Front Cover
Reproductive and Developmental Toxicology
Reproductive and Developmental Toxicology
Copyright
Dedication
Contents
Contributors
Introduction
I - General
1 - Reproductive anatomy and physiology
Introduction
Important definitions and concepts
Reproduction
Hormones and hormone receptors
Gonadal steroid hormones and their “nuclear” receptors
Genomic and nongenomic mechanisms of action of gonadal steroid hormones
Review of normal human reproduction
Historical perspectives and complexity of reproductive function
Relevance of a basic understanding of human reproductive anatomy and physiology
Neuroendocrine control of reproduction
Puberty and sexual maturity
The onset of puberty
The endocrinology of puberty
Normal male reproductive anatomy and physiology
Developmental perspectives
Reproductive anatomy of the male
Testicular structure
Excurrent duct system
Accessory sex glands
External genitalia
Spermatogenesis
Proliferation (mitosis or spermatocytogenesis)
Meiosis
Differentiation (spermiogenesis)
The cycle of the seminiferous epithelium
Male reproductive physiology
Gonadal steroid synthesis in the testes
Endocrine regulation of spermatogenesis
Positive and negative feedback loops involved in male reproduction
Epididymal and accessory sex gland function
Sexual behavior, erection, emission, and ejaculation
Normal female reproductive anatomy and physiology
Developmental perspectives
Reproductive anatomy of the female
Female reproductive physiology
The estrous cycle
The menstrual cycle
Follicular development
Ovarian follicular synthesis of estrogens
The effects of estrogenic feedback on the hypothalamic–pituitary–gonadal axis
Ovulation
Formation and function of a corpus luteum
Summary of the effects of estrogens and progesterone during the female reproductive cycle
Oocyte/sperm transport, normal capacitation of sperm, and fertilization
Transport of the ovulated oocyte
Transport and capacitation of spermatozoa
Transport of spermatozoa
Capacitation of spermatozoa
Fertilization
Important aspects of normal embryonic and fetal development
Historical perspective
Blastocyst formation and differentiation of the germ cell layers
“Maternal recognition of pregnancy” and implantation
Formation of the extraembryonic membranes
Concepts and definitions
Placental types
Placental function
The “placental barrier”
Sex determination and sexual differentiation of reproductive function
Genotypic sex and development of the primitive sex cords
Gonadal sex determination and phenotypic sexual differentiation
Development of the male phenotype
Development of the female phenotype
Sexual differentiation of the brain
The endocrinology of pregnancy
Gestational hormones
Parturition
Physiology of parturition
The mammary glands
Anatomy
Physiology of lactation
Lactogenesis
Control of prolactin secretion
Reproductive senescence
Concluding remarks and future directions
References
2 - Pharmacokinetics in pregnancy
Introduction
Factors affecting pharmacokinetics in pregnancy
Absorption
Distribution
Metabolism
Renal excretion
Drug transport
The fetal compartment
Drug metabolism within the fetal compartment
Drug accumulation within 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
References
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
References
4 - Adverse Outcome Pathways in reproductive and developmental toxicology
Introduction
Adverse outcome pathways: principles of development and assessment
AOPs in reproductive toxicity
Spermatogenesis-related reproductive toxicity
Dose and exposure in reproductive toxicity
Endocrine-disruptor initiated reproductive toxicity
Aquatic organism reproductive toxicity
Metabolism-related reproductive toxicity
Metal-induced reproductive toxicity
AOPs on developmental toxicity
Embryonic vascular disruption
Axial malformations
Epigenetics
Endocrine-disrupting chemicals
Developmental neurotoxicity
Issues relevant to reproductive and developmental AOPs
Concluding remarks and future directions
Disclaimer
References
II - Toxicity testing models, safety evaluation, and regulatory aspect
5 - Juvenile toxicology testing
Introduction
Considerations regarding toxicology studies conducted for submission to regulatory agencies
Test species—selection and numbers
Microsampling techniques for bioanalytical analysis
Historical control data
Proper dosage selection—the value of dosage-range studies
Selection of the proper model
Route and method of administration
Gavage
Intravenous
Infusion
Subcutaneous or intramuscular
Dermal
Inhalation
Distribution of animals to dosage groups
Preweaning dosing
Postweaning dosing
Anatomical and functional assessments
Body weight and food consumption
Crown–rump length
Bone measurements
Clinical pathology
Physical landmarks
Sexual maturation
Behavioral evaluations
Motor activity
Auditory startle response
Learning and memory
Water maze
Passive or active avoidance
Functional observational battery
Behavioral testing in larger animals
Eye blink
Behavioral testing in pigs
Reproduction
Evaluation of estrous cycling
Evaluation of mating behavior and fertilization
Sperm collection
Cesarean-sectioning procedures and fetal evaluations
Immunotoxicity
Postmortem analyses
Concluding remarks and future directions
References
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
References
7 - Alternative methods to animal experimentation for testing developmental toxicity
Introduction
The necessity of alternative models for testing reproductive and developmental toxicology
Methods for testing embryotoxicity based on animal cells
The embryonic stem cell test
Alternative approaches for enhancing performance of EST
The micromass test
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
Whole embryo culture
Alternative approaches for enhancing performance of WEC
Frog embryo teratogenesis assay
Developmental toxicity assays with zebrafish
Dario rerio embryotoxicity test
Variants about the DarT
Batteries of assays and integrated approaches to testing and assessment for testing developmental toxicity
Example of battery of assays for testing developmental toxicity on the basis of alternative methods
Example of IATA for testing neurodevelopmental toxicity
Concluding remarks and future directions
References
8 - Use of computational toxicology tools to predict in vivo endpoints
Introduction
Methods: data sources used
Open access literature: in vivo endpoints related to the endocannabinoid system
Chlorpyrifos
Chlorpyrifos-oxon
Δ9Tetrahydrocannabinol
ToxCast/Tox21 in vitro assays
Toxicological prioritization index graphical user interface
High-throughput toxicokinetics
Results
ToxCast/Tox21 active hit-calls
ToxCast/Tox21 target and occurrence by developmental age
Chlorpyrifos
Chlorpyrifos-oxon
Δ9Tetrahydrocannabinol
The ToxPi program
High-throughput toxicokinetics
Chlorpyrifos
Chlorpyrifos-oxon
Δ9Tetrahydrocannabinol
Concordance between in vivo data and predictions from CompTox tools
Discussion
Acknowledgments
References
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
References
10 - Reproductive toxicity: in vivo testing guidelines from OECD
Introduction
Prenatal developmental toxicity study (OECD 414)
Uterine contents
Examination of fetuses
Data and reporting
Endpoints
Interpretation of results
Two-generation reproduction toxicity study (OECD 416)
Dosing
Observations
Reporting of data
Reproduction/developmental toxicity screening test (OECD 421)
Principle of the test
Observations
Data and reporting
Combined repeated-dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422)
Principle of the test
Procedure
Observations
Data and reporting
Developmental neurotoxicity study (OECD 426)
Procedure
Observations
Data and reporting
Extended one-generation reproductive toxicity study (OECD 443)
Procedure
Observations
Data and reporting
Other methods not included in the OECD test guidelines
