Biologic Markers in Reproductive Toxicology

Publisher: National Academies Press
ISBN: 9780309039796
eISBN Pdf: 9780309568142
Place of publication: United States
Year of digital publication: 1989
Month: January
Pages: 420
Language: English

Caption

Does exposure to environmental toxicants inhibit our ability to have healthy children who develop normally? Biologic markers—indicators that can tell us when environmental factors have caused a change at the cellular or biochemical level that might affect reproductive ability—are a promising tool for research aimed at answering that important question. Biologic Markers in Reproductive Toxicology examines the potential of these markers in environmental health studies; clarifies definitions, underlying concepts, and possible applications; and shows the benefits to be gained from their use in reproductive and neurodevelopmental research.

Biologic Markers in Reproductive Toxicology
Copyright
Preface
Contents
Executive Summary
- ORGANIZATION OF THIS REPORT
- CONCEPTS AND DEFINITIONS
  - Markers of Exposure
  - Markers of Effect
  - Markers of Susceptibility
- EXTRAPOLATION FROM ANIMALS TO HUMANS
- QUALITY AND QUANTITY OF DATA
- BIOLOGIC MARKERS ASSOCIATED WITH REPRODUCTIVE AND NEURODEVELOPMENTAL TOXICOLOGY
- BIOLOGIC MARKERS ASSOCIATED WITH MALE REPRODUCTION
  - Markers of Physiologic Damage
  - Markers of Genetic Damage and Heritable Mutations
- BIOLOGIC MARKERS ASSOCIATED WITH FEMALE REPRODUCTION
  - Germ Cell Damage
  - Development and Aging
  - Cyclic Ovarian Function
  - Fertilization, Implantation, and Early Loss
- BIOLOGIC MARKERS ASSOCIATED WITH PREGNANCY
- BIOLOGIC MARKERS ASSOCIATED WITH NEURODEVELOPMENT
- GENERAL RECOMMENDATIONS AND CONCLUSIONS
1 Report of the Oversight Committee
- CONCEPTS AND DEFINITIONS
  - Biologic Markers of Exposure
  - Biologic Markers of Effect
  - Biologic Markers of Susceptibility
- PRINCIPLES OF SELECTION OF MARKERS
  - Biologic Considerations
  - Practical Limitations
  - Batteries of Biologic Markers
  - Ethical Issues
- VALIDATION OF BIOLOGIC MARKERS
  - Sensitivity and Specificity
  - Uses
  - Animal Models
  - Quality Assurance
  - Sensitivity of Measurements
  - Markers of Specific Exposures
- ECOLOGIC MARKERS
- USE OF BIOLOGIC MARKERS IN RISK ASSESSMENT
- EXTRAPOLATION FROM ANIMALS TO HUMANS
- QUALITY AND QUANTITY OF DATA
- IMPLEMENTATION OF BIOLOGIC MARKERS IN POPULATION STUDIES
- LONG-TERM TISSUE AND CELL STORAGE FOR RETROSPECTIVE ANALYSIS
- USE OF BIOLOGIC MARKERS IN REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY
  - Studies of Male Reproductive Toxicants
  - Studies of Female Reproductive Toxicants
  - Studies of Pregnancy Toxicants
  - Studies of Neurodevelopmental Toxicants
- SUMMARY
I Biologic Markers in Male Reproductive and Gametic Genetic Toxicology
- 2 Introduction
  - BIOLOGIC MARKERS OF MALE PHYSIOLOGIC DAMAGE
  - BIOLOGIC MARKERS OF GENETIC DAMAGE AND HERITABLE MUTATIONS IN HUMAN GERM CELLS
  - IMPORTANCE OF ANIMAL STUDIES IN MARKER DEVELOPMENT
  - ORGANIZATION OF MALE REPRODUCTION SECTION
- 3 Clinical Evaluation of Male Infertility
  - MEDICAL HISTORY
  - PHYSICAL EXAMINATION
  - SEMEN CHARACTERISTICS
- 4 Biologic Markers of Testicular Function
  - PHYSICAL AND CHEMICAL MARKERS OF TESTICULAR FUNCTION
    - Markers in Use
    - Markers Requiring Research and Development
  - LEYDIG CELLS
    - Markers in Use
