Section I. General
Chapter 1. Introduction
Chapter 2. Reproductive Anatomy and Physiology
- Introduction
- Important Definitions and Concepts
- Review of Normal Human Reproduction
- Concluding Remarks and Future Directions
Chapter 3. Pharmacokinetics in Pregnancy
- Introduction
- Factors Affecting Pharmacokinetics in Pregnancy
- The Fetal Compartment
- Highlighting the Value of PK Information in Pregnancy: Tocolytic Therapy
- Maternal Disease and Obstetrical Complications
- Origins of the Knowledge Gap
- Current Initiatives and Future Directions
- Physiologically Based Pharmacokinetic Modeling
- Concluding Remarks and Future Directions
Chapter 4. Physiologically Based Pharmacokinetic Models in Reproductive and Developmental Toxicology
- Introduction
- PBPK Modeling: Basic Concepts and Tools
- PBPK Modeling in Reproductive and Developmental Toxicology
- PBPK Model Applications in Reproductive and Developmental Toxicology
- Concluding Remarks and Future Directions
Chapter 5. Drugs and Chemical Contaminants in Human Breast Milk
- Introduction
- Breast-Feeding
- Drug Excretion Into Breast Milk
- Drug Disposition in the Infant
- Drugs That Should Be Used With Caution
- Commonly Used Herbal Products
- Nonmedicinal Substances
- Environmental Pollutants
- Concluding Remarks and Future Directions
Section II. Toxicity Testing Models and Safety Evaluation
Chapter 6. Reproductive and Developmental Safety Evaluation of New Pharmaceutical Compounds
- Introduction
- Overview of Human Pharmaceutical Development Process
- Developmental and Reproductive Toxicity Studies Needed for Development of Innovative Human Pharmaceuticals
- Interpretation of Human Risk From the Reproductive and Developmental Toxicity Studies in Animals
- Reproductive Risks Communication and Management
- Concluding Remarks and Future Directions
Chapter 7. Juvenile Toxicology Testing
- Introduction
- Considerations Regarding Toxicology Studies Conducted for Submission to Regulatory Agencies
- Anatomical and Functional Assessments
- Concluding Remarks and Future Directions
Chapter 8. Postmarket Surveillance and Regulatory Considerations in Reproductive and Developmental Toxicology: A Food and Drug Administration Perspective
- Introduction
- Drugs Intended for Use in Humans
- Vaccines Intended for Use in Humans
- Drugs Intended for Use in Animals
Chapter 9. OECD Guidelines for In Vivo Testing of Reproductive Toxicity
- Introduction
- Prenatal Developmental Toxicity Study (OECD 414)
- One-Generation Reproduction Toxicity Study (OECD 415)
- Two-Generation Reproduction Toxicity Study (OECD 416)
- Reproduction/Developmental Toxicity Screening Test (OECD 421)
- Combined Repeated-Dose Toxicity Study With the Reproductive/Developmental Toxicity Screening Test (OECD 422)
- Developmental Neurotoxicity Study (OECD 426)
- Extended One-Generation Reproductive Toxicity Study (OECD 443)
- Other Methods Not Included in the OECD Test Guidelines
- Concluding Remarks and Future Directions
Chapter 10. Guidelines for Reproductive and Developmental Toxicity Testing and Risk Assessment of Chemicals
- Introduction
- Regulation of Chemicals and Guidelines
- Risk Assessment and the Use of Data From Testing
- Concluding Remarks and Future Directions
Chapter 11. Validated and Nonvalidated Mechanism-Based Methods for Testing Developmental Toxicity
- Introduction
- Validated Alternative Models for Testing Developmental Toxicology
- Nonvalidated Cellular Methods
- Nonvalidated Alternative Models Using Whole Embryos
- Concluding Remarks and Future Directions
Chapter 12. Relevance of Animal Testing and Sensitivity of End Points in Reproductive and Developmental Toxicity
- Introduction
- Choice of Animal Test Models
- Nonmammalian Animal Models
- End Points of Reproductive Toxicity
- Tests and Test Guidelines
- Types of Studies
