Drug Toxicity in Embryonic Development II

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.