Drug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects: Mechanistics Understanding of Human Developm by Robert J. KavlockDrug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects: Mechanistics Understanding of Human Developm by Robert J. Kavlock

Drug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects…

byRobert J. Kavlock, George P. Daston

Paperback | September 27, 2011

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Having received the invitation from Springer-Verlag to produce a volume on drug-induced birth defects for the Handbook of Experimental Pharmacology, we asked ourselves what new approach could we offer that would capture the state of the science and bring a new synthesis of the information on this topic to the world's literature. We chose a three-pronged approach, centered around those particular drugs for which we have a relatively well established basis for understanding how they exert their unwanted effects on the human embryo. We then supplemented this information with a series of reviews of critical biological processes involved in the established normal developmental patterns, with emphasis on what happens to the embryo when the processes are perturbed by experimental means. Knowing that the search for mechanisms in teratology has often been inhibited by the lack of understanding of how normal development proceeds, we also included chapters describing the amazing new discoveries related to the molecular control of normal morphogenesis for several organ systems in the hope that experimental toxicologists and molecular biologists will begin to better appreciate each others questions and progress. Several times during the last two years of developing outlines, issuing invitations, reviewing chapters, and cajoling belated contributors, we have wondered whether we made the correct decision to undertake this effort.
Title:Drug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects…Format:PaperbackDimensions:486 pagesPublished:September 27, 2011Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