- Path to Alternative Tests and Concluding Remarks
Chapter 13. Embryonic Toxic Lesions and Stem Cell Therapy
- Introduction
- Development and Establishment of Mammalian Vasculogenesis and Embryonic and Fetal Hematopoiesis
- Experiments on the Correction of Impaired Embryonic Vasculogenesis and Primary Hematopoiesis
- In Vivo Experiments on the Correction of Impaired Early Fetal Liver Hematopoiesis
- Concluding Remarks and Future Directions
Chapter 14. In Vitro and Alternative Approaches to Developmental Neurotoxicity
- Introduction
- In Vivo Testing for Neurotoxicity and Developmental Neurotoxicity
- In Vitro Approaches to Developmental Neurotoxicity
- Concluding Remarks and Future Directions
Chapter 15. In Vitro Biomarkers of Developmental Neurotoxicity
- Introduction
- Cell Proliferation and Apoptosis
- Neurite Outgrowth
- Neurotransmission/Synaptogenesis
- Cytoskeleton
- Transcription Factors and Signaling Pathways
- Concluding Remarks and Future Directions
Chapter 16. Using Zebrafish to Assess Developmental Neurotoxicity
- Introduction
- Early Development
- Vulnerability of the Developing Nervous System
- Evaluating Testing for Adverse Effects Produced by Developmental Neurotoxicants
- Alternative Animal Models
- Practical Considerations in Zebrafish Neurotoxicological Research
- Zebrafish as a Model of Developmental Neurotoxicity
- The Importance of Screens
- Screening Approaches Using Larval Zebrafish: Some Basic Principles
- Zebrafish Developmental Neurotoxicity Testing
- The Zebrafish/Human Connection
- Emerging Novel Technologies
- Concluding Remarks and Future Directions
Chapter 17. Caenorhabditis elegans as a Model to Assess Reproductive and Developmental Toxicity
- Introduction
- C. elegans as a Model Organism
- Concluding Remarks and Future Directions
Chapter 18. A Primate as an Animal Model for Reproductive and Developmental Toxicology Testing
- Introduction
- Developmental and Reproductive Toxicity Studies
- Enhanced Pre- and Postnatal Development
- Immunogenicity
- Logistical and/or Technical Challenges
- Strength and Limitations
- Concluding Remarks and Future Directions
Section III. Nanoparticles and Radiation
Chapter 19. Developmental Toxicity of Engineered Nanomaterials
- Introduction
- Characteristics, Production, and Applications of Some Engineered Industrial Nanomaterials
- Special Features of Nanomaterials in Relation to Their Developmental Toxicity
- Exposure and Assessment of Exposure to Engineered Nanomaterial
- Crossing Biological Barriers
- Developmental and Reproductive Toxicity
- Risk Assessment of Engineered Nanomaterials
- Concluding Remarks and Future Directions
Chapter 20. Toxicity of Radiation: Biological Effects of Ionizing Radiation Exposure on Reproduction
- Introduction
- Radiation Dose and Risk
- Effects of Radiation on Different Organs
- Radiation Exposure and Genetic Hazards
- Effect of Radiation Exposure on the Hypothalamus–Pituitary–Gonadal Axis
- Female Reproductive Functions and Radiation Effects
- Radiation Effects on Male Reproductive System
- Concluding Remarks and Future Directions
Section IV. Gases and Solvents
Chapter 21. Reproductive and Developmental Toxicity of Solvents and Gases
- Introduction
- Carbon Tetrachloride (CASRN 56-23-5)
- Tetrachloroethylene (CASRN 127-18-4)
- Styrene (CASRN 100-42-5)
- Toluene (CASRN 108-88-3)
- Benzene (CASRN 608-93-5)
- Gasoline (CASRN 8006-61-9)
- Kerosene and Jet Fuels
- Formaldehyde (CASRN 50-00-0)
- Concluding Remarks and Future Directions
Section V. Drugs of Abuse and Addiction, Smoking and Alcohol
Chapter 22. Caffeine
- Introduction
- Historical Background
- Toxicokinetics
- Mechanism of Action
- Toxicity
- Risk Assessment
- Treatment
- Concluding Remarks and Future Directions
Chapter 23. Developmental Neurotoxicity of Abused Drugs
- Introduction
- Animal Models of Developmental Neurotoxicity