    - Markers Requiring Research and Development
  - SEMINIFEROUS TUBULES
    - Sertoli Cells
      - Markers in Use
      - Markers Requiring Research and Development
    - Germ Cells
      - Markers in Use
      - Markers Requiring Research and Development
- 5 Biologic Markers of Epididymal Structure and Function
  - MARKERS OF EPIDIDYMAL TISSUE
  - CHANGES IN MATURING SPERMATOZOA
    - Structural Changes
    - Biochemical Changes
    - Functional Changes
      - Content of Epididymal Spermatozoa
      - Transport of Spermatozoa
      - Acquisition of Fertilizing Ability
      - Storage of Spermatozoa
  - EPIDIDYMAL LUMINAL FLUID
  - EPIDIDYMAL EPITHELIAL FUNCTION
    - Histology
      - Presence and Relative Distribution of Various Cell Types
      - Blood-Epididymis Barrier
      - Spermiophagy
    - Biochemical Markers
      - Hormone Receptors and Regulation of Epididymal Function
      - Steroid Biosynthesis and Metabolism
      - Intermediary Metabolism
  - EPIDIDYMALLY MEDIATED TOXIC DRUG EFFECTS
- 6 Biologic Markers of Accessory Sex Organ Structure and Function
  - PHYSICAL MARKERS
  - STRUCTURAL MARKERS
  - FUNCTIONAL MARKERS
- 7 Biologic Markers of Human Male Reproductive Health and Physiologic Damage
  - NEEDS FOR BIOLOGIC MARKERS OF HUMAN MALE REPRODUCTIVE HEALTH
  - EPIDEMIOLOGIC STUDIES OF HUMAN SPERM PRODUCTION AND FERTILITY
    - Epidemiologic Surveys of Fertility Status
    - Markers of Early Pregnancy
    - Cohort Studies with Semen and Blood Samples
  - HUMAN SPERMATOGENESIS AND DEVELOPMENT OF SEMEN-BASED MARKERS OF MALE REPRODUCTIVE HEALTH
  - PHYSICAL CHARACTERISTICS OF THE HUMAN EJACULATE
  - PRESENCE OF NONSPERM CELLS IN SEMEN
  - SPERM NUMBER
    - As Marker of Sperm Production
    - As Marker of Fertility Status
    - As Indicator of Exposure to Toxic Agents
    - Other Factors That Affect Sperm Number
  - SPERM STRUCTURE
    - As Marker of the Quality of Sperm Production
    - As Marker of Fertility Status
    - As Indicator of Exposure to Toxic Agents
    - Other Factors That Affect Sperm Structure
  - SPERM MOTILITY
    - As Marker of Sperm Function
    - As Marker of Fertility Status
    - As Indicator of Exposure to Toxic Agents
    - Other Factors That Affect Sperm Motility
  - SPERM VIABILITY
  - SPERM FUNCTION
    - Cervical-Mucus Penetration
    - Sperm-Oocyte Interaction
  - OTHER SPERM MEASUREMENTS
    - Sperm Agglutination
    - Nuclear Chromatin
    - Double F Bodies
  - CHEMICAL COMPOSITION OF SEMINAL FLUID
  - PROMISING RESEARCH CONCEPTS
    - Automated Sperm Measurements
      - Machine-Based Sperm-Motility Measurements
      - Quantitative Sperm Structure
      - General Considerations Regarding Automated Methods
    - Markers of Sperm Function
    - Immunologic Reagents for Studies of Semen and Spermatogenesis
      - Sperm Surface Domains
      - Components in the Sperm
      - Use of Antibodies for Studying Gene Expression
      - Antibodies for Characterizing Semen
  - SEMEN MARKERS OF SERTOLI CELL AND LEYDIG CELL FUNCTION
  - RECOMBINANT-DNA METHODS FOR STUDY OF HUMAN SPERMATOGENESIS AND SEMEN
- 8 Assessing Transmitted Mutations in Mice
  - ASSESSING MARKERS IN LABORATORY ANIMALS
  - MARKERS OF EXPOSURE
    - Cytotoxicity
    - Cytogenetic Effects
    - Biochemical Responses
    - Molecular Binding
    - Cellular Morphologic Responses
