocyst 397
  40. Inefficient Capacity for Oxidative Phosphorylation of the Trophoblast as a Cause of Delayed Implantation in the Mouse 415
  41. Influence of Micromanipulation of Ova on the Postnatal Development of Mice (AKR) 423
  42. Investigations on the Mechanism of Action and on the Pharmacokinetics of Cyclophosphamide Treatment during the Preimplantation Period in the Mouse 435
  43. Benzo(a)pyrene Metabolism in Early Mouse Embryos 447
  44. IV. Studies on Cell and Tissue Cultures
  45. Influence of Different Antisera on Mouse Epiphyseal Chondrocytes in Monolayer Culture 457
  46. Cell Movement during Blastema Formation. Effect of Cytochalasin B on Cartilage Development In Vitro 465
  47. Cell-Substrate Adhesion of Fibroblast-like Cells Under Different In Vitro Conditions. A Scanning and Transmission Electron-Microscopic Study 477
  48. Development of Cytochrome P-450-Dependent Drug Metabolizing Enzyme Activities in Mouse and Human Tissues In Vitro 495
  49. In Vitro Treatment with Metallocene Dichlorides: Determination of the Intracellular Distribution of the Metal Atoms by Use of the Electron Energy Loss Spectroscopy 509
  50. Morphological Changes Induced by 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) in Epithelial Monolayer Culture Using Human and Rodent Fetal Tissues 519
  51. V. Studies on Non-mammalian Tissues
  52. The Chick Embryo: A Standard Against Which to Judge In Vitro Systems 529
  53. Experimental Manipulation Leading to Cardiac Malformation in Chick Embryo 539
  54. Morphogenese Systems and In Vitro Techniques in Teratology 553
  55. VI. Culture Techniques for "Screening" on Teratogenicity
  56. An Assessment of the Available In Vitro Techniques for Detecting Teratogens 561
  57. On the Predictability of Developmental Toxicity -especially Prenatal Toxicity - On the Basis of Culture Experiments 567
  58. VII. Some Methods Used for Culturing Embryonic Tissues
  59. A. Whole-Embryo-Culture: Beck; Anschiitz 587
  60. B. Limb Bud Method: Blankenburg 590
  61. C. Trowell Method: Zimmermann 594
  62. D. "Micro-Mass Culture": Zimmermann 595
  63. E. Preimplantation-Embryo Culture 598
  64. F. Teratogenicity Testing Method (Chick) 598
  65. G. CHEST I and II (Chick): Jelinek and Peterka 599
  66. Glossary 607
  67. List of Participants 608
  68. Index 612
  69. Backmatter 622
no recommendation found
https://doi.org/10.1515/9783110858242-023

Chapters in this book

  1. Frontmatter 1
  2. Dedication 5
  3. Preface 7
  4. Table of Contents 9
  5. Introduction 13
  6. I. Studies on Whole-Embryo Culture
  7. Differentiation of Embryonic Tissues in Whole-Embryo Cultures as Compared to the Development In Vivo 19
  8. The Differentiation Between Teratogenic Action on Mother, Fetal Membranes and Embryos Using the Whole-Embryo Culture Method 37
  9. Trypan Blue Teratogenesis in the Rat In Vitro 43
  10. Studies on Embryotoxic Effects of Thallium Using the Whole-Embryo Culture Technique 57
  11. Evaluation of Serum Teratogenic Activity Using Rat Embryo Cultures 67
  12. Regulation of Mouse Embryogenesis by Exogenous Growth Factors 83
  13. Preliminary Communication on the Feasibility of Culturing Whole Embryos in a Chemically Defined Medium 97
  14. In Vitro Development of the Heart Under Influence of Retinole Acid 101
  15. II. Studies on Organ Cultures
  16. A. Differentiation of the Skeleton (predominantly Extremities)
  17. Simulation of Limb Bud Skeletogenesis In Vitro 119
  18. Comparison of the Differentiation of Muscle and Connective Tissue of Mouse Limb Buds in Culture and In Vivo: A Morphological Study by Indirect Immunofluorescence 135
  19. Quantification of Collagen Types I and II in Mouse Limbs during Differentiation In Vitro and In Vivo 161
  20. Feasibility of Storing Embryonic Tissues for Subsequent Use in Organ Culture 171
  21. Limb Bud Organ Cultures from Mouse Embryos after Apparent Induction of Monooxygenases In Utero. Effects of Cyclophosphamide, Dimethylnitrosamine and Some Thalidomide Derivatives 175
  22. On the Significance of Ascorbate and of Cysteine on Differentiation of Limb Buds in Organ Culture 197