Developmental immunotoxicity
Concluding remarks and future directions
References
11 - In vitro biomarkers of developmental neurotoxicity
Introduction
Cell proliferation and apoptosis
Heavy metals
Mercury
Lead
Arsenic
Organic solvents
Ethanol
Toluene
Pesticides
Polychlorinated biphenyls
Polybrominated diphenyl ethers
Neurite outgrowth
Heavy metals
Mercury
Lead
Arsenic
Organic solvents
Ethanol
Pesticides
PCBs/dioxins
Neurotransmission/synaptogenesis
Heavy metals
Mercury
Lead
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
Disclaimer
References
12 - Reproductive and developmental safety evaluation of new pharmaceutical compounds
Introduction
Overview of human pharmaceutical development process
Innovator pharmaceuticals—small molecules or biotherapeutics
Generic drug approval for small-molecule candidates
Overview of history of generic drug approval process in the United States
Biosimilar or biobetter drugs or biotherapeutics
Developmental and reproductive toxicity studies needed for development of innovative human pharmaceuticals
Overview
History and evolution of reproductive testing guidelines
Outlines of developmental and reproductive toxicity studies (per ICH guidelines)
Description of existing guidelines
ICH stages
General considerations defined by ICH S5 (R3)
Consideration for performing DART studies for biotherapeutics
Timing of DART studies during drug development process
Options to improve detection and interpretation of reproductive hazards
Interpretation of human risk from the reproductive and developmental toxicity studies in animals
Overview
Current FDA approach for human reproductive risk assessment when only animal data are available
Predictive value of animal DART studies for effects in humans
Reproductive risks communication and management
Product label as an effective communication tool
Management of reproductive risks after drug approval
Concluding remarks and future directions
Development and validation of new DART tests using emerging technologies
Modern imaging procedures for morphological examination of fetuses
References
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
Acknowledgments
References
14 - Caenorhabditis elegans as a model to assess reproductive and developmental toxicity
Introduction
C. elegans as a model organism
Reproduction and development
Important signaling pathways involved in development
The Wnt/β-catenin pathway
The Notch pathway
The apoptosis pathway in development
Practical aspects of worm husbandry
Common endpoints in assessing C. elegans development and reproduction
Assaying brood size
Assaying development
Transgenic worms
Mutant strains
Developmental and reproductive toxicity testing in C. elegans
Validation of the model organism
Bisphenol A as a developmental and reproductive toxicant in C. elegans
Mancozeb and maneb as a developmental and reproductive toxicants in C. elegans
Concluding remarks and future directions
References
15 - Postmarket surveillance and regulatory considerations in reproductive and developmental toxicology: a Food and ...
Introduction
Brief history of the Food and Drug Administration
Overview of the FDA's postmarket surveillance and pharmacovigilance
Drugs intended for use in humans
Vaccines intended for use in humans
Drugs intended for use in animals
Disclaimer
References
III - Nanoparticles and radiation
16 - Developmental toxicity of engineered nanomaterials
Introduction
Characteristics, production, and applications of some engineered industrial nanomaterials
Carbon nanoparticles
Inorganic nanoparticles
Special features of nanomaterials in relation to their developmental toxicity
Oxidative stress
Inflammation
Genotoxicity
Biopersistence and biodegradation of nanoparticles
Exposure to engineered nanomaterial
Crossing biological barriers
Translocation from lung to blood
Translocation of particles across the placenta
Potential mechanisms of action in developmental toxicity
Developmental toxicity of NPs
Pregnancy and fetal development
Central nervous system
Male reproductive system
Immune system
Cardiovascular system
Concluding remarks and future directions
Acknowledgments
References
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
Acknowledgments
References
IV - Gases and solvents
18 - Reproductive and developmental toxicity of solvents and gases
Introduction
Carbon tetrachloride (CASRN 56-23-5)
Properties, use, and exposure
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Tetrachloroethylene (CASRN 127-18-4)
Properties, use, and exposure
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Styrene (CASRN 100-42-5)
Properties, use, and exposure
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Toluene (CASRN 108-88-3)
Properties, use, and exposure
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Benzene (CASRN 608-93-5)
Properties, use, and exposure
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Gasoline (CASRN 8006-61-9)
Properties, use, and exposure
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Kerosene and jet fuels
Properties, use, and exposure
Toxicokinetics
General toxicity
Reproductive and developmental toxicity
Concluding remarks and future directions
References
V - Drugs of abuse and addiction, smoking, and alcohol
19 - Developmental neurotoxicity of drugs of abuse
Introduction
Animal models of developmental neurotoxicity
Rationale for animal models
Considerations in formulating and evaluating an animal model
Species considerations
Dosing considerations
Outcome measures
Model evaluation
Psychostimulants
Cocaine
Introduction, pharmacodynamics, and pharmacokinetics
Developmental neurotoxicology
Mechanisms of toxicity
Amphetamines
Introduction, pharmacodynamics, and pharmacokinetics
Developmental neurotoxicology
Mechanisms of toxicity
Opioids
Introduction, pharmacodynamics, and pharmacokinetics
Developmental neurotoxicology
Mechanisms of toxicity
Cannabinoids
Introduction, pharmacodynamics, and pharmacokinetics
Developmental neurotoxicology
Mechanisms of toxicity
Sedative-hypnotic and anxiolytic drugs
Introduction, pharmacodynamics, and pharmacokinetics
Developmental neurotoxicology
Mechanisms of toxicity
Hallucinogens
Introduction, pharmacodynamics, and pharmacokinetics
Developmental neurotoxicology
Mechanisms of toxicity
Inhalants
Introduction, pharmacodynamics, and pharmacokinetics
Developmental neurotoxicology
Mechanisms of toxicity
Concluding remarks and future directions
Acknowledgments
References
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
FAS/FASD prevalence
Pharmacokinetics of alcohol
Mechanisms of ethanol-induced teratogenesis
Effects of ethanol on reproduction and embryogenesis
CNS dysfunctions caused by prenatal alcohol exposure
Neurobehavioral and structural disorders associated with prenatal alcohol exposure in humans
Risk factors that influence the effects of prenatal alcohol exposure on the developing brain
Pattern of alcohol drinking
Critical periods of ethanol-induced damage during brain development
Potential mechanisms of ethanol-induced CNS alterations
Alterations in trophic factors
Disturbances in molecules that mediate Cell–Cell interactions
Derangements in glial proliferation, differentiation, and functioning
Oxidative stress and free radical damage
Genetic and epigenetic changes
Innate immune response
Biomarkers of fetal alcohol exposure
Therapeutics of FASD
Concluding remarks and future directions
References
21 - Cigarette and E-cigarettes smoking and reproductive and developmental toxicity
Introduction
Cigarette smoking and reproductive and developmental toxicity
Pharmacokinetics/toxicokinetics
Nicotine
Carbon monoxide
Nitrosamines
Mechanism of action
Nicotine
Carbon monoxide
Nitrosamines
Polycyclic aromatic hydrocarbon
Metals
Toxicity of tobacco components
Fertility effects
Teratogenic effects
Peri- and postnatal effects