- Psychostimulants
- Concluding Remarks and Future Directions
Chapter 24. Effects of Alcohol on Embryo/Fetal Development
- Introduction
- Historical Background and Terminology Used to Describe the Effects of Alcohol
- Clinical Features of FAS/FASD
- Pharmacokinetics of Alcohol
- Mechanisms of Ethanol-Induced Teratogenesis
- Effects of Ethanol on Reproduction and Embryogenesis
- CNS Dysfunctions Caused by Prenatal Alcohol Exposure
- Biomarkers of Fetal Alcohol Exposure
- Therapeutics of FASD
- Concluding Remarks and Future Directions
Chapter 25. Cigarette Smoking and Reproductive and Developmental Toxicity
- Introduction
- Historical Background
- Pharmacokinetics/Toxicokinetics
- Mechanisms of Action
- Toxicity
- Treatment
- Concluding Remarks and Future Directions
Section VI. Pharmaceuticals and Food Additives
Chapter 26. Thalidomide
- Introduction
- Historical Background
- Thalidomide Embryopathy (Thalidomide Syndrome)
- Pharmacology
- Mechanism of Action—Adult Clinical Conditions
- Mechanism of Action—Thalidomide Embryopathy
- Phocomelia
- Framework of Thalidomide Teratogenicity
- Toxicity and Risk Assessment
- Treatment
- Concluding Remarks and Future Directions
Chapter 27. Retinoids
- Introduction
- Metabolism
- Retinoids in Reproduction
- Toxicity in General
- Veterinary Medicine
- Developmental Toxicity
- Patchy Perspective for Vitamin A Support
- Anticancer Effects in the Reproductive System
- Concluding Remarks and Future Directions
Chapter 28. Melamine and Cyanuric Acid
- Introduction
- Historical Background
- Pharmacokinetics/Toxicokinetics
- Mechanism of Action
- Toxicity
- Risk Assessment
- Treatment
- Concluding Remarks and Future Directions
Chapter 29. Ionophores
- Introduction
- Pharmacology/Pharmacokinetics/Mechanism of Action
- Ionophore Toxic Syndrome
- Safety and Toxicity Studies in Cattle
- Safety and Toxicity Studies in Chickens
- Safety and Toxicity Studies in Pigs
- Single-Dose and Multidose Toxicity in Laboratory Animals
- Reproductive and Developmental Toxicity
- Reproductive Safety in Cattle
- Reproductive Safety in Nontarget Animal Species
- Risk Assessment
- Concluding Remarks and Future Directions
Section VII. Metals
Chapter 30. Boron
- Introduction
- Historical Background and Sources
- Exposure
- Toxicokinetics
- Mechanism of Action
- Toxicity
- Therapeutic Strategies
- Concluding Remarks and Future Directions
Chapter 31. Arsenic, Cadmium, and Lead
- Introduction
- Arsenic
- Cadmium
- Lead
- Therapeutic Strategies
- Concluding Remarks and Future Directions
Chapter 32. Manganese
- Introduction
- Historical Background
- Pharmacokinetics/Pharmacodynamics
- Mechanism of Action
- Toxicity
- Risk Assessment
- Treatment
- Concluding Remarks and Future Directions
Chapter 33. Mercury
- Introduction
- Historical Background
- Toxicokinetics
- Toxicity
- Risk Assessment
- Treatment
- Concluding Remarks and Future Directions
Chapter 34. Selenium
- Introduction
- Historical Background
- Pharmacokinetics/Toxicokinetics
- Mechanism of Action
- General Toxicity
- Toxic Effects of Selenium on Reproduction
- Treatment
- Concluding Remarks and Future Direction
Section VIII. Pesticides, Industrial and Other Environmental Contaminants
Chapter 35. Organophosphates and Carbamates
- Introduction
- Historical Background
- Toxicokinetics
- Adverse Outcome Pathways in General Toxicity
- Adverse Outcome Pathways in Reproductive and Developmental Toxicity
- Toxicity
- Biomarkers
- Risk Assessment
- Treatment
- Concluding Remarks and Future Directions
Chapter 36. Chlorinated Hydrocarbons and Pyrethrins/Pyrethroids
- Introduction
- Historical Background
- Toxicokinetics
- Adverse Outcome Pathways in General Toxicity
- Adverse Outcome Pathways in Reproductive and Developmental Toxicity
- Endocrine Disruption
- Toxicity
- Risk Assessment
- Biomarkers
