Drug Toxicity in Embryonic Development.Vol.1

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