In vitro testing tobacco products
E-cigarettes and reproductive and developmental toxicity
Introduction
Composition and types of E-cigarettes
Toxicity of E-cigarettes components
Humectants
Propylene glycol
Glycerol
Flavorings
Carbonyl compounds
Nitrosamines
Polycyclic aromatic hydrocarbons
Metals
Aerosols
Risk of nicotine use and dependence
Toxicity
Pregnant women
Adverse effects resulting from E-cigarettes in secondhand smoke
Developing fetus
Children
Adolescents
In vitro testing toxicity of E-Cigarettes
Conclusion remarks and future directions
Smoking cigarettes
Electronic cigarettes (E-cigarettes)
Acknowledgments
References
VI - Pharmaceuticals, nutraceuticals, and food additives
22 - Thalidomide
Introduction
Historical background
Thalidomide today
New thalidomide analogs
Thalidomide embryopathy (thalidomide syndrome)
Period of greatest sensitivity upon embryonic morphogenesis
Limb defects
Eye and ear defects
Internal organ defects
Nerve and CNS defects
Pharmacology
Mechanism of action—adult clinical conditions
Antiangiogenic actions
Antiproliferative and antimyeloma actions
Antiinflammatory and immunomodulatory actions
Mechanism of action—thalidomide embryopathy
Thalidomide prevents limb outgrowth by inhibiting angiogenesis
Molecular target(s) of thalidomide
Cereblon
Phocomelia
Framework of thalidomide teratogenicity
Toxicity and risk assessment
Treatment
Concluding remarks and future directions
Acknowledgments
References
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
References
24 - Safety of cannabis- and hemp-derived constituents in reproduction and development
Introduction
Introduction on hemp/cannabis
Constituents of cannabis and hemp
THC
CBD
Brief review of medicinal uses of THC/CBD
Brief review on the toxicity of THC and CBD
Role of the endocannabinoid system on reproductive functions
Female reproductive system
Male reproductive system
Reproductive and developmental toxicity of constituents of hemp and cannabis
Reproductive system toxicity of THC
In vitro data
Male reproductive toxicity
Female reproductive toxicity
Preclinical studies
THC-induced male reproductive toxicity in animal models
THC inhibits fertilization and negatively impacts sperm
Effects of THC on testicular enzymatic processes and on the hypothalamic–pituitary–gonadal axis
Effects on reproductive organs
THC impairs sexual function
THC-induced female reproductive toxicity in animal models
THC alters the hypothalamic–pituitary–gonadal axis and the ECS
THC disrupts ovulatory cycles and inhibits embryo implantation
Effect of THC on human reproductive physiology: an outstanding concern for reproductive health
Pharmacokinetics and toxicity of THC in pregnancy and breastfeeding mothers
Developmental toxicity of THC
Evidence from preclinical studies
THC causes fetotoxicity and long-term developmental impairments in adulthood
Developmental toxicity of THC with varying routes of exposure
Human evidence of THC-induced developmental toxicity
Reproductive system toxicity of CBD
In vitro data
CBD-induced reproductive toxicity: evidence from preclinical studies
Developmental toxicity of CBD
Preclinical animal models reveal mixed developmental outcomes following CBD exposure
Lack of human data reveals gap in understanding of developmental safety of CBD
Neurodevelopmental toxicity of cannabinoids
Reproductive and developmental toxicity of terpenes in cannabis
Nerolidol
α-bisabolol
β-myrcene
d-limonene
Concluding remarks and future directions
References
25 - Caffeine
Introduction
Toxicokinetics
Mechanism of action
Distribution and signaling of adenosine receptors
Caffeine as a blocker of adenosine function
Toxicity
Caffeine exposure and fecundability
Caffeine exposure and pre- and postnatal development
Risk assessment
Early caffeine exposure as a therapeutic measure and risk concern
Concluding remarks and future directions
References
26 - Melamine and cyanuric acid
Introduction
Historical background
Pharmacokinetics/toxicokinetics
Mechanism of action
Toxicity
General toxicity
Reproductive and developmental toxicity
Risk assessment
Treatment
Concluding remarks and future directions
References
27 - Ionophores
Introduction
Pharmacology/pharmacokinetics/mechanism of action
Ionophore toxic syndrome
Safety and toxicity studies in cattle
Acute toxicity study in beef cattle
Multiple-dose gavage toxicity study in steers
Acute tolerance study in lactating dairy cattle
Safety and toxicity studies in chickens
Safety and toxicity studies in pigs
Acute toxicity in growing pigs
Subchronic feeding study in growing-finishing pigs
Single-dose and multidose toxicity in laboratory animals
Reproductive and developmental toxicity
Multigeneration reproduction studies in rats
Teratologic study in rabbits
Reproductive safety in cattle
Breeding bulls
Dairy replacement heifers
Breeding and pregnant beef heifers
Breeding and pregnant beef cows
Lactating dairy cattle
Reproductive safety in nontarget animal species
Growing and breeding pigs
Sows and gilts
Broiler breeder and layer chickens
Risk assessment
Concluding remarks and future directions
References
VII - Metals
28 - Boron
Introduction
Historical background and sources
Exposure
Toxicokinetics
Oral absorption
Dermal absorption
Pulmonary absorption
Distribution
Metabolism
Excretion/elimination
Mechanism of action
Toxicity
Acute and short-time toxicity
Mutagenicity/genotoxicity
Repeated-dose toxicity
Reproductive and developmental toxicity
Female reproductive toxicity
Male reproductive toxicity
Developmental toxicity
Therapeutic strategies
Concluding remarks and future directions
References
29 - Arsenic, cadmium, and lead
Introduction
Arsenic
Introduction
Toxicokinetics
Absorption
Distribution
Transportation in blood
Tissue distribution
Metabolism
Mechanism of action
Mechanism for the cross-placental barrier
Oxidative stress
Direct binding with thiol group
Other mechanisms
Toxicity
Male reproductive system
Female reproductive system
Developmental toxicity
Cadmium
Introduction
Toxicokinetics
Mechanism of action
Oxidative stress
Toxicity
Male reproductive system
Female reproductive system
Developmental toxicity
Lead
Introduction
Historical background
Toxicokinetics
Mechanism of action
Mimicking essential metal: Ca2+
Oxidative stress
Toxicity
Male reproductive system
Female reproductive system
Developmental toxicity
Developmental effects on brain
Therapeutic strategies
Antioxidant supplementation
Chelation therapy
Concluding remarks and future directions
References
30 - Mercury
Introduction
Historical background
Toxicokinetics
Mechanisms of neurotoxicity
Toxicity
Toxicity in developing brains
Toxicity in other organs/systems
Risk assessment
Treatment
Concluding remarks and future directions
Acknowledgments
References
31 - Manganese
Introduction
Historical background
Pharmacokinetics/pharmacodynamics
Mechanism of action
Toxicity
Risk assessment
Treatment
Concluding remarks and future directions
Acknowledgments
References
32 - Selenium
Introduction
Historical background
Pharmacokinetics/toxicokinetics
Absorption
Distribution
Metabolism
Elimination
Mechanism of action
General toxicity
Toxic effects of selenium on reproduction
Reduced conception rate/embryo viability
Abortions/teratogenesis
Decreased growth rate
Spermatogenesis
Secondary effects on reproduction of selenium toxicosis
Treatment
Concluding remarks and future directions
References
VIII - Pesticides, industrial, and other environmental contaminants
33 - Organophosphates and carbamates
Introduction
Historical background
Toxicokinetics
Adverse outcome pathways in general toxicity
Adverse outcome pathways in reproductive and developmental toxicity
Oxidative/nitrosative stress in developmental neurotoxicity
Endocrine disruption
Toxicity
General consideration
Sensitivity of young versus adult: is brain the primary target?
