Drug Toxicity in Embryonic Development I

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 the 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.

1 Introduction.- Section I: Recent Advances in Understanding Normal Development at the Biochemical and Molecular Level.- 2 Cardiac Morphogenesis: Formation and Septation of the Primary Heart Tube.- A. Introduction.- B. Establishing Heart-Forming Primordia.- I. Commitment to the Heart Lineage.- II. Formation of the Heart-Forming Fields.- III. Segregation of Lineage Within the Heart Fields.- IV. Molecular Regulation of the Cardiomyogenic Lineage.- V. Regulation of the Endocardial Lineage.- VI. Fate of the Heart Fields.- C. Morphogenesis of the Primary Heart Tube.- I. Elongation and Segmentation of the Tubular Heart.- II. Morphology of the Primitive Segments.- III. Developmental Fate of the Primitive Segments.- 1. Atrium.- 2. Ventricles.- 3. Atrioventricular Canal and Conotruncus.- D. Septation and Remodeling of the Tubular Heart into Four Chambers.- I. Looping.- II. Integration of Septal Primordia into Adult Partitions.- E. Conclusion.- References.- 3 Vertebrate Limb Development.- A. Introduction.- B. Developmental Anatomy of the Limb.- C. Pattern Regulation.- I. The Apical Ectodermal Ridge and Fibroblast Growth Factors.- II. The Zone of Polarizing Activity and the Supernumerary Response.- III. Sonic Hedgehog and Zone of Polarizing Activity Signaling.- IV. Regulation of Zone of Polarizing Activity Signaling/Sonic Hedgehog Expression.- V. Retinoic Acid and the Zone of Polarizing Activity Signal.- D. Homeobox-Containing Genes and Positional Information.- E. Digit Morphogenesis.- F. Conclusions.- References.- 4 Axial Skeleton.- A. Introduction.- B. Morphogenesis.- I. Formation of the Primitive Streak and the Notochord.- II. Segmentation of the Paraxial Mesoderm into Somites.- III. Differentiation of Somites into Dermomyotome and Sclerotome.- IV. From Sclerotomes to Mesenchymal Prevertebrae.- V. Chondrification of Prevertebrae.- VI. Ossification of Prevertebrae.- C. Genes Involved in Axial Skeleton Formation.- I. Gastrulation and Formation of Paraxial Mesoderm.- 1. Growth Factors, Signaling Molecules, and Their Receptors.- 2. Transcription Factors.- II. Segmentation of the Paraxial Mesoderm into Somites.- 1. Intercellular Signaling.- 2. Cell Adhesion.- 3. Extracellular Matrix Components.- 4. Transcription Factors.- III. Patterning of Somites.- 1. Craniocaudal Patterning: Cranial and Caudal Somite Halves.- 2. Dorsoventral Patterning.- a) Signaling Molecule Sonic Hedgehog.- b) Interpretation of the Inductive Sonic Hedgehog Signal: Transcription Factors of the Pax Gene Family.- c) Connection Between the Inductive Sonic Hedgehog Signal and the Nuclear Response Mediated by Pax Genes: Signal Transduction Via Cyclic Adenosine Monophosphate-Dependent Protein Kinases.- IV. Further Development of the Somite Compartments.- V. Regionalization Along the Craniocaudal Axis and Hox Genes.- VI. Local Control of Bone Shape During Embryogenesis and Growth.- 1. Bone Morphogenetic Proteins.- 2. Fibroblast Growth Factors and Their Receptors.- 3. Parathyroid Hormone-Related Peptide.- VII. Collagens and the Extracellular Matrix.- VIII. Regulation of Bone Maintenance and Bone Remodeling: Osteopetrosis and Osteoporosis.- IX. Influence of Teratogens on Axial Skeleton Development.- References.- 5 Molecular Mechanisms Regulating the Early Development of the Vertebrate Nervous System.