Reproductive and Developmental Toxicology

3rd Edition - February 11, 2022
Editor: Ramesh C Gupta
Language: English
Hardback ISBN:
9 7 8 - 0 - 3 2 3 - 8 9 7 7 3 - 0
eBook ISBN:
9 7 8 - 0 - 3 2 3 - 9 1 5 6 0 - 1

Reproductive and Developmental Toxicology, Third Edition is a comprehensive and authoritative resource, providing the latest literature on this complex subject by focusing… Read more

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Reproductive and Developmental Toxicology, Third Edition is a comprehensive and authoritative resource, providing the latest literature on this complex subject by focusing on three core components - parent, placenta and fetus - and the continuous changes that occur in each. Enriched with relevant references describing every aspect of reproductive toxicology, this revised and updated resource addresses the totality of the subject, discussing a broad range of topics including nanoparticles and radiation, gases and solvents, smoking, alcohol and drugs of abuse, and metals, among others. In addition, it is the only resource to include reproductive and developmental toxicity in domestic animals, fish and wildlife

With a special focus on placental toxicity, this book is the only available reference to connect the three key risk stages. Completely revised and updated to include the most recent developments in the field, this book is an essential resource for advanced students and researchers in toxicology, as well as biologists, pharmacologists and teratologists from academia, industry and regulatory agencies.

Cover image
Title page
Table of Contents
Copyright
Dedication
Contributors
Introduction
Section I. General
Chapter 1. Reproductive anatomy and physiology
Introduction
Important definitions and concepts
Review of normal human reproduction
Concluding remarks and future directions
Chapter 2. 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 (PBPK) modeling
Concluding remarks and future directions
Chapter 3. 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 4. Adverse Outcome Pathways in reproductive and developmental toxicology
Introduction
AOPs in reproductive toxicity
AOPs on developmental toxicity
Issues relevant to reproductive and developmental AOPs
Concluding remarks and future directions
Disclaimer
Section II. Toxicity testing models, safety evaluation, and regulatory aspect
Chapter 5. Juvenile toxicology testing
Introduction
Considerations regarding toxicology studies conducted for submission to regulatory agencies
Anatomical and functional assessments
Concluding remarks and future directions
Chapter 6. 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
Male end points for reproductive studies
Female end points for reproductive studies
Couple-mediated end points for reproductive studies
Tests and test guidelines
Other guidelines
Types of studies
Single-generation reproduction study
Extended one-generation reproductive toxicity study
Multigeneration reproduction study
Reproductive assessment by continuous breeding study
Dominant lethal study
Total reproductive capacity
Path to alternative tests and concluding remarks
Chapter 7. Alternative methods to animal experimentation for testing developmental toxicity
Introduction
Methods for testing embryotoxicity based on animal cells
Methods for testing embryotoxicity based on human cells
Three-dimensional cultures and organoids for testing developmental toxicity
Alternative models based on embryos for testing developmental toxicology
Batteries of assays and integrated approaches to testing and assessment for testing developmental toxicity
Concluding remarks and future directions
Chapter 8. Use of computational toxicology tools to predict in vivo endpoints
Introduction
Methods: data sources used
Results
Concordance between in vivo data and predictions from CompTox tools
Discussion
Chapter 9. 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
Paradigm shifts and future directions
Chapter 10. Reproductive toxicity: in vivo testing guidelines from OECD
Introduction
Prenatal developmental toxicity study (OECD 414)
Two-generation reproduction toxicity study (OECD 416)
Reproduction/developmental toxicity screening test (OECD 421)
Combined repeated-dose toxicity study with the reproduction/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 11. In vitro biomarkers of developmental neurotoxicity
Introduction