Effects in male reproductive system
Effects in female reproductive and developmental systems
Biomarkers
Risk assessment
Treatment
Concluding remarks and future directions
References
34 - 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
References
35 - Herbicides and fungicides
Introduction
Herbicides
Historical background
Reproductive toxicity
Male reproductive toxicity
Female reproductive toxicity
Developmental toxicity
Experimental studies
Phenoxy acid derivatives
Bipyridyl derivatives
Ureas and thioureas
Phosphonomethyl amino acids or inhibitors of aromatic acid biosynthesis
Protoporphyrinogen oxidase inhibitors
Triazines and triazoles
Substituted anilines
Amides and acetamides
Dinitrophenol compounds
Triazolopyrimidine herbicides
Imidazolinones
Benzoic acids
Carbamates, thiocarbamates, and dithiocarbamate compounds
Dinitroaniline
Others
Epidemiological evidence
Fungicides
Historical background
Reproductive toxicity
Male reproductive toxicity
Female reproductive toxicity
Developmental toxicity
Experimental studies
Halogenated substituted monocyclic aromatics
Chloroalkylthiodicarboximides (phthalimides)
Anilinopyrimidines
Carbamic acid derivatives or dialkyldithiocarbamates
Benzimidazoles
Conazoles
Morpholines
Amides
Others
Endocrine disruption
Concluding remarks and future directions
References
36 - Brominated flame retardants
Introduction
Environmental contamination and human exposure
Effects on human health
Health effects in animals and wildlife
Developmental effects (neurotoxicity, thyroid hormone effects, immunotoxicity, and carcinogenicity)
Male reproductive effects
In vivo studies in rodents
Organophosphate ester flame retardants
In vitro studies examining effects on steroid binding, synthesis, and clearance
Effects on AR binding
Effects on steroidogenesis
Human evidence
Human studies: OPER exposure and associations with male reproductive outcomes
Female reproductive effects
Human evidence
Metabolic effects
Toxicokinetics and metabolites
Tetrabromobisphenol A
Hexabromocyclododecane
Polybrominated diphenyl ether
Higher brominated PBDE congeners
Debromination of PBDE congeners
Lower brominated PBDE congeners
PBDE metabolites
PBDE mixture studies
Concluding remarks and future directions
Acknowledgments
References
References
37 - Polychlorinated biphenyls, polybrominated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated di ...
Introduction
Historical background
Sources
Environmental fate
Exposure
PCBs in public school buildings
PBB incident in Michigan
Toxicokinetics
PCBs and PBBs
PCDDs and PCDFs
Health effects
General considerations
Male reproductive effects
Sexual development
Sperm quality
Female reproductive effects
Sexual development
Fecundity
Embryotoxicity
Endometriosis
Ovary
Placenta
Uterus, vagina, and cervix
Mammary gland
Developmental and teratogenic effects
Cardiovascular effects
Hydronephrosis and cleft palate
Neuroendocrine effects
Hypothalamo–pituitary–gonadal axis
Hypothalamo–pituitary–thyroid axis
Dentition effects
Neurobehavioral and neurochemical effects
Mechanism of action
Dioxin-like chemicals
Non-dioxin-like chemicals
Differential toxicity of PCBs, PBBs, PCDDs, and PCDFs
Toxic equivalency factors
Concluding remarks and future directions
Acknowledgments
References
38 - Reproductive toxicity of polycyclic aromatic hydrocarbons
Introduction
Historical background
Pharmacokinetics/toxicokinetics
Mechanism of action
Toxicity
Effect of benzo(a)pyrene on female reproduction
Overview of developmental effects of benzo(a)pyrene
Effect of benzo(a)pyrene on follicular growth
Effect of benzo(a)pyrene on fetal survival
Effect of benzo(a)pyrene-induced reduction in estrogen synthesis on puberty, reproductive tract function, and menopause
Effect of benzo(a)pyrene on male reproduction/fertility
Polycyclic aromatic hydrocarbon–induced DNA damage in reproductive tissues
Concluding remarks and future directions
References
39 - Bisphenol A—toxicity and risk assessment update with academic and regulatory perspectives and physiologically ...