  - TESTS IN MICE TO DETERMINE TRANSMITTED GENETIC EFFECTS
    - Specific-Locus Test with Visible Markers
    - Specific-Locus Test with Biochemical Markers
    - Specific-Locus Test with Immunologic Markers (H Test)
    - Recessive Lethal Test
    - Dominant Lethal Test
    - Heritable-Translocation Test
    - Inversions
    - Sex-Chromosome Loss
    - Nondisjunction Test
    - Cytogenetic Analysis of Zygotes
    - Tests for Dominant Mutations
  - NEEDED RESEARCH ON GENETIC DAMAGE IN LABORATORY ANIMALS
    - Relationship Between Molecular Target Sites and Production of Various Types of Mutations
    - Molecular Nature and Expression of Mutations
    - Mutagen-Caused Induction of Integration of Endogenous Transposable Elements in New Sites
    - Mouse Mutants as Models of Human Genetic Diseases
    - Nondisjunction
    - DNA Methods
- 9 Markers for Measuring Germinal Genetic Toxicity and Heritable Mutations in People
  - CURRENT METHODS FOR MEASURING HUMAN HERITABLE MUTATIONS
    - Sentinel Phenotypes
    - Chromosomal Abnormalities
    - Prevalence of Chromosomal Abnormalities at Birth
    - Mutant Proteins
  - RESULTS OF EPIDEMIOLOGIC STUDIES OF HUMAN HERITABLE MUTATIONS IN EXPOSED POPULATIONS
    - Atomic Bomb Survivors
    - Survivors of Cancer Chemotherapy
    - Other Exposure Groups
  - HUMAN SOMATIC MUTATION METHODS
    - Detection of Somatic Mutations in White Blood Cells
    - Detection of Somatic Mutations in Red Blood Cells
  - NEW MOLECULAR APPROACHES FOR DETECTING HUMAN HERITABLE MUTATIONS
    - DNA Sequencing
    - Restriction-Fragment-Length Polymorphism (RFLP)
    - Ribonuclease Cleavage
    - Subtractive Hybridization
    - Pulse-Field Gel Electrophoresis
    - One-Dimensional Denaturing Gel Electrophoresis
    - Two-Dimensional Denaturing Gradient Gel Electrophoresis
  - TESTICULAR MARKERS OF HUMAN GERMINAL CYTOGENETIC DAMAGE
  - SEMEN MARKERS OF HUMAN GERMINAL MUTATIONS AND GENETIC TOXICITY
    - Cytogenetics of Human Sperm
    - Sperm-DNA Alkaline Elution
    - Specific-Locus Mutations in Sperm
    - DNA Adduction in Sperm
    - Aneuploidy Detection in Sperm
    - Cytogenetic Analysis of Meiotic Cells in Semen
    - Micronuclei in Seminal Spermatids
  - SUMMARY
- 10 Conclusions and Recommendations
  - IDENTIFICATION OF MARKERS OF ABNORMAL PHYSIOLOGIC FUNCTION
    - Testes
    - Epididymis
    - Accessory Sex Organs
  - SEMEN MARKERS OF ABNORMAL PHYSIOLOGIC FUNCTION
  - NEED FOR IMPROVED MEASURES OF FERTILITY STATUS AND EXPOSURE
  - IDENTIFICATION OF MARKERS OF GERMINAL GENETIC TOXICITY AND HERITABLE MUTATIONS
  - CRITERIA FOR DEVELOPMENT AND VALIDATION OF MARKERS OF MALE REPRODUCTION
  - STRATEGY FOR TESTING EFFECT OF TOXIC CHEMICALS ON MARKERS OF MALE REPRODUCTION
II Biologic Markers in Female Reproductive Toxicology
- 11 Introduction
  - OOGENESIS
  - DEVELOPMENT OF THE FEMALE REPRODUCTIVE TRACT
  - MATURATION
    - Hormonal Changes
    - Menarche
    - Adrenarche
    - Thelarche
  - CYCLIC OVARIAN FUNCTION
  - FERTILIZATION
  - REPRODUCTIVE SENESCENCE
- 12 Biologic Markers of Genetic Damage in Females
  - MARKERS OF EXPOSURE
  - MARKERS OF OOCYTE TOXICITY
  - MARKERS OF GENOTOXIC DAMAGE OR REPAIR
    - DNA Adducts
    - Unscheduled DNA Synthesis
    - Sister-Chromatid Exchange
  - MARKERS OF MUTATIONAL EVENTS
    - Laboratory Animals
    - Human Oocytes
    - Human Somatic Cells
      - Chromosomal Aberrations
      - Micronuclei