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ISBN - 10:3642644090

ISBN - 13:9783642644092

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Table of Contents

Section III: Pathogenesis and Mechanisms of Drug Toxicity in Development.- 21 Retinoids.- A. Introduction.- B. Vitamin A Deficiency in Development.- C. Retinoid Receptors.- D. Developmental Effects of Receptor Inactivation.- E. Retinoid-Induced Teratogenesis.- I. Hypervitaminosis A.- II. Retinoic Acid and Retinoic Acid Isomers.- 1. Laboratory Animals.- 2. Humans.- III. Synthetic Retinoids.- 1. Laboratory Animals.- 2. Humans.- F. Pathogenesis.- I. Receptor Involvement in Teratogenesis.- 1. Retinoic Acid Receptors Versus Retinoid X Receptors.- 2. Retinoic Acid Receptor Upregulation by Retinoids.- 3. Retinoic Acid Effects in Receptor Null Mutants.- II. Retinoic Acid-Regulated Molecules in Teratogenesis.- References.- 22 Peculiarities and Possible Mode of Actions of Thalidomide.- A. Introduction.- B. Historic Overview.- I. Chemical Structure of Thalidomide and Derivatives.- II. Pharmacokinetics and Metabolism of Thalidomide and Derivatives.- 1. Pharmacokinetics in Humans.- C. Specific Effects Induced by Thalidomide on Prenatal Development.- I. Recognition of the Teratogenic Potential.- 1. Experimental Testing in the Mid-1950s.- 2. Teratogenic Risk in Humans.- II. Types of Teratogenic Effects and Organotropy.- III. Frequency of Specific Malformations Observed in Some Areas of Germany.- IV. Phase Specificity of Teratogenic Effects.- V. Species Specificity of Teratogenic Effects.- 1. Rodents.- 2. Rabbits.- 3. Nonhuman Primates.- 4. Effects Reported from In Vitro Studies.- VI. Relationship Between Structure and Teratogenic Effect of Thalidomide-Type Substances.- 1. Teratogenicity of Enantiomers of Thalidomide or Derivatives.- D. Effects Other than Sedative/Hypnotic Ones Induced in Adults.- I. Anti-inflammatory and Immunosuppressive Effects.- 1. Clinical Effects Observed in Humans.- 2. Effects Demonstrated in Experimental Animals.- a) Anti-inflammatory Effects.- b.) Transplant Rejection.- c.) Graft Versus Host Disease.- d.) Other Immunological Reactions.- II. White Blood Cells of Primates.- 1. Number and Function of Leukocytes..- 2. Lymphocyte Proliferation.- 3. Blood Cell Surface Receptors.- 4. Correlation of Effects on White Blood Cells and Teratogenic Potency.- III. Neurotoxic Effects.- E. Possible Mechanisms of Action.- I. Tissue of Adult Organisms.- 1. Importance of Metabolic Activation.- 2. Fibroblast Growth Factor-Induced Angiogenesis in the Rabbit Cornea.- 3. Cytokine Formation In Vitro.- II. Teratogenic Action.- 1. Older Speculations.- a) Mutagenic Effects.- b) Interference with Formation and Effects of Tumor Necrosis Factor-? on Prenatal Development.- 2. Cell Adhesion in Nonembryonic Model Systems.- a) Significance of Metabolic Activation for Adhesion of thaliodomide of the inhibition of Tumor Cells on Coated Disks.- b) A Thalidomide Metabolite as the Active Agent.- 3. Primate Embryos.- a) Inductive Functions of the Mesonephros of Human Embryos.- b) Surface Receptors of the Embryo.- F. Possible Implications of Recent Findings for Prenatal Toxicology.- References.- 23 Anticonvulsant Drugs: Mechanisms and Pathogenesis of Teratogenicity.- A. Introduction.- B. Human Studies.- I. Fetal Antiepileptic Drug Syndromes: The Case for a Single Syndrome Designation.- II. Antiepileptic Drugs and Congenital Malformations.- III. Other Teratogenic End Points.- 1. Mental and Behavioral Deficits.- 2. Growth Retardation.- 3. Stillbirths and Neonatal and Infant Mortality.- C. Application of the General Principles of Teratogenesis to Antiepileptic Drugs.- I. Genetic Susceptibility.- II. Teratogenic Timing.- III. Mechanisms of Teratogenesis.- IV. Drug Access.- V. Drug Dosage.- D. Experimental Animal Studies.- I. Overview.- II. Valproic Acid.- III. Phenytoin.- IV. Phenobarbital/Primidone.- V. Carbamazepine.- E. Conclusion.- References.- 24 Cardiovascular Active Drugs.- A. Introduction.