- Treatment
- Concluding Remarks and Future Directions
Chapter 37. Herbicides and Fungicides
- Introduction
- Herbicides
- Fungicides
- Endocrine Disruption
- Concluding Remarks and Future Directions
Chapter 38. Brominated Flame Retardants
- Introduction
- Environmental Contamination and Human Exposure
- Effects on Human Health
- Health Effects in Animals and Wildlife
- Toxicokinetics and Metabolites
- Concluding Remarks and Future Directions
Chapter 39. Polychlorinated Biphenyls, Polybrominated Biphenyls, Polychlorinated Dibenzo-p-dioxins, and Polychlorinated Dibenzofurans
- Introduction
- Historical Background
- Toxicokinetics
- Health Effects
- Mechanism of Action
- Concluding Remarks and Future Directions
Chapter 40. Reproductive Toxicity of Polycyclic Aromatic Hydrocarbons
- Introduction
- Historical Background
- Pharmacokinetics/Toxicokinetics
- Mechanism of Action
- Toxicity
- Concluding Remarks and Future Directions
Chapter 41. Toxicity and Risk Assessment of Bisphenol A
- Introduction
- The Endocrine System
- Toxicology
- Metabolism, Pharmacokinetics/Toxicokinetics
- Major Evaluations and Assessments
- Low-Dose Effects and Nonmonotonicity
- Regulatory Aspects
- Concluding Remarks and Future Directions
Chapter 42. Ethylene Glycol
- Introduction
- Acute Toxicity
- Chronic Toxicity/Carcinogenicity
- Reproductive Toxicity
- Developmental Toxicity
- Toxicokinetics
- Mechanism of Action
- Risk Assessment
- Concluding Remarks and Future Directions
Chapter 43. Perfluorooctane Sulfonate and Perfluorooctanoic Acid
- Introduction
- Historical Background
- Toxicokinetics
- Mechanism of Action
- Toxicity
- Risk Assessment
- Concluding Remarks and Future Directions
Chapter 44. Phthalates
- Introduction
- Toxicokinetics
- Mechanism of Action
- Toxicity
- Risk Assessment and Phthalate Action Plans
- Concluding Remarks and Future Directions
Chapter 45. Personal Care Products and Cosmetics
- Introduction
- Phthalates
- Parabens
- Triclosan
- Other Chemicals in PCPs
- Concluding Remarks and Future Directions
Section IX. Phytotoxicants, Mycotoxins and Zootoxins
Chapter 46. Toxic plants
- Introduction
- Locoweeds, Astragalus, and Oxytropis spp.
- Pine Needle Abortion, Ponderosa Pine, and Related Species
- Broom Snakeweed
- Poisonous Plants That Affect Embryo and Fetal Health
- Mechanism of Action
- Prevention and Treatment
- Veratrum spp. (Skunk Cabbage, False Hellebore)
- Other Plant Species With Suspected Teratogenic Activity
- Concluding Remarks and Future Directions
Chapter 47. Fumonisins
- Introduction
- Pharmacokinetics, Toxicokinetics, and Metabolism in Animals
- Bioavailability and Urinary Biomarker Studies in Humans
- Mechanism of Action
- Evidence for Ceramide Synthase Inhibition in Humans
- Systemic Toxicity in Animals
- Reproductive and Developmental Toxicity
- Fumonisins and Neural Tube Defects
- Fumonisins and Growth Retardation
- Risk Assessment and Regulatory Action
- Concluding Remarks and Future Directions
Chapter 48. Aflatoxins, Ochratoxins, and Citrinin
- Introduction
- Historical Background
- Pharmacokinetics/Toxicokinetics
- Mechanism of Action
- Toxicity
- Biomarkers
- Risk Assessment
- Treatment
- Concluding Remarks and Future Directions
Chapter 49. Zootoxins
- Introduction
- Historical Background
- Marine Zootoxins
- Insects
- Arachnida
- Reptilia
- Concluding Remarks and Future Directions
Section X. Special Topics
Chapter 50. Systems Toxicology and Predictive Modeling of Male Developmental Toxicity
- Introduction
- Male Developmental Toxicity
- Systems Toxicology Model
- Spatial Models
- Cell Agent-Based Models
- Concluding Remarks and Future Directions
Chapter 51. Stem Cells in Developmental Toxicity Testing
- Introduction
- Use of Stem Cells in Developmental Toxicology
- Assays for Predicting Developmental Osteotoxicity
- Assays for Predicting Developmental Neurotoxicity