      - Specific-Locus Mutations
- 13 Biologic Markers of Reproductive Development and Aging
  - MARKERS OF MATURATION
    - Adrenarche
    - Ovary and Uterus
    - Menarche
    - Thelarche and Pubic Hair
  - MENSTRUATION
    - LOSS OF FERTILITY AND FECUNDITY
  - PRECOCIOUS MENOPAUSE
  - OVARIAN OOCYTE DEPLETION
  - HORMONES
    - Gonadotropins
    - Steroids
  - NERVOUS SYSTEM
    - Behavior
    - Cell Populations
  - OBSERVATIONS ON THE USE OF THESE MARKERS
    - Need for Multiple Biologic Markers
    - Differential Susceptibility of Individuals and Populations
    - Analysis of Menstrual Cycle Lengths
    - Long-Term Neurologic Consequences of Toxicant Exposure
- 14 Biologic Markers of Nonconceptive Menstrual Cycles
  - SPECIFIC MARKERS
    - Cyclicity
    - Character of Menstrual Flow
    - Detection of Corpus Luteum
      - Progesterone in the Peripheral Serum
      - Basal Body-Temperature Shift
      - Cervical Mucus Changes
      - Vaginal Cytology
      - Endometrial Histology
      - Secretion of Progesterone-Stimulated Endometrial Proteins into Uterine Lumen
    - Reproductive Endocrinology In Vivo
    - In Vitro Markers
  - BIOLOGIC RATIONALE
- 15 Developing Assays of Biologic Markers for Epidemiologic Studies: Experience with a Marker of Pregnancy and Early Loss
  - ASSAYS OF HCG
  - FIELD STUDIES OF EARLY FETAL LOSS: TESTING THE UTILITY OF THE HCG ASSAY
  - FUTURE ASSAY DEVELOPMENTS
    - Improved Methods for hCG Detection
    - New Monoclonal Antibodies for hCG Detection
    - Nonradioactive Methods for hCG Detection
    - Requirement to Measure Other Biologic Markers
    - OTHER CLINICAL OPPORTUNITIES
- 16 Conclusions and Recommendations
  - SPECIAL RESEARCH OPPORTUNITIES
  - SPECIFIC RESEARCH RECOMMENDATIONS
    - Germ Cell Damage
    - Sexual Differentiation
    - Puberty
    - Ovulation
    - Clinically Inapparent Loss
    - Ovarian Senescence
  - NATIONAL DATA BASE
    - EXPERIMENTAL STUDIES
III Biologic Markers of Toxicity During Pregnancy
- 17 Introduction
  - THE EVENTS OF PREGNANCY
  - MATERNAL PHYSIOLOGY
  - EMBRYONIC/FETAL CHANGES
  - PLACENTAL INVOLVEMENT
- 18 Molecular Biology: Developing DNA Markers of Genotoxic Effects
  - DETECTING HERITABLE GENETIC DAMAGE
  - MARKERS OF EXPOSURE
- 19 Reproductive Immunology: Biologic Markers of Compromised Pregnancies
  - MATERNAL IMMUNOLOGIC RECOGNITION AND REACTION DURING NORMAL PREGNANCY
  - TESTS TO DETERMINE MARKERS OF MECHANISMS OF RECURRENT PREGNANCY LOSS
    - Mixed-Lymphocyte-Culture Reactions
    - Lymphocytotoxic Antibodies and Histocompatibility Typing
    - Autoimmunity Tests
  - PROMISING MARKERS OF MATERNAL-FETAL INTERACTIONS
    - Trophoblast Antigens and Classes of Couples with Recurrent Spontaneous Abortions
    - Major Basic Protein
    - Early Pregnancy Factor
  - PROMISING TECHNIQUES THAT MIGHT YIELD BIOLOGIC MARKERS
    - Fluorescence-Activated Cell Sorting
    - Immunotherapy to Prevent Spontaneous Abortion
    - Immunopharmacology
- 20 Cell Biology: Identifying Biologic Markers Expressed During Early Pregnancy
  - IMPLANTATION
  - ASSESSING ENDOMETRIAL SIGNALS
    - Uterine Secretions
    - Uterine Epithelial Cells
    - Uterine Stromal Cells
    - Investigations of Cervix and Vagina
  - TROPHOBLAST BIOLOGIC MARKERS
    - Trophectoderm
    - Steroidogenesis
    - Trophoblast Giant Cells and Placental Hormones