- B. Uterine Vessel Clamping.- C. Vasoactive Drugs.- I. Vasoconstrictors.- 1. Sympathomimetic Drugs.- 2. Vasopressin (Antidiuretic Hormone).- 3. Ergotamine.- 4. Cocaine.- 5. Nicotine.- II. Vasodilators.- 1. Calcium Channel Antagonists and Hydralazine.- III. Caffeine.- D. Cardioactive Drugs.- I. Antiarrhythmic Agents.- 1. Class III Antiarrhythmic Agents.- 2. Phenytoin.- II. ?-Adrenergic Antagonists.- E. Discussion.- References.- 25 Anticoagulants.- A. Introduction.- B. Use of Anticoagulants in Pregnancy.- C. Coumarin Derivatives.- I. Historical Overview.- II. Mode of Action.- 1. Vitamin K.- 2. Mechanism of Anticoagulation.- III. Warfarin Embryopathy.- 1. Initial Recognition.- 2. Phenotypic Manifestations.- 3. Critical Period of Exposure.- 4. Pathogenetic Mechanism Resulting in the Warfarin Embryopathy.- a) Pseudowarfarin Embryopathy.- ?) Vitamin K and Coagulation.- ?) Vitamin K-Dependent Coagulopathies.- ?) Association of Vitamin K-Dependent Coagulopathy and the Phenotype the of Warfarin Embryopathy.- ?) Vitamin K-Dependent Bone and Cartilage Proteins.- b) Proposed Mechanism.- 5. Relationship to Other Disorders Which Cause Radiographic Stippling 203.- a.) Processes Which May Share a Common Pathogenesis.- ?) Hydantoins.- ?) Alcohol.- ?) Maternal Malnutrition.- b)Binder Syndrome.- c)Other Syndromes with Stippling: Chondrodysplasia Punctata.- IV. Other Effects of Coumarin Derivative Exposure.- 1. Hemorrhage.- 2. Central Nervous System Effects.- a) Recognition and Phenotype.- b)Distinction from the Warfarin Embryopathy.- c)Patterns of Abnormality and Likely Pathogenetic Mechanism.- 3.Other Malformations.- V. Animal Models.- VI. Estimation of Risks.- D. Heparin.- I. Historical Overview.- II. Mode of Action.- III. Use and Effects in Pregnancy.- 1. Maternal Risks.- 2. Placental Barrier.- 3. Fetal Risks.- E. Recommendations for Anticoagulation in Pregnancy.- References.- 26 Antiviral Agents.- A. Introduction.- B. Reproductive Toxicity of Antiviral Agents.- I. Nucleoside Analogues.- 1. Acyclovir.- a) Pharmacology and Clinical Use.- b) Experimental Data.- ?) In Vitro Data.- ?) In Vivo Data.- ?) Human Data.- 2. Didanosine and Dideoxyadenosine.- a) Pharmacology and Clinical Use.- b)Experimental Data.- ?) In Vitro Data.- ?) In Vivo Data.- ?) Human Data.- 3. Ganciclovir.- a)Pharmacology and Clinical Use.- b)Experimental Data.- ?) In Vitro Data.- ?) In Vivo Data.- 4. Idoxuridine.- a)Pharmacology and Clinical Use.- b)Experimental Data.- 5. Ribavirin.- a) Pharmacology and Clinical Use.- b) Experimental Data.- ?) In Vitro Data.- ?) In Vivo Data.- ?) Human Data.- 6. Vidarabine.- a) Pharmacology and Clinical Use.- b)Experimental Data.- ?) In Vitro Data.- ?) In Vivo Data.- 7. Zalcitabine.- a) Pharmacology and Clinical Use.- b) Experimental Data.- ?) In Vitro Data.- ?) In Vivo Data.- ?) Human Data.- 8. Zidovudine.- a) Pharmacology and Clinical Use.- b) Experimental Data.- ?) In Vitro Data.- ?) In Vivo Data.- ?) Human Data.- 9. Comparative Studies of Several Nucleoside Analogues.- a) In Vitro Data.- b) In Vivo Data.- II. Other Virustatics (Non-nucleoside Analogues).- 1. Amantadine and Rimantadine.- a) Pharmacology and Clinical Use.- b) Experimental Data.- ?) In Vivo Data.- ?) Human Data.- 2. Foscarnet.- a) Pharmacology and Clinical Use.- b) Experimental Data.- ?) In Vivo Data.- c) Summary.- References.- 27 Angiotensin-Converting Enzyme Inhibitor Fetopathy.- A. Introduction.- B. Review of the Renin-Angiotensin System.- C Genetic Diversity and Receptor Types.- D. Clinical Uses of Angiotensin-Converting Enzyme Inhibitors.- E. Adverse Effects of Angiotensin-Converting Enzyme Inhibitors.- F. Animal Developmental Toxicity Studies.- I. Rabbit.- II. Rat.- III. Sheep.- IV. Need for a Better Animal Model.- G. Human Angiotensin-Converting Enzyme Inhibitor Fetopathy.- I. Renal Tubular Dysgenesis.- II. Hypocalvaria.- III. Intrauterine Growth Restriction.- IV. Patent Ductus Arteriosus.- V. Could It Be the Maternal Disease and Not the Drug?.- VI. Caution About Angiotensin Receptor Antagonists.