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
BPA effects on the prostate
BPA effects on the urethra and dorsal prostate
Effects of BPA on the mammary gland
Effects of BPA on the ovary
Behavioral endpoints
Effects of BPA on neural DNA methylation, gene expression, and spatial navigational ability
Effects of BPA on the heart
Effects of BPA on the thyroid
The CLARITY-BPA study, its findings, and discussions
Reported integrative correlation analysis for independent CLARITY-BPA studies
Other analysis of the NTP core study
Other CLARITY-BPA studies not in the integrative analysis by Heindel et al. (2020)
Reproductive system
Mammary gland
Testes and sperm
Fetal development of UGS
Behavior
Neurodevelopmental effects
Cardiac
Immune system
Non-CLARITY BPA studies
Male reproductive toxicity
Sperm
Female reproduction
Immune system
Mechanism
Concluding remarks and future directions
References
References
40 - Ethylene glycol
Introduction
Chronic toxicity/carcinogenicity
Reproductive toxicity
Developmental toxicity
Gavage studies
Other routes of exposure
Postnatal effects and reversibility
Toxicokinetics
Absorption
Distribution
Metabolism
Elimination
Toxicokinetics in pregnancy
Mechanism of action
Identification of proximate toxicant
Role of metabolic acidosis
Linking developmental toxicity and kinetics
Species-specific GA kinetics and developmental toxicity
Implications for humans
Risk assessment
Model of EG developmental toxicity
Risk to humans
Concluding remarks and future directions
References
41 - Perfluorooctane sulfonate and perfluorooctanoic acid
Introduction
Exposure
Toxicokinetics
Mechanisms involved in toxicity
Reproductive toxic effects
Male reproductive toxicity
Female reproductive toxicity
Developmental toxicity
Risk assessment
Concluding remarks and future directions
References
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
Human studies
Animal studies
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
Acknowledgments
References
43 - Environmental pollutants and embryonic implantation and embryonic development
Introduction
The process of embryo implantation
Environmental pollutants affecting embryo implantation
Persistent EDCs
Pesticides
Organochlorine pesticides
Organophosphates
Pyrethroids
Organotins
Other persistent organic pollutants
Polychlorinated biphenyls
Incomplete combustion by-products
Nonpersistent EDCs
Bisphenol A
Phthalates
Parabens
Combined effects of nonpersistent EDC mixtures
Mechanism of action of environmental pollutants on embryo implantation
Impact of environmental pollutant exposure on preimplantation embryo development
Impact of environmental pollutant exposure on endometrial receptivity
Impact of environmental pollutant exposure on the embryo implantation process
Apposition
Attachment
Invasion
Decidualization
Concluding remarks and future directions
References
References
44 - Personal care products and cosmetics
Introduction
Phthalates
The effects of phthalates on female reproduction
Ovarian development
Postnatal ovary
Ovarian steroidogenesis
Uterine structure and function
Anterior pituitary gland
Puberty
Menstrual/estrous cyclicity and fertility
Endometriosis and leiomyoma
Pregnancy and birth
The effects of phthalates on males
Developing male sex organs
Postnatal male sex organs
Steroidogenesis
Anogenital distance
Hypothalamus and pituitary
Puberty
Fertility
Reproductive diseases and complications
Parabens
The effects of parabens on female reproduction
Ovarian development
Postnatal ovary
Ovarian steroidogenesis
Uterine structure and function
Anterior pituitary
Puberty
Premature ovarian failure and early menopause
Cyclicity, fertility, pregnancy, and birth
Birth defects
The effects of parabens on males
Development of male sex organs
Postnatal male sex organs
Testicular steroidogenesis
Anterior pituitary
Puberty
Fertility
Triclosan
The effects of triclosan on female reproduction
Postnatal ovary
Ovarian steroidogenesis
Uterine structure and function
Anterior pituitary
Puberty
Estrous cyclicity and fertility
Polycystic ovary syndrome
Pregnancy and birth
Placenta
The effects of triclosan on males
Testis development
Adult testis
Testicular steroidogenesis
Anterior pituitary
Puberty
Fertility
Other chemicals in PCPs
Effects of UV filters on reproductive health
Effects of synthetic musks on reproductive health
Concluding remarks and future directions
References
45 - UV screening chemicals
Introduction
Oxybenzone
Sources of exposure to oxybenzone and other chemical sunscreens
Human exposure levels
Measurements in the environment
ADME
Adsorption
Distribution
Metabolism
Excretion
Aquatic toxicity and effects on wildlife
Acute and subchronic toxicity
Toxicity testing in rats
Toxicity testing in mice
NTP's toxicity summary of 2- and 13-week oral and dermal exposures
Skin sensitization
Reproductive toxicity testing
Endocrine disruption
ER agonist activities
ER antagonist activity
AR agonist and antagonist properties
Summary of endocrine disrupting properties
Genotoxicity and carcinogenesis
Epidemiology
Benzotriazole UV stabilizers
Uses in products/sources of exposure
Measurements in the environment
Measurements in wildlife and humans
ADME
Toxicity
Concluding remarks and future directions
References
References
IX - Phytotoxicants and mycotoxins
46 - Toxic plants
Introduction
Locoweeds (Astragalus and Oxytropis spp.)
Effects on female reproduction
Effects on male reproduction
Pine needle abortion, ponderosa pine, and related species
Broom snakeweed
Lupines, poison hemlock, and Nicotiana glauca
Lupine toxicity
Poison hemlock (Conium maculatum) toxicoses
Nicotiana spp.