- A. Early Development of the Nervous System.- B. Neurogenesis: The Role of the Helix-Loop-Helix Proneural Genes.- C. Establishing Identities Along the Anterior-Posterior Axis.- D. Segmentation and Patterning of the Hindbrain.- E. Generation of the Midbrain-Hindbrain Junction: The Role of Wnt1, En1 and Pax2.- F. Dorsoventral Patterning: The Opposing Roles of Sonic Hedgehog and BMPs.- References.- 6 Genetic Control of Kidney Morphogenesis.- A. Kidney Development as a Paradigm for Organogenesis.- B. Experimental Approaches for Studying Kidney Morphogenesis.- I. Transfilter Recombination System.- II. Genetic Analysis of Nephrogenesis Using Knockout, Transgenic, and Spontaneous Mouse Mutations.- III. Cell Culture Systems.- C. Early Morphogenetic Events.- I. Pronephros, Mesonephros, and Metanephros.- II. Commitment to Nephrogenic Fate.- III. Nephric Duct and Ureteric Bud Outgrowth.- IV. Pole of Hox Genes.- D. Ureteric Bud and Metanephric Induction.- I. Transmission of the Inductive Signal from Ureteric Bud to Metanephric Mesenchyme.- II. Propagation of the Inductive Signal Within the Mesenchyme.- III. Epithelial-Mesenchymal Transformation.- IV. Pole of Pax-2.- V. Establishment of Epithelial Polarity.- VI. Tubule Formation.- E. Glomerular Development.- I. Glomerular Epithelium.- II. Mesangial Cells and Angiogenesis.- III. Glomerular Basement Membrane.- F. Human Urogenital Anomalies and Malformation Syndromes.- I. Renal Agenesis and Dysplasias.- II. Renal Cystic Disease.- III. Role of Environmental Factors.- G. Conclusions.- References.- 7 Palate.- A. Why Study the Palate?.- B. Morphogenesis of the Palate.- C. Reorientation of the Palate.- I. Extracellular Matrix and Mesenchyme.- II. Epithelium.- D. Fusion of the Palate.- E. Mesenchymal-Epithelial Interactions.- F. Neurotransmitters.- I. Serotonin.- II. Catecholamines.- III. ?-Aminobutyric Acid and Diazepam.- G. Growth Factors.- I. Glucocorticoids.- II. Transforming Growth Factor-?, Epidermal Growth Factor, and Epidermal Growth Factor Receptor.- III. Transforming Growth Factor-?1 , -?2, and -?3, and Their Receptors.- IV. Insulin-Like Growth Factors I and II.- V. Acidic and Basic Fibroblast Growth Factor.- VI. Interactions.- H. Homeobox Genes.- I. Patterns of Expression.- II. Homeobox Mutations and Cleft Palate.- III. Signaling Relationships.- I. Association of Cleft Palate in Humans with Candidate Genes.- References.- Section II: Common Biochemical, Metabolic, and Physiological Mechanisms of Abnormal Development.- 8 Cell Death.- A. Introduction.- B. Embryonic Cell Death.- I. Orthotopic Pattern.- II. Homotopic Patterns.- III. Heterotopic Patterns.- C. Mechanisms of Cell Death.- I. Necrosis.- II. Apoptosis.- 1. Chromatin Degradation.- 2. Protease Involvement.- D. Implications for Drug Toxicity.- I. Three Planes of Damage.- II. Signal Transduction.- III. Metabolic Imbalance.- E. Death Circuits.- I. B Cell Lymphoma/Leukemia-2.- II. Tumor Suppressor Gene p53.- References.- 9 Cellular Responses to Stress.- A. Introduction.- B. Cellular Responses to Stress.- I. Genotoxic Stress Response.- 1. Introduction.- 2. Prokaryotes.- 3. Eukaryotes.- a) Yeast.- b) Mammals.- ?) DNA Damage-Inducible Genes.- ?) DNA Repair Genes.- ?) Cell-Signaling Genes.- ?) Other DNA Damage-Inducible Genes.- ?) Regulation of the Genotoxic Response.- ?) Mammalian Embryonic DNA Damage-Inducible Genes.- II. Oxidative Stress Response.- 1. Introduction.- 2. Prokaryotes.- a) The oxyR Regulon Gene.- b) The SoxRS Regulon Gene.