- H. Summary.- I. Recommendations.- References.- 28 Anesthetics.- A. Introduction.- B. In Vitro Fertilization Procedures.- I. Human Studies.- II. Animal Studies.- C. Nonobstetrical Surgery During Pregnancy.- I. Human Studies.- II. Animal Studies.- 1. Anesthetic Agents.- a) Inhalational Anesthetics.- b) Combination of N20 and Other Agents.- c) Local Anesthetics.- d) Intravenous Anesthetics.- e) Opioids.- f) Muscle Relaxants.- g) Others.- 2. Abnormal Physiological Conditions.- 3. Mechanisms of N20-Induced Developmental Toxicity.- D. Fetal Therapy/Surgery.- I. Human Studies.- II. Animal Studies.- E. Delivery.- I. Human Studies.- II. Animal Studies.- F. Waste Inhalational Anesthetics in the Workplace.- I. Human Studies.- II. Animal Studies.- References.- 29 Alcohols: Ethanol and Methanol.- A. Introduction.- B. Human Toxicity.- I. Ethanol: Fetal Alcohol Syndrome.- II. Methanol: Adult Human Toxicity.- C. Pharmacokinetics and Metabolism.- I. Absorption and Distribution.- II. Metabolism.- 1. Oxidation to Acetaldehyde or Formaldehyde.- 2. Oxidation to Acetate or Formate.- 3. Conversion to C20 and H20.- a) Ethanol.- b) Methanol.- 4. Free Radicals.- D. Animal Models of Fetal Alcohol Syndrome.- I. Chronic Exposures.- II. Acute Exposures.- III. Pathogenesis of Ethanol-Induced Birth Defects.- 1. Craniofacial Malformations.- 2. Limb Malformations.- IV. Mechanisms Underlying Ethanol-Related Birth Defects.- 1. Determination of the Proximate Teratogen - Ethanol or Acetaldehyde?.- a) Whole Animal Studies with Acetaldehyde.- b) In Vitro Studies with Ethanol and Acetaldehyde.- 2. Maternal Nutrition and Transfer of Nutrients to the Conceptus.- a) Zinc.- b) Vitamin A.- c) Folate.- 3. Prostaglandins.- 4. Hypoxia.- 5. Free Radicals.- 6. Effects on Cell Membranes.- 7. Interrelationship of Putative Mechanisms.- E. Developmental Toxicity of Methanol in Experimental Animals.- I. Effects of Exposure During Pregnancy.- 1. Rats.- 2. Mice.- II. Pathogenesis of Methanol-Induced Birth Defects.- 1. Whole Animal Studies.- 2. In Vitro Studies.- III. Mechanisms Underlying Methanol-Induced Birth Defects.- 1. Determination of Proximate Teratogen - Methanol or Formate?.- 2. Role for Formaldehyde?.- 3. Folate Deficiency 201 A Susceptibility Factor in Methanol Developmental Toxicity?.- Conclusions.- References.- 30 Developmental Toxicity of Dioxin: Searching for the Cellular and Molecular Basis of Morphological Responses.- A. Introduction.- I. Overview.- II. Dioxin in the Environment.- III. General Biological Effects.- B. Pathogenesis and Mechanisms of Developmental Toxicity.- I. Overview.- II. The Dioxin Receptor.- III. Cleft Palate.- IV. Synergistic Interactions with Dioxin.- 1. Hydrocortisone.- 2. Retinoic Acid.- C. Hydronephrosis, Reproductive Toxicity, and Immunosuppression.- I. Hydronephrosis.- II. Developmental Reproductive Toxicity.- III. Immunotoxicity.- D:Nonhuman Primate and Human Developmental Toxicity.- E. Future Directions.- References.- 31 Endocrine Disruptors: Effects on Sex Steroid Hormone Receptors and Sex Development.- A. Introduction.- B. Sex Differentiation and Chemical Effects.- C.Steroid Hormone Receptor Structure and Function.- D. Mechanisms of Antihormone Action.- E. Androgen Receptor.- I. Introduction.- II. Androgen Receptor: Mechanism and Effects of Select Chemicals.- 1. Drugs.- 2. Androgens.- 3. Estrogens.- 4. Progestins.- 5. Vinclozolin.- 6. Dichlorodiphenyl-trichloroethane Metabolites.- 7. Plant Products.- F. Estrogen Receptor.- I. Introduction.- II. Estrogen Receptor: Mechanism and Effects of Select Chemicals.- 1. Drugs.- 2. Diethylstibestrol.- 3. Plant Estrogens.- 4. Zearalenone (A Fungal Estrogen).- 5. Estrogenic Pesticides.- 6. Estrogenic Polychlorinated Biphenyls and Phenols.- G. Progesterone Receptor.- I. Introduction.- II. Progesterone Receptor: Mechanism and Effects of Select Chemicals.- 1. RU486 (Mifepristone).- 2. Androgens.- 3. Estrogens.- 4. Progestins.- H. Hormone Disruption-Testing Strategies.- I. Conclusions.- References.