  23. Effects of Some "Indirectly" Alkylating Agents on Differentiation of Limb Buds in Organ Culture 207
  24. Comparison of Effects on Limb Development In Vivo and In Vitro Using Methyl(acetoxymethyl)nitrosamine 223
  25. Development of Limb Buds in Organ Culture: Examination of Hydroxyurea Enhancement of Bromodeoxyuridine Toxicity Using Image Analysis 237
  26. Biochemical Characterization of Mouse Hereditary Chondrodystrophies in Organ Culture 255
  27. Effect of Teratogens on Human Embryonic Skeletal Tissue In Vitro 269
  28. Aspirin Induced Polydactyly in Rats Mediated by Inhibition of Prostaglandin Synthesis 277
  29. B. Differentiation of other Organ Anlagen (kidneys, lungs, heart, prostate gland, haematopoetic system, and intestine)
  30. The Developing Kidney as a Model System for Normal and Impaired Organogenesis 291
  31. The Embryonic Lung as In Vitro Model for Testing Teratogenic Substances 301
  32. The Toxic Effects of Metal Dusts on Human Foetal Lungs In Vitro 319
  33. Effects of Substances Influencing Glycosaminoglycan Synthesis on Lung Development in Culture 331
  34. Effects of L-azetidine-2-carboxylic Acid and ß-D-xylosides on Lung Development In Vitro 341
  35. Interaction of Epithelium and Mesenchyme in the Induction of Foetal Rat and Mouse Prostate Glands by Androgens in Organ Culture 359
  36. In Vivo and In Vitro Assays of Trisomie Cells Isolated from the Fetal Organism or Rescued by Transfer to Non-Trisomic Hosts 371
  37. Effects of Gliadin-derived Peptides from Bread and Durum Wheat on Small Intestine Cultures from Rat Fetus and Coeliac Children 385
  38. III. Studies on Preimplantation Embryos
  39. Differential Adhesiveness as a Mechanism of Cell Allocation to Inner Cell.Mass and Trophectoderm in the Mouse Blastocyst 397
  40. Inefficient Capacity for Oxidative Phosphorylation of the Trophoblast as a Cause of Delayed Implantation in the Mouse 415
  41. Influence of Micromanipulation of Ova on the Postnatal Development of Mice (AKR) 423
  42. Investigations on the Mechanism of Action and on the Pharmacokinetics of Cyclophosphamide Treatment during the Preimplantation Period in the Mouse 435
  43. Benzo(a)pyrene Metabolism in Early Mouse Embryos 447
  44. IV. Studies on Cell and Tissue Cultures
  45. Influence of Different Antisera on Mouse Epiphyseal Chondrocytes in Monolayer Culture 457
  46. Cell Movement during Blastema Formation. Effect of Cytochalasin B on Cartilage Development In Vitro 465
  47. Cell-Substrate Adhesion of Fibroblast-like Cells Under Different In Vitro Conditions. A Scanning and Transmission Electron-Microscopic Study 477
  48. Development of Cytochrome P-450-Dependent Drug Metabolizing Enzyme Activities in Mouse and Human Tissues In Vitro 495
  49. In Vitro Treatment with Metallocene Dichlorides: Determination of the Intracellular Distribution of the Metal Atoms by Use of the Electron Energy Loss Spectroscopy 509
  50. Morphological Changes Induced by 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) in Epithelial Monolayer Culture Using Human and Rodent Fetal Tissues 519
  51. V. Studies on Non-mammalian Tissues
  52. The Chick Embryo: A Standard Against Which to Judge In Vitro Systems 529
  53. Experimental Manipulation Leading to Cardiac Malformation in Chick Embryo 539
  54. Morphogenese Systems and In Vitro Techniques in Teratology 553
  55. VI. Culture Techniques for "Screening" on Teratogenicity
  56. An Assessment of the Available In Vitro Techniques for Detecting Teratogens 561
  57. On the Predictability of Developmental Toxicity -especially Prenatal Toxicity - On the Basis of Culture Experiments 567
  58. VII. Some Methods Used for Culturing Embryonic Tissues
  59. A. Whole-Embryo-Culture: Beck; Anschiitz 587
  60. B. Limb Bud Method: Blankenburg 590
  61. C. Trowell Method: Zimmermann 594
  62. D. "Micro-Mass Culture": Zimmermann 595
  63. E. Preimplantation-Embryo Culture 598
  64. F. Teratogenicity Testing Method (Chick) 598
  65. G. CHEST I and II (Chick): Jelinek and Peterka 599
  66. Glossary 607
  67. List of Participants 608
  68. Index 612
  69. Backmatter 622
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