Teratogenicity of lupines, poison hemlock, and Nicotiana glauca
Susceptible periods of gestation
Livestock species and breed differences
Structure–activity relationship
Mechanism of action
Prevention and treatment
Veratrum spp. (skunk cabbage, false hellebore)
Other plant species with suspected teratogenic activity
Concluding remarks and future directions
References
47 - Fumonisins
Introduction
Fumonisin in human foods
Human exposures and regulatory guidelines for fumonisins in foods
Hydrolyzed fumonisin
Fumonisin and sphingolipid metabolism
Fumonisin B1 inhibition of ceramide synthase (CerS) disrupts sphingolipid metabolism
Pharmacokinetics and biomarkers of FB1 exposure
Bioavailability and pharmacokinetics in animals
Bioavailability and urinary biomarker studies in humans
Inhibition of CerS and sphingolipid biomarkers in animals
Evidence for fumonisin inhibition of CerS in humans
Systemic toxicity in animals
Reproductive and developmental toxicity
In ovo and in vitro studies
In vivo experiments
Fumonisin and neural tube defects (NTDs)
Background and epidemiology
Induction of NTDs in cultured mouse embryos
In vivo induction of NTDs in mice
Hydrolyzed FB1 and NTDs in rodents
Proposed mechanisms of action for FB1-induction of NTDs
FB1 inhibition of CerS and elevation of upstream sphingoid bases and 1-phosphates
Elevated sphingoid base-1-phosphates (Sa 1-P and So 1-P)
Cytoplasmic sphingoid base-1-phosphates as bioactive ligands for S1P receptors
(Extracellular) sphingoid base-1-phosphates and inhibition of autotaxin
Nuclear sphingoid base-1-phosphates and histone deacetylase (HDAC) inhibition
Elevated sphingoid bases (Sa and So)
Inhibition of Trpm6/7
FB1 inhibition of CerS, depletion of downstream gangliosides and altered folate transport
Folate supplementation and prevention of neural tube defects
Folate fortification of enriched cereal grain products and corn masa flour
Folate-deficient diet and NTD induction by FB1 in mice
Additional mechanistic considerations
Fumonisins and growth retardation
Concluding remarks and future directions
References
References
48 - Aflatoxins, ochratoxins, and citrinin
Introduction
Historical background
Toxicokinetics
Aflatoxins
Ochratoxins and citrinin
Mechanism of action
Aflatoxins
Ochratoxins and citrinin
Toxicity
Aflatoxins
General toxicity
Reproductive and developmental toxicity
Ochratoxins and citrinin
General toxicity
Reproductive and developmental toxicity
Biomarkers
Aflatoxins
Ochratoxin A and citrinin
Risk assessment
Aflatoxins
Ochratoxins and citrinin
Treatment
Concluding remarks and future directions
References
49 - Trichothecenes and zearalenone
Introduction
Trichothecenes
Zearalenone
Toxicokinetics
Trichothecenes
Zearalenone
General toxicity
Trichothecenes
Zearalenone
Reproductive and developmental toxicity
Trichothecenes
Zearalenone
Endocrine-disrupting activity
Risk assessment
Trichothecenes
Zearalenone
Treatment
Concluding remarks and future directions
References
X - Special topics
50 - Drugs and chemical contaminants in human breast milk
Introduction
Breastfeeding
Drug excretion into breast milk
Maternal pharmacokinetics in the postpartum period
Drug medications interfering with milk production
Drugs that decrease lactation
Drugs that increase lactation (galactogogues)
Passage of medications into the mother's milk and drug transport
Drug milk-to-plasma ratio
Drug dose received by the infant (level of exposure)
Amount of medication in milk and relative dose
Exposure index
Relative dose
Drug disposition in the infant
Gastrointestinal biotransformation and transport in the newborn and infant
Hepatic biotransformation in the fetus and neonate
Renal excretion
Immune system in neonates
Drug passage into the CNS
Drugs that should be used with caution
Analgesics
Narcotic analgesics
Acetylsalicylic acid (aspirin)
NSAIDs
Antibiotics
Tetracyclines
Fluoroquinolones
Erythromycin and other macrolides
Nitroimidazole antibiotics
Synthetic nucleoside analogues (antiviral)
Antifungal antibiotics
Cardiovascular drugs
Steroidal hormonal drugs
Antiepileptics
Psychoactive drugs
Sedatives and hypnotics
Antidepressants
Anticoagulants
Antihypertensives
Beta-blockers
Calcium channel blockers
Methyldopa
Angiotensin-converting enzyme inhibitors
Potential improvement of study of antihypertensive drugs in breastfeeding women
Chemotherapeutic drugs
Commonly used herbal products
Food/dietary supplements
Nonmedicinal substances
Recreational drugs
Opiates
Heroin
Stimulants
Cocaine
Amphetamines
Hallucinogens
Marijuana (cannabis)
Lysergic acid diethylamide
Phencyclidine (PCP)
Alcohol
“Sniffed” substances
Toluene
Gasoline
Environmental pollutants
Persistent organic pollutants in breast milk
Organochlorines and polychlorinated biphenyls
Polychlorinated dibenzodioxins and polychlorinated dibenzofurans
Polybrominated diphenyl ethers
Poly and perfluoroalkyl substances
Endocrine-disrupting compounds
Bisphenol A
Di-(2-ethylhexyl) phthalate
Nonylphenols
Heavy metals
Lead
Cadmium
Mercury
Arsenic
Food and environmental toxins
Mycotoxins
Concluding remarks and future directions
Acknowledgments
References
51 - Stem cells in developmental toxicity testing
Introduction
Use of stem cells in developmental toxicology
The ESC test
Assays for predicting developmental osteotoxicity
Assays for predicting developmental neurotoxicity
Stem Cell–Based assays
Transcriptomic-based assays
Non–stem cell human cell lines
Assays using human cells
Concluding remarks and future directions
References
52 - Embryonic and fetal toxic lesions and stem cell therapy
Introduction
Development and establishment of mammalian vasculogenesis and embryonic and fetal hematopoiesis
Yolk sac
Aorta–gonad–mesonephros region
Placental hematopoiesis
Allantois
Fetal liver
Experiments on the correction of impaired embryonic vasculogenesis and primary hematopoiesis
Experimental design
Experimental model of impaired vasculogenesis and early hematopoiesis in rat embryos
Modes of cell transplantation to extraembryonic/embryonic tissues
In vitro experiments on the correction of impaired early embryonic liver hematopoiesis/vasculogenesis
In vivo experiments on the correction of impaired early fetal liver hematopoiesis
Experimental model of impaired secondary hematopoiesis in rats and mice
Correction of secondary hepatic hematopoiesis in rats
Correction of secondary hepatic hematopoiesis in mice
Concluding remarks and future directions
References
53 - Epigenetics in reproduction and development
Introduction
Major epigenetic reprogramming landmarks during development
Epigenetic reprogramming of primordial germ cells
Asymmetrical histone modifications, bivalent promoters, and epigenetic regulation of temporal gene expression in stem cells
Epigenetic reprogramming of the gametes and the zygote
Epigenetic reprogramming of the spermatozoa
Epigenetic reprogramming of the oocyte
Epigenetic reprogramming of the zygote and the preimplantation embryo
Genomic imprinting
Epigenetic modifications during prenatal development
Epigenetic modifications after birth
Postnatal epigenetic modifications in response to environment
Epigenetic modifications in healthy individuals as a function of aging
Concluding remarks and future directions
Acknowledgments
References
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
References
55 - Cell signaling mechanisms in developmental neurotoxicity
Introduction
Developmental neurotoxic chemicals
Vulnerability of the developing brain
Cell signaling mechanisms in developmental neurotoxicity
Cell membrane damage
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
