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Reproductive Toxicology

Reproductive Toxicology. Developmental Toxicity.

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Reproductive Toxicology

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  1. Reproductive Toxicology

  2. Developmental Toxicity Occurrence of adverse effects on the developing organism occurring anytime during the lifetime of the organism that may result from exposure to environmental agents prior to conception (either parent), during prenatal development, or postnatally until the time of puberty.

  3. Sequence of Human Development Red - most sensitive, Gray - Less

  4. Three Areas • Reproduction – issues associated with the egg and sperm • Pregnancy – the critical environment of early development • Development of the infant.

  5. Ancient Awareness • Many ancient cultures had fertility goddess • Many ancient documentation of malformations • Malformations rich aspect of mythology • 6500 BC – Turkey - figurine of conjoined twins • 4000-5000 BC – Australia drawings of twins • 2000 BC - Tablet of Nineveh – describes 62 malformations and predicts the future

  6. Historical Awareness • 15th-16th centuries malformations caused by the Devil, mother and child killed • 1830’s - Etienne Geoffroy Saint-Hilaire experimented with chicken eggs • 1900’s began acceptance of malformations related to genetics • 1940’s - Josef Warkany – environmental factors affect rat development

  7. Historical Events • 1941 – Human malformations linked to rubella virus • 1960’s – Thalidomide (a sedative and anti-nausea drug) found to cause human malformations • 1950’s – Methylmercury recognized as developmental toxicant • 1970’s – Alcohol related to developmental effects – Fetal Alcohol Syndrome (FAS)

  8. Current Chemical Facts • Approximately 80,000 chemicals listed by EPA • Most of these chemicals have not been tested for developmental toxicity • For example, High Production Volume (HPV) Chemicals • Chemicals produced at >1 million lbs/year • Approximately 3,000 chemicals identified internationally • Few tested for both reproductive and developmental toxicity

  9. Human Reproductive Facts • 50% of pregnancies end in miscarriage or spontaneous abortion often before pregnancy is recognized • 15% of couples of reproductive age are infertile

  10. Reproductive Toxicity • The occurrence of biologically adverse effects on the reproductive systems of females or males that may result from exposure to environmental agents. • The toxicity may be expressed as alterations to the female or male reproductive organs, the related endocrine system, or pregnancy outcomes.

  11. Reproductive Endpoints REPRODUCTIVE Toxicity Reproductive toxicity involves toxic damage to either male or female reproductive system. Toxic effects may cause Decrease LIBIDO and IMPOTENCE INFERTILITY Interrupted pregnancy ( abortion, fatal death, or premature delivery) Infant death or childhood morbidity Altered sex ratio and multiple birth Chromosome abnormalities and birth defects Childhood cancer.

  12. Reproductive Toxicants • Endocrine disruptors • DDT, Dioxin, Phthalates • Heavy metals • Lead (decreased sperm) • Organic Solvents • Toluene, benzene • Drugs • Alcohol

  13. Pregnancy Effects the Women • Cardiovascular • Increased - cardiac output heart rate, blood pressure, blood volume expands • Oxygen consumption increases by 15-20% • Urine volume increases • Gut absorption changes • Increases in iron and calcium (toxic lead substitutes for calcium) • Liver metabolism decreases for some drugs or chemicals (caffeine)

  14. Developmental Endpoints • Teratology (physical malformations) • Birth weight • Growth • Neurobehavioral • Decreased intelligence • Decreases learning and memory

  15. Effects Amplified Lower doses  toxic effects Repro system