- Transcriptomic-Based Assays
- Non Stem Cell Human Cell Lines
- Assays Using Human Cells
- Concluding Remarks and Future Directions
Chapter 52. Epigenetics in Reproduction and Development
- Introduction
- Epigenetic Modifications During Reproduction and Early Development
- Epigenetic Modifications After Birth
- Concluding Remarks and Future Directions
Chapter 53. Mitochondrial Dysfunction in Reproductive and Developmental Toxicity
- Introduction
- Mitochondrial Structure
- Mitochondria and Energy Production: Oxidative Phosphorylation
- Mitochondria, ROS, and Oxidative Stress
- Mitochondria and Calcium Homeostasis
- The Mitochondrial Permeability Transition
- Regulation and Significance of the MPT Induction
- Mitochondria in the Germ Line
- Testis Mitochondria and Spermatogenesis
- The Particular Characteristics of Testicular Bioenergetics
- Mitochondria and Toxicology Studies in the Reproductive System
- Concluding Remarks and Future Directions
Chapter 54. Cell Signaling Mechanisms in Developmental Neurotoxicity
- Introduction
- Developmental Neurotoxic Chemicals
- Vulnerability of the Developing Brain
- Cell Signaling Mechanisms in Developmental Neurotoxicity
- Mitochondrial Dysfunction, Free Radicals Generation, and Oxidative Stress
- Impacts on DNA Synthesis
- Gene Expression Deregulation
- Protein Modification
- Epigenetic Modifications
- Cell Signaling Integration
- Concluding Remarks and Future Directions
Chapter 55. Neuroinflammation and Oxidative Injury in Developmental Neurotoxicity
- Introduction
- Neuroinflammation and Oxidative Damage
- Suppression of Innate Immunity-Mediated Neuronal Damage
- Aging
- Concluding Remarks and Future Directions
Chapter 56. Effects of Stress on Reproductive and Developmental Biology
- Introduction
- Stressors and Their Impact on Biological Systems
- Stress and Developmental Biology
- Stress and Reproductive Biology
- Concluding Remarks and Future Directions
Chapter 57. Disruption of Cholesterol Homeostasis in Developmental Neurotoxicity
- Introduction
- Cholesterol Homeostasis in the Brain
- Cholesterol and Brain Development
- Cholesterol and Neurodevelopmental Disorders
- Opposite Effects of Brain Cholesterol in Development and Aging
- Concluding Remarks and Future Directions
Section XI. Endocrine Disruption, Mutagenicity, Carcinogenicity, Infertility and Teratogenicity
Chapter 58. Endocrine Disruption
- Introduction
- Definitions and Important Concepts
- Mechanisms of Endocrine Disruption
- Effects of Endocrine-Disrupting Chemicals
- Screening for Endocrine Disruptors
- Remaining Questions About Endocrine Disruption
- Concluding Remarks and Future Directions
Chapter 59. Developmental and Reproductive Disorders—Role of Endocrine Disruptors in Testicular Toxicity
- Introduction
- Development of Male Genital System
- Male Reproductive Tract as Target Site
- Hormonal Control
- Endocrine Disruptors
- Exposure and Regulation of EDs
- Association Between EDs and Testicular Dysgenesis Syndrome
- Effect of Various Endocrine Disruptors on Male Fertility
- Molecular Mechanism of Endocrine Disrupting Chemicals
- Concluding Remarks and Future Directions
Chapter 60. Mutagenicity and Carcinogenicity: Human Reproductive Cancer and Risk Factors
- Introduction
- Mutagenesis and Reproductive Organ Diseases
- Carcinogenicity and Reproductive Diseases
- Transgenerational Effects on Reproductive and Developmental Diseases
- Concluding Remarks and Future Directions
Chapter 61. Environmental Pollutants and Neural Tube Defects
- Introduction
- Polycyclic Aromatic Hydrocarbons
- Arsenic
- Pesticides
- Organic Solvents
- Ambient and Indoor Air Pollution
- Nitrate and Nitrite
- Disinfection By-products
- Concluding Remarks and Future Directions
Chapter 62. Teratogenicity
- Introduction
- The Principles of Teratology
- Birth Defect Prevalence
- Teratogenesis and Pregnancy
- Workplace, Occupation, and Adverse Reproductive Effects
- General Testing Methods for Teratogenic Effects in Experimental Animals
- Neurodevelopmental Toxicity
- The Role of Epigenetics
- Gene Editing
- Concluding Remarks and Future Directions
Chapter 63. Micro–Computed Tomography and Volumetric Imaging in Developmental Toxicology
- Introduction
- X-ray Microimaging and Micro-CT
- Concluding Remarks and Future Directions
Section XII. Toxicologic Pathology
Chapter 64. Toxicologic Pathology of the Reproductive System
- Introduction
- Reproductive Toxicity Studies
- Hormonal Regulation of Male and Female Reproduction
- Potential Mechanisms Involved in Reproductive Toxicity
- Evaluation of Reproductive Toxicity
- Nonneoplastic Lesions of Male and Female Reproductive Systems
- Role of Toxicokinetics in Male and Female Reproductive Toxicity
- Molecular Mechanisms of Teratogenesis
- Concluding Remarks and Future Directions
Section XIII. Placental Toxicity
Chapter 65. The Placental Role in Developmental Programming
- Introduction
- Placental Function and Regulation
- The Placental Barrier
- Diffusion Across the Placenta
- Placental Transport
- Regulation of Placental Transfer
- The Placenta as an Endocrine Organ
- Fetal Programming
- Epidemiological Evidence
- Animal Evidence
- Periconceptional Influences
- Mechanisms of Programming
- Epigenetics and Programming
- Developmental Alterations
- Evolutionary Perspectives
- Programming Summary
- Other Exposures
- The “Placental Phenotype,” Interventions, and Treatments
- Interventions
- Concluding Remarks and Future Directions
Chapter 66. Strategies for Investigating Hemochorial Placentation
- Introduction
- Early Development of the Placenta
- The Definitive Placenta in Humans and Rodents
- Appropriate Models of Hemochorial Placentation
- Concluding Remarks and Future Directions
Chapter 67. The Significance of ABC Transporters in Human Placenta for the Exposure of Fetus to Xenobiotics
- Introduction
- Structure, Localization, Function, and Polymorphisms of Human Placental ABC Transporters
- Models to Study Human Placental Transporters
- Studies on Transplacental Transport and Placental Transporters
- Significance of ABC Transporters in Fetal Health and Important Targets for Future Studies
- Concluding Remarks and Future Directions
Chapter 68. Placental Toxicity
- Introduction
- Placental Structure, Function, and Species Differences
- Placental Barrier
- Placental Susceptibility to Chemical Toxicity
- Placental-Toxicity-Modifying Factors
- Toxicity
- Concluding Remarks and Future Directions
Chapter 69. Placental Pathology
- Introduction
- Maternal “Effect” Pathologies of the Placenta
- Maldevelopment of the Placental Implantation Site
- Intraplacental Interference to Maternal Flow
- Fetal Pathologies of the Placenta
- Primary Placental Pathologies
- Concluding Remarks and Future Directions
Section XIV. Domestic and Wildlife Species
Chapter 70. Reproductive and Developmental Toxicity in Avian Species
- Introduction
- Background
- Mating Behavior and Nest Building
- Egg Laying and Reproductive Outcomes
- Endocrine Disruption
- Generation Effects and Teratology
- Toxicology of Specific Agents
- Concluding Remarks and Future Directions
Chapter 71. Endocrine Disruption in Wildlife Species
- Introduction
- Life History Exposure to Persistent Organic Pollutants
- Neuroendocrine Disruption
- Adrenal Gland
- Thyroid
- Sex Hormones and Reproduction
- Ecological Effects
- Concluding Remarks and Future Directions
Chapter 72. Teratogenesis in Livestock
- Introduction
- Embryology of Domestic Animals
- Teratogenic Viruses
- Nutritional Links With Fetal Development and Teratology
- Mycotoxins
- Pesticides
- Drugs
- Environmental Chemicals and Factors
- Concluding Remarks and Future Directions