Acknowledgments
References
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
Acknowledgments
References
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
Role of the neuroendocrine axis during fetal development
Origins of individual differences in organism development
Prenatal stress and its impact on fetal growth
Prenatal stress and its impact on later life
Maternal neuroendocrine environment and fetal development
Endocrine immune interactions during developmental biology
Prenatal meditation and its impact on infant behaviors
Animal studies on developmental biology
Stress and reproductive biology
Stress and reproductive function
Stressor types affecting reproductive function
Stress and reproductive functions: role of sex differences
Stress, reproductive function, and the neuroendocrine axis: role of glucocorticoids
Oxidative stress and reproductive function
Concluding remarks and future directions
References
XI - Endocrine disruption
58 - Endocrine disruption
Introduction
The relevant and controversial nature of the topic
The susceptibility of reproductive processes to “disruption”
Definitions and important concepts
Hormones and endocrine function
Hormone receptors
Endocrine disruption
Endocrine-disrupting chemicals, endocrine disruptor, and hormonally active agents
Dose and dosage
Route of exposure
Mechanisms of endocrine disruption
Critical windows of exposure to endocrine-disrupting chemicals
The susceptibility of embryonic and fetal development to endocrine disruption
The susceptibility of pre- and peripubertal reproductive development to endocrine disruption
The susceptibility of postpubertal reproductive function to endocrine disruption
Specific mechanisms for endocrine disruption
“Classic” receptor-mediated endocrine disruption
Estrogen receptor agonists/antagonists
Selective estrogen receptor modulators
Androgen receptor antagonists
Endocrine disruption independent of receptor-mediated interactions
Unique receptor-independent antiandrogenic effects of phthalates
“Androgenic” and “estrogenic” effects of xenobiotics
Aryl hydrocarbon receptor–mediated endocrine disruption
Epigenetic mechanisms of action of endocrine-disrupting chemicals
Disruption of “nonreproductive” endocrine systems
Effects of endocrine-disrupting chemicals
The scope of the endocrine disruption problem: “high-dose” versus “low-dose” effects
“Low-dose” effects and “nonmonotonic” dose–response curves
Documented cases of endocrine disruption in wildlife, domestic animals, and humans
Adverse reproductive effects of endocrine disruption on wildlife and domestic animals
Adverse reproductive effects of “androgenic” and “estrogenic” chemicals on animal species
The adverse reproductive effects of zearalenone on domestic animals
Documented adverse reproductive effects of endocrine-disrupting chemicals on humans
Adverse effects of diethylstilbestrol on human reproduction
Adverse reproductive effects of other xenoestrogens on human reproduction
Adverse “antiestrogenic”/“antiandrogenic” effects of heavy metals on human reproduction
“Documented” adverse reproductive effects of “antiandrogens” on human reproduction
“Documented” adverse aryl hydrocarbon receptor–mediated effects on human reproduction
Screening for endocrine disruptors
Remaining questions about endocrine disruption
Possible effects of mixtures
Importance of differences in the biological activities of xenobiotic metabolites/isomers
The “real-life” impact of bisphenol A
Concluding remarks and future directions
References
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
Testes
Leydig cells
Sertoli cells
Spermatogenesis and spermiation
Steroidogenesis
Hormonal control
Endocrine disruptors
Exposure and regulation of EDs
Association between EDs and testicular dysgenesis syndrome
Cryptorchidism
Testicular cancer
Effect of various endocrine disruptors on male fertility
Bisphenol A
Phthalate
Alkylphenols and their derivatives
Molecular mechanism of endocrine-disrupting chemicals
DNA integrity
Induction of oxidative stress
COVID-19 impact on male reproductive hormones
Concluding remarks and future directions
References
References
XII - Infertility and teratogenicity
60 - Toxicology of reproduction process and problems of male infertility
Introduction
Early gametogenesis
Gamete formation. Migration to the genital ridges
Spermatogenesis regulation mechanisms and their role in infertility induction
Sperm chromatin organization and infertility
Capacitation, oxidative stress, and sperm DNA damage
Acrosome reaction
Proteins involved in the fertilization process and their functions. Matrix proteins of the anterior acrosome
Antisperm antibodies. Effects of the immune system on reproductive processes
Y chromosome defects and male infertility
Environmental factors and induction of male infertility
Doxorubicin: experimental induction of infertility in male mice
Immunohistochemical analysis of DNA DS breaks with identification of the γH2AX locus
Concluding remarks and future directions
References
61 - Environmental pollutants and neural tube defects
Introduction
Polycyclic aromatic hydrocarbons
Animal studies
Epidemiological studies
Summary of PAH studies
Arsenic
Animal studies
Epidemiological studies
Summary of arsenic studies
Pesticides
Animal studies
Epidemiological studies
Summary of pesticide studies
Organic solvents
Animal studies
Epidemiological studies
Summary of solvent studies
Ambient air pollution
Animal studies
Epidemiological studies
Summary of ambient air pollution studies
Nitrate and nitrite
Animal studies
Epidemiological studies
Summary of nitrate and nitrite studies
Disinfection byproducts
Animal studies
Epidemiological studies
Summary of DBPs studies
Concluding remarks and future directions
References
References
62 - Teratogenicity
Introduction
The principles of teratology
Birth defect prevalence
Teratogenesis and pregnancy
Physiology of pregnancy
Developing cardiovascular system
Metabolism in the prospective mother
Metabolism in the fetus
Metabolism in the placenta
Maternal respiration
Maternal renal function
Summary
Workplace, occupation, and adverse reproductive effects
Nursing/health-care workers
Maternal and paternal exposure to organic solvents
Radiation
Prospective studies of pregnant workers
General testing methods for teratogenic effects in experimental animals
Neurodevelopmental toxicity
The role of epigenetics
Epigenetic mechanisms
DNA methylation
Histone modification and chromatin function
Evidence for epigenetic effects on lifelong and multigenerational phenotypic change
Nutrition and diet
Hypertension
Neurodevelopment and stress
Substances of abuse
Cancer
Gene editing
Concluding remarks and future directions
References
63 - Micro-CT and volumetric imaging in developmental toxicology
Introduction
Biomedical imaging
“Of mice and men”—from clinical to preclinical imaging
“Of fetuses and adults”—bioimaging of small animal fetuses
X-ray micro-imaging and micro-CT
X-ray properties and imaging
Basic principles of X-ray computed tomography
Micro-CT systems
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
Concluding remarks
Future directions
Acknowledgments
References
XIII - Toxicologic pathology
64 - Toxicologic pathology of the reproductive system
Introduction
Reproductive toxicity studies
Hormonal regulation of male and female reproduction
Hormonal regulation of the estrus cycle
Hormonal regulation of spermatogenesis
Morphology of female reproductive tract during the normal estrus cycle
Vagina
Uterus
Ovary
Potential mechanisms involved in reproductive toxicity
Directly acting toxicants
Indirectly acting toxicants