    - Trophoblast Giant Cell Cytoskeleton
    - Ectoplacental Cone Cells
    - Regulation of Trophoblast Hormone Synthesis
  - EXTRAPOLATION TO HUMAN TROPHOBLASTS
    - Human Chorionic Gonadotropin
    - Placental Lactogens
    - Pregnancy-Associated Factors
- 21 Physiologic Assessment of Fetal Compromise
  - ULTRASONOGRAPHY
  - AMNIOCENTESIS
  - CHORIONIC VILLUS SAMPLING
  - FETOSCOPY
  - FETAL BLOOD AND TISSUE SAMPLING
  - MEASURING FETAL BODY AND BREATHING MOVEMENTS
  - ELECTRONIC FETAL HEART-RATE MONITORING
  - BIOPHYSICAL PROFILE
  - MAGNETIC RESONANCE IMAGING
- 22 Biologic Markers of Exposure During Pregnancy: Pharmacokinetic Assessments
  - ASSESSMENTS FOR PHARMACOKINETIC ANALYSES
  - CURRENT AND PROMISING MARKERS
- 23 Conclusions and Recommendations
  - RESEARCH STRATEGIES
  - ACCOMPLISHING THE RESEARCH GOAL
  - BRINGING THE ASSAY OUT OF THE LABORATORY AND INTO THE PUBLIC HEALTH DOMAIN
  - ASSESSMENTS OF THE STATUS OF SPECIFIC MARKERS RELATED TO PREGNANCY
    - Markers of Effect Before and Around Implantation
    - Organogenesis
    - The Fetal and Neonatal Period
  - MARKERS OF EXPOSURE
IV Biologic Markers in Neurodevelopmental Toxicology
- 24 Introduction
  - BIOLOGIC MARKERS OF EXPOSURE: PHARMACOKINETIC CONSIDERATIONS
  - BIOLOGIC MARKERS OF EFFECT: PHARMACODYNAMIC CONSIDERATIONS
    - Markers in the Mother
    - Placental Markers
    - Markers in the Newborn
    - Markers in Children
- 25 Developmental Neurobiology of the Central Nervous System
  - BASIC MORPHOGENESIS
  - BASIC CYTOGENESIS
    - Development of Major Subdivisions
    - Specific Development of Neuronal Type
  - NEUROCHEMISTRY OF NEURONAL COMMUNICATION
- 26 Morphologic, Neurochemical, and Behavioral Responses to Toxic Agents
  - EFFECTS OF TIME OF EXPOSURE AND DOSE: IRRADIATION AS A PARADIGM
  - MICRONEURONAL RADIATION
    - Cerebellum
    - Hippocampus
  - APPLICATION TO OTHER TOXIC SUBSTANCES
  - RELATIONSHIP BETWEEN MINOR PHYSICAL ANOMALIES AND BEHAVIORAL EFFECTS
  - NEUROCHEMICAL EFFECTS
  - BEHAVIORAL EFFECTS
- 27 Methodologic Issues of Extrapolation from Animal Studies to Human Toxicant Exposure
  - INVESTIGATION OF UNDERLYING MECHANISMS
  - STUDY OF COMPARABLE FUNCTIONAL END
  - DIRECT COMPARISONS BETWEEN ANIMALS AND HUMANS
  - DATA INTERPRETATION
- 28 Lead as a Paradigm for the Study of Neurodevelopmental Toxicity
  - MARKERS OF EXPOSURE TO LEAD
    - Surrogate Markers
    - Blood Lead
    - Hair Lead
    - Erythrocyte Protoporphyrin
    - Chelatable Lead
    - Bone Lead
    - Tooth Lead
    - X-ray Fluorescence of Bone
  - MARKERS OF EFFECT
  - MARKERS OF SUSCEPTIBILITY
  - METHODOLOGIC CONSIDERATIONS IN THE ESTABLISHMENT AND EVALUATION OF MARKERS OF DEVELOPMENT
    - Differentiating Markers of Exposure and Effect
  - ADVERSE HEALTH EFFECTS
    - Causal Inferences in Toxicant Exposure
- 29 Conclusions and Recommendations
  - MODELS OF NEURODEVELOPMENT
  - NEUROENDOCRINE AND NEUROIMMUNOLOGIC MARKERS
    - Nervous System-Endocrine Interactions
    - Nervous System-Immune System Interactions
  - NEUROCHEMICAL MARKERS
    - Recent Advances in Neurochemical Methods
    - Surrogate Cell Systems
Appendix
Appendix Assessing the Validity of Biologic Markers: Alpha-Fetoprotein
- ASSESSING THE VALIDITY OF BIOLOGIC MARKERS
  - VALIDITY OF MATERNAL SERUM AFP MEASUREMENT AS A BIOLOGIC MARKER OF NTDs
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