Cell proliferation and apoptosis
Heavy metals
Organic solvents
Pesticides
Polychlorinated biphenyls
Polybrominated diphenyl ethers
Neurite outgrowth
Heavy metals
Organic solvents
Pesticides
PCBs/dioxins
Neurotransmission/synaptogenesis
Heavy metals
Cytoskeleton
Heavy metals
Organic solvents
Pesticides
Polychlorinated biphenyls
Transcription factors and signaling pathways
Heavy metals
Organic solvents
Pesticides
PCBs and PBDEs
Concluding remarks and future directions
Chapter 12. 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 13. Using zebrafish to assess developmental neurotoxicity
Introduction
Early development
Alternative animal models
Practical considerations in zebrafish neurotoxicological research
Zebrafish as a model organism for developmental neurotoxicity testing
The importance of screens
Screening approaches using larval zebrafish: some basic principles
Zebrafish developmental neurotoxicity testing
Potential confounders and methodological challenges
The zebrafish/human connection
The zebrafish/ecotoxicology connection
Emerging novel technologies
Concluding remarks and future directions
Chapter 14. Caenorhabditis elegans as a model to assess reproductive and developmental toxicity
Introduction
C. elegans as a model organism
Concluding remarks and future directions
Chapter 15. 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
Section III. Nanoparticles and radiation
Chapter 16. 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 to engineered nanomaterial
Crossing biological barriers
Developmental toxicity of NPs
Concluding remarks and future directions
Chapter 17. Effects of ionizing radiation on reproduction and development
Introduction
Conceptual framework
Nomenclature
Sources of radiation dose
Key early events (prior to World War II) in radiation science
Historical overview of radiation protection standards
Early development of radiation protection standards
Discovery of fission changed the world
The Manhattan Project
The tolerance dose
The first nuclear weapons
Post–World War II nuclear weapons development and testing
Contemporary nuclear activities
Post–World War II research, advisory, and regulatory organizations
Health effects of nuclear weapons
Exposures to radioactive materials and radiation dose
Radiation induced health effects: sources of information on radiation effects
Japanese bombing cohorts
Results from studies with laboratory animals
Potential health effects (other than cancer) of prenatal exposure
Linear nonthreshold models
Current radiation protection guidance
Concluding remarks and future directions
Dedication
Section IV. Gases and solvents
Chapter 18. 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
Concluding remarks and future directions
Section V. Drugs of abuse and addiction, smoking, and alcohol
Chapter 19. Developmental neurotoxicity of drugs of abuse
Introduction
Animal models of developmental neurotoxicity
Psychostimulants
Concluding remarks and future directions
Chapter 20. 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 21. Cigarette and E-cigarettes smoking and reproductive and developmental toxicity
Introduction
Cigarette smoking and reproductive and developmental toxicity
Pharmacokinetics/toxicokinetics
Mechanism of action
Toxicity of tobacco components
Fertility effects
Teratogenic effects
Peri- and postnatal effects
In vitro testing tobacco products
E-cigarettes and reproductive and developmental toxicity
Toxicity of E-cigarettes components
Toxicity
Conclusion remarks and future directions
Section VI. Pharmaceuticals, nutraceuticals, and food additives
Chapter 22. 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 23. 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 24. Safety of cannabis- and hemp-derived constituents in reproduction and development
Introduction
Role of the endocannabinoid system on reproductive functions
Reproductive and developmental toxicity of constituents of hemp and cannabis
Concluding remarks and future directions
Chapter 25. Caffeine
Introduction
Toxicokinetics
Mechanism of action
Toxicity
Risk assessment
Concluding remarks and future directions
Chapter 26. Melamine and cyanuric acid
Introduction
Historical background
Pharmacokinetics/toxicokinetics
Mechanism of action
Toxicity
Risk assessment
Treatment
Concluding remarks and future directions
Chapter 27. 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 28. Boron
Introduction