Potential mechanisms and morphological pattern of female reproductive toxicity
Potential mechanisms of female reproductive toxicity
Morphological patterns of female reproductive toxicity
Potential mechanisms and morphological pattern of male reproductive toxicity
Pattern of damage associated with sertoli cell toxicity
Pattern of damage associated with germ cell toxicity
Pattern of damage associated with leydig cell toxicity
Pattern of damage associated with vascular changes
Pattern of damage associated with disturbances of fluid balance
Evaluation of reproductive toxicity
Endpoints used in the assessment of male and female reproductive toxicity
Clinical pathology
Dissection
Organ weights
Tissue fixation
Tissue sampling and trimming
Embedding and staining
Microscopic evaluation of tissues
Testicular staging
Approach for microscopic examination of testis
Oocyte staging
Nonneoplastic lesions of male and female reproductive systems
Male reproductive system
Lesions of testis
Testicular atrophy
Necrosis of seminiferous tubules
Leydig cell hyperplasia
Lesions of epididymis
Degeneration
Granulomatous inflammation (sperm granulomas)
Lesions of seminal vesicle and prostate glands
Atrophy
Hypertrophy and hyperplasia of the prostate gland
Squamous metaplasia of the prostate
Female reproductive system
Lesions of ovaries
Oocyte or ovarian follicular degeneration
Ovarian atrophy
Ovarian (follicular and luteal) cysts
Ovarian hyperplasia
Lesions of the uterus
Endometrial atrophy
Squamous metaplasia of endometrial glands
Endometrial hyperplasia
Endometriosis and adenomyosis
Decidual reaction (deciduoma)
Lesions of the vagina and cervix
Vaginal hyperkeratosis and hyperplasia
Vaginal mucification
Squamous metaplasia
Lesions of the mammary gland
Mammary glandular atrophy
Mammary glandular hyperplasia
Role of toxicokinetics in male and female reproductive toxicity
Fertility and embryo–fetal development study in rats
Pre- and postnatal development studies in rats
Placental transfer studies
Milk transfer studies
Molecular mechanisms of teratogenesis
Concluding remarks and future directions
References
XIV - Placental toxicity
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
Maternal and environmental influences on placental function and fetal development
Maternal body composition and placental function
Maternal diet and dietary balance
Macronutrients
Micronutrients
Dietary balance
Other exposures
Exercise
Maternal stress and illness
Environmental toxins
The “placental phenotype,” interventions, and treatments
Interventions
Concluding remarks and future directions
Acknowledgments
References
References
66 - Strategies for investigating hemochorial placentation
Introduction
Early development of the placenta
Derivation of the trophoblast lineage
Early trophoblast development
The definitive placenta in humans and rodents
Development of the maternal–fetal exchange surface of the placenta
Extravillous trophoblast cells and decidual–trophoblast interactions
Models of hemochorial placentation
Noninvasive approaches
Ex vivo approaches
Early embryo culture
Placental perfusion
Placental explants
In vitro approaches using cell culture models
Primary cell culture
TS cell culture
Human ES and pluripotent stem cells
Spontaneous, immortalized, and transformed trophoblast cell lines
In vivo approaches
Transgenesis and gene targeting
Lentiviral-mediated gene delivery in trophoblast cells
In vivo models of trophoblast invasion
Concluding remarks and future directions
Acknowledgments
References
References
67 - The significance of ABC transporters in human placenta for the exposure of fetus to xenobiotics
Introduction
Human placental ABC transporters
ABCB1/MDR1/P-glycoprotein
ABCG2/BCRP
ABCC/MRP
In vitro studies on transplacental transport and placental ABC transporters
Trophoblastic cancer cell lines (BeWo, Jeg-3, JAr)
Placental villous explant cultures
Placental membrane vesicles
Primary human placental trophoblasts
Ex vivo and in vivo studies on placental transport and ABC transporters
Animal studies
Human placental perfusion studies
Human in vivo studies
Significance of ABC transporters in fetal health
Concluding remarks and future directions
Acknowledgments
References
68 - Placental toxicity
Introduction
Placental structure, function, and species differences
Placental barrier
Placental susceptibility to chemical toxicity
Placental-toxicity-modifying factors
Maternal toxicity
Placental transport of nutrients and toxicants
Placental–fetal metabolism
Toxicity
Abused drugs
Alcohol
Nicotine/tobacco
Morphine
Cocaine
Metals
Aluminum
Arsenic
Cadmium
Lead
Mercury
Nickel
Insecticides
Organophosphates and carbamates
Cholinergic effects
Protein synthesis
Endocrinal effects
Histopathologic changes
Organochlorines
Pyrethroids
Dioxins and polychlorinated biphenyls
Dioxins
Polychlorinated biphenyls
Concluding remarks and future directions
Acknowledgments
References
69 - Placental pathology
Introduction
Anatomic
Infectious
Inflammatory
Hypoxic
Vascular pathologies
Maternal vascular malperfusion
Fetal vascular malperfusion
Intervillous thrombus
Massive perivillous fibrin deposition/maternal floor infarct
Other placental pathologies
Concluding remarks and future directions
References
XV - Domestic and wildlife species
70 - Endocrine disruption in wildlife species
Introduction
Pathways and exposure to endocrine disrupting chemicals
Endocrine disruption—life history
Adrenal cortex
Adrenal cortex physiology
Mechanisms of toxicity on adrenal cortex
Adrenal cortex as a target for ECDs
Thyroid
Brief review of thyroid physiology
Mechanisms of thyroid ECDs
Thyroid as a target for ECDs
Seals
Bears
Sex hormones and reproduction
Brief review of physiology
Mechanisms of ECDs
ECDs and the mammary gland
ECDs and sex hormones
ECDs and reproductive organs
Seals
Mink
Ruminants
Chlormequat
Petroleum and dolphin health, endocrine status, and reproduction
Ecological effects
Interactions
Anthropogenic noise
Concluding remarks and future directions
References
71 - Teratogenesis in livestock
Introduction
Embryology of domestic animals
Examples of terata
Teratogenic plants
Background
Apiaceae
Dennstaedtiaceae
Fabaceae
Liliaceae
Pinaceae
Poaceae
Rosaceae
Solanaceae
Nutritional links with fetal development and teratology
Minerals and vitamins
Manganese deficiency
Copper–molybdenum
Iodine deficiency
Vitamin A
Mycotoxins
Drugs
Prenatal and environmental influences—programing for life
Intrauterine growth
Environmental pollutants
Teratogenic viruses
Introduction
Aino virus
Akabane virus
Cache Valley virus
Rift Valley fever virus
Flaviviridae
Bovine virus diarrhea virus
Border disease virus
Hog cholera virus
Other teratogenic viruses
Diagnosing causation
Concluding remarks and future directions
References
72 - Reproductive and developmental toxicity in avian species
Introduction
Background
Mating behavior and nest building
Nesting territory, courtship, and mating behavior
Nest building and defense
Ovipositing and reproductive outcomes
Sex ratios
Fertility, eggshell formation, oviposition, clutch size, brooding, hatching, and fledgling
Eggshell thinning and reproductive performance
Incubation
Endocrine disruption
Generation effects and teratology
Skeletal defects
Soft tissue defects nervous system
Soft tissues and feathers
Toxicology of specific agents
Electromagnetic fields (EMFs)
Exposure to radionuclides
Reproductive effects of petroleum
Sensory pollution
Concluding remarks and future directions
References
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z
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