- 3. Eukaryotes.- a) Stress-Inducible Genes.- b) Heme Oxygenase.- c) Aromatic Hydrocarbon-Responsive Gene Battery.- d) Embryonic Oxidative Stress-Inducible Genes.- III. Heat Shock Response.- 1. Introduction.- 2. Heat Shock Proteins.- 3. Heat Shock Proteins as Chaperones.- 4. Heat Shock Proteins and Thermotolerance.- 5. Heat Shock Proteins and Mammalian Development.- C. Summary and Future Directions.- References.- 10 Cell-Cell Interactions.- A. Introduction.- B. Cell-Cell Recognition and Cell Adhesion.- I. Cell-Cell Recognition and/or Adhesion Molecules.- C. How Could Normal Functioning Be Disrupted (Teratogenesis)?.- D. In Vitro and In Situ Analyses.- I. Ligand-Receptor Interaction Blockade.- II. Availability (Expression and Functional Regulation).- III. Downstream Signaling Cascade.- E. Conclusions.- References.- 11 Growth Factor Disturbance.- A. Introduction.- B. Technological Approaches.- C. Perturbation Studies on Growth Factor Families.- I. Transforming Growth Factor-?.- II. Fibroblast Growth Factors.- III. Platelet-Derived Growth Factors.- IV. Transforming Growth Factor-?.- V. Insulin-Like Growth Factors.- 1. Human Disorders Associated with Insulin-Like Growth Factor II Gene Dysfunction.- D. Conclusions.- References.- 12 Targeted Gene Disruptions as Models of Abnormal Development.- A. Introduction.- B. Insertional Mutants.- C. Knockout Mice.- D. Antisense.- E. Gene-Teratogen Interactions.- References.- 13 Nucleotide Pool Imbalance.- A. Introduction.- B. Determination of Nucleotide Pools.- C. Interruption of Pyrimidine Nucleotide Pools.- I. Fluoropyrimidines.- II. Other Halogenated Pyrimidines.- III. Cytosine Arabinoside.- IV. Azauridine.- D. Interruption of Purine Nucleotide Pools.- I. 6-Mercaptopurine and 6-Thioguanine.- II. Deoxycoformycin and Chlorodeoxyadenosine.- III. Hydroxyurea.- IV. Methotrexate.- E. Conclusion.- References.- 14 Interference with Embryonic Intermediary Metabolism.- A. Introduction.- B. Normal Glucose Metabolism.- C. Preimplantation Pattern of Glucose Metabolism.- D. Glucose Metabolism During the Post-implantation Stage.- I. The Krebs Cycle and the Pentose Phosphate Pathway.- 1. The Pentose Phosphate Pathway.- 2. The Krebs Cycle.- II. Anabolic Uses.- E. Perturbation of Glucose Metabolism.- I. Hypoglycemia.- II. Hyperglycemia.- III. Other Substrates.- IV. Glycolytic Inhibitors.- V. Pentose Phosphate Pathway Inhibitors.- VI. Krebs Cycle Inhibitors.- VII. Oxidative Phosphorylation Inhibitors.- F. Future Research.- References.- 15 Alterations in Folate Metabolism as a Possible Mechanism of Embryotoxicity.- A. Introduction.- I. Dietary Sources.- II. Recommended Dietary Allowances.- III. Assay Methods.- IV. Characteristics of Folate Deficiency.- B. Biochemical Pathways Involving Folates.- I. One-Carbon Metabolism.- II. Involvement in Methionine Metabolism.- C. Embryotoxicity of Folate Deficiency.- I. Human Studies.- II. Serum Folate Levels Associated with Embryotoxicity.- III. Animal Studies.- IV. Role of Other Compounds in Embryotoxicity.- D. Compounds Which Adversely Affect Folate Levels.- I. Triamterene.- II. Trimethoprim.- III. Sulfasalazine.- IV. 2-Methoxyethanol.- E. Developmental Toxicants Which May Act Via Folate Perturbations.- I. Aminopterin and Methotrexate.- II. Phenytoin.- III. Valproic Acid.- IV. Alcohol.- V. Pyrimethamine.- F. Conclusions.- References.- 16 Prostaglandin Metabolism.- A. Introduction.- B. Signal Transduction.- C. Arachidonic Acid Cascade.- D. Individual Teratogens.- I. Glucocorticoid- and Diphenylhydantoin-Induced Embryopathy.- II. Diabetic Embryopathy.- III. Cyclosporin A.- E. Conclusion.- References.- 17 Reactive Intermediates.- A. Introduction.- B. Elimination.- C. Bioactivation.- I. Cytochromes P450.- 1. Embryological Considerations.- 2. Mixed-Function Monooxygenase Activity.- 3. Peroxygenase Activity.- 4. Free Radical Production.- II. Peroxidases.- 1. Prostaglandin H Synthase and Other Peroxidases.- 2. Mechanisms of Bioactivation.- a) Peroxidase-Mediated Bioactivation.- b) Peroxyl Radical-Mediated Bioactivation.- c) Co-substrate-Derived Oxidant.- D. Reactive Intermediates.- I. Electrophiles.- II. Free Radicals.- E. Detoxification.- I. Glutathione.- II. Glutathione S-transferase.- III. Epoxide Hydrolase.- F. Oxidative Stress.- I. Embryological Considerations.- II. Measurements of Oxidative Stress.- 1. Salicylate Hydroxylation.- 2. Electron Paramagnetic (Spin) Resonance Spectrometry.- 3. Fluorescence Detection of Free Radicals and Oxidative Damage.- 4. Oxidative Damage.- 5. Protein/Gene Expression.- G. Cytoprotection.- I. Glutathione.- II. Antioxidants.- III. Glutathione Peroxidase.- IV. Glutathione Reductase.- V. Glucose-6-phosphate Dehydrogenase.- VI. Superoxide Dismutase and Catalase.- H. Molecular Target Damage.- I. Covalent Binding.- 1. DNA.- a) Electrophilic Reactive Intermediates.- b) Reaction of Free Radicals with DNA and Its Nucleotides.- c) Detection of DNA Adducts.- ?) Exhaustive Washing.- ?) 32P-Postlabelling.- 2. Protein and Lipids.- a) Binding of Electrophiles to Proteins.- b) Binding of Free Radicals to Proteins.- c) Detection of Protein Adducts.- ?) Radiolabelled Substrate.- ?) Antibodies.- II. Oxidation.- 1. DNA.- 2. Lipids.- 3. Protein.- I. Repair.- I. Protein.- II. DNA.- References.- 18 Hypoxia and Altered Redox Status in Embryotoxicity.- A. Introduction.- B. Hypoxia.- I. Hypoxia as a Cause of Birth Defects.- II. Vascular Clamping — Experimentation.- III. Edema Syndrome.- IV. Chemicals and Response in Hypoxia.- 1. Smoking and Nicotine.- 2. Cocaine.- 3. Niridazole and Related Nitroheterocyclic Agents.- 4. Phenytoin, Vasodilators, and Vasoconstrictors.- C. Hypoxia and Redox Status.- I. Glutathione and Related Low-Molecular-Weight Thiols.- II. Pyridine Nucleotide Status.- III. Control of pH and Hypoxia.- References.- 19 Altered Embryonic pH.- A. Introduction.- B. Historical Perspective of Agents Hypothesized to Act by Altering Embryonic Intracellular pH.- I. Acetazolamide and CO2.- II. Anticonvulsants.- 1. Valproic Acid.- 2. Trimethadione.- III. Cadmium.- IV. Ethanol.- V. Hyperthermia.- C. pH of Embryo Tissues and Fluids.- D. Pharmacokinetics.- E. Cellular Regulation of Intracellular pH.- I. Na+/H+ Exchange.- II. Cl-/HCO3- Exchange.- III. Na+ Channels.- IV. H+ Channels.- F. Potentiation of Teratogenesis by Inhibitors of Intracellular pH Recovery.- G. Cellular Activities Associated with pH.- H. Conclusion.- References.- 20 Maternal Physiological Disruption.- A. Introduction.- B. Specific Maternal Physiological Disruptions.- I. Acid-Base Imbalance.- II. Osmotic Disruption.- III. Maternal Cardiovascular Disturbances.- 1. Introduction.- 2. Maternal Cardiac Function.- 3. Uterine Vasoconstriction.- 4. Maternal Anemias.- IV. Body Temperature.- 1. Introduction.- 2. Hyperthermia.- 3. Hypothermia.- V. Stress.- VI. Other Physiological Disruptions.- C. Strategies and Methods for Future Research.- D. Maternal Toxicity and Risk Assessment.- E. Conclusions.- References.