Historical background and sources
Exposure
Toxicokinetics
Mechanism of action
Toxicity
Therapeutic strategies
Concluding remarks and future directions
Chapter 29. Arsenic, cadmium, and lead
Introduction
Arsenic
Cadmium
Lead
Therapeutic strategies
Concluding remarks and future directions
Chapter 30. Mercury
Introduction
Historical background
Toxicokinetics
Mechanisms of neurotoxicity
Toxicity
Risk assessment
Treatment
Concluding remarks and future directions
Chapter 31. Manganese
Introduction
Historical background
Pharmacokinetics/pharmacodynamics
Mechanism of action
Toxicity
Risk assessment
Treatment
Concluding remarks and future directions
Chapter 32. Selenium
Introduction
Historical background
Pharmacokinetics/toxicokinetics
Mechanism of action
General toxicity
Toxic effects of selenium on reproduction
Treatment
Concluding remarks and future directions
Section VIII. Pesticides, industrial, and other environmental contaminants
Chapter 33. 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 34. Chlorinated hydrocarbons and pyrethrins/pyrethroids
Introduction
Historical background
Toxicokinetics
Adverse outcome pathways in general toxicity
Adverse outcome pathways in reproductive and developmental toxicity
Toxicity
Risk assessment
Treatment
Concluding remarks and future directions
Chapter 35. Herbicides and fungicides
Introduction
Herbicides
Fungicides
Endocrine disruption
Concluding remarks and future directions
Chapter 36. Brominated flame retardants
Introduction
Environmental contamination and human exposure
Effects on human health
Health effects in animals and wildlife
Metabolic effects
Toxicokinetics and metabolites
Concluding remarks and future directions
Chapter 37. Polychlorinated biphenyls, polybrominated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans
Introduction
Historical background
Toxicokinetics
Health effects
Concluding remarks and future directions
Chapter 38. Reproductive toxicity of polycyclic aromatic hydrocarbons
Introduction
Historical background
Pharmacokinetics/toxicokinetics
Mechanism of action
Toxicity
Concluding remarks and future directions
Chapter 39. Bisphenol A—toxicity and risk assessment update with academic and regulatory perspectives and physiologically based pharmacokinetic modeling
Introduction
New advances in BPA PBPK modeling
The Consortium Linking Academic and Regulatory Insights on BPA toxicity (CLARITY-BPA) program
National Toxicology Program (NTP) studies
The CLARITY-BPA core study
Academic studies
The CLARITY-BPA study, its findings, and discussions
Other analysis of the NTP core study
Other CLARITY-BPA studies not in the integrative analysis by Heindel et al. (2020)
Non-CLARITY BPA studies
Concluding remarks and future directions
Chapter 40. Ethylene glycol
Introduction
Chronic toxicity/carcinogenicity
Reproductive toxicity
Developmental toxicity
Toxicokinetics
Mechanism of action
Risk assessment
Concluding remarks and future directions
Chapter 41. Perfluorooctane sulfonate and perfluorooctanoic acid
Introduction
Exposure
Toxicokinetics
Mechanisms involved in toxicity
Reproductive toxic effects
Concluding remarks and future directions
Chapter 42. Traffic-related air pollution and the developing brain
Air pollution: a complex mixture adversely affecting health
The central nervous system is an important additional target for air pollution
The developing central nervous system is peculiarly sensitive to environmental insult
Effects of air pollution on the developing nervous system
Developmental exposure to air pollution as a risk factor for autism spectrum disorder?
Mechanisms underlying the developmental neurotoxicity of air pollution
Future perspectives and research needs
Chapter 43. Environmental pollutants and embryonic implantation and embryonic development
Introduction
The process of embryo implantation
Environmental pollutants affecting embryo implantation
Mechanism of action of environmental pollutants on embryo implantation
Concluding remarks and future directions
Chapter 44. Personal care products and cosmetics
Introduction
Phthalates
Parabens
Triclosan
Other chemicals in PCPs
Concluding remarks and future directions
Chapter 45. UV screening chemicals
Introduction
Oxybenzone
Benzotriazole UV stabilizers
Concluding remarks and future directions
Section IX. Phytotoxicants and mycotoxins
Chapter 46. Toxic plants
Introduction
Locoweeds (Astragalus and Oxytropis spp.)
Pine needle abortion, ponderosa pine, and related species
Broom snakeweed
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
Fumonisin in human foods
Fumonisin and sphingolipid metabolism
Pharmacokinetics and biomarkers of FB1 exposure
Systemic toxicity in animals
Reproductive and developmental toxicity
Fumonisin and neural tube defects (NTDs)
Proposed mechanisms of action for FB1-induction of NTDs
Additional mechanistic considerations
Fumonisins and growth retardation
Concluding remarks and future directions
Chapter 48. Aflatoxins, ochratoxins, and citrinin
Introduction
Historical background
Toxicokinetics
Mechanism of action
Toxicity
Risk assessment
Treatment
Concluding remarks and future directions
Chapter 49. Trichothecenes and zearalenone
Introduction
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Risk assessment
Treatment
Concluding remarks and future directions
Section X. Special topics
Chapter 50. Drugs and chemical contaminants in human breast milk
Introduction
Breastfeeding
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
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. Embryonic and fetal 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
Concluding remarks and future directions
Chapter 53. Epigenetics in reproduction and development
Introduction
Major epigenetic reprogramming landmarks during development
Epigenetic modifications after birth
Concluding remarks and future directions
Chapter 54. 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 55. Cell signaling mechanisms in developmental neurotoxicity
Introduction
Developmental neurotoxic chemicals
Vulnerability of the developing brain
Cell signaling mechanisms in developmental neurotoxicity
Instability of cytoskeleton proteins
Mitochondrial dysfunction, free radicals generation, and oxidative stress
Impact on DNA synthesis
Gene expression deregulation
Protein modification
Epigenetic modifications
Cell signaling integration
Concluding remarks and future directions
Chapter 56. 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 57. Effects of stress on reproductive function and fetal development
Introduction
Stress and its impact on biological systems
Neuroanatomy of stress response
Modulation of stress hormones during pregnancy
Stress and developmental biology
Animal studies on developmental biology
Stress and reproductive biology
Concluding remarks and future directions
Section XI. Endocrine disruption
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. Role of endocrine disruptors in male infertility and impact of COVID-19 on male reproduction
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
COVID-19 impact on male reproductive hormones
Concluding remarks and future directions
Section XII. Infertility and teratogenicity
Chapter 60. Toxicology of reproduction process and problems of male infertility
Introduction
Early gametogenesis
Sperm chromatin organization and infertility
Antisperm antibodies. Effects of the immune system on reproductive processes
Y chromosome defects and male infertility
Environmental factors and induction of male infertility
Concluding remarks and future directions
Chapter 61. Environmental pollutants and neural tube defects
Introduction
Polycyclic aromatic hydrocarbons
Arsenic
Pesticides
Organic solvents
Ambient air pollution
Nitrate and nitrite
Disinfection byproducts
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-CT and volumetric imaging in developmental toxicology
Introduction
X-ray micro-imaging and micro-CT
Micro-CT imaging of unstained fetal skeletons
Micro-CT imaging of alizarin red-S stained fetuses
High-resolution micro-CT imaging of fetal bone microarchitecture
Noninvasive in vivo micro-CT imaging approach
Micro-CT imaging of contrast agent stained soft tissues and organs of fetuses
Other volumetric imaging modalities in developmental toxicology
Concluding remarks and future directions
Section XiiI. Toxicologic pathology
Chapter 64. Toxicologic pathology of the reproductive system
Introduction
Reproductive toxicity studies
Hormonal regulation of male and female reproduction
Morphology of female reproductive tract during the normal estrus cycle
Potential mechanisms involved in reproductive toxicity
Potential mechanisms and morphological pattern of female reproductive toxicity
Potential mechanisms and morphological pattern of male reproductive toxicity
Evaluation of reproductive toxicity
Endpoints used in the assessment of male and female 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 XIV. 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
Pre- and 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
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
Human placental ABC transporters
In vitro studies on transplacental transport and placental ABC transporters
Ex vivo and in vivo studies on placental transport and ABC transporters
Significance of ABC transporters in fetal health
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
Vascular pathologies
Concluding remarks and future directions
Section XV. Domestic and wildlife species
Chapter 70. Endocrine disruption in wildlife species
Introduction
Pathways and exposure to endocrine disrupting chemicals
Endocrine disruption—life history
Adrenal cortex
Thyroid
Sex hormones and reproduction
Mechanisms of ECDs
Ecological effects
Anthropogenic noise
Concluding remarks and future directions
Chapter 71. Teratogenesis in livestock
Introduction
Embryology of domestic animals
Examples of terata
Teratogenic plants
Nutritional links with fetal development and teratology
Mycotoxins
Drugs
Prenatal and environmental influences—programing for life
Teratogenic viruses
Diagnosing causation
Concluding remarks and future directions
Chapter 72. Reproductive and developmental toxicity in avian species
Introduction
Background
Mating behavior and nest building
Ovipositing and reproductive outcomes
Endocrine disruption
Generation effects and teratology
Toxicology of specific agents
Concluding remarks and future directions
Index

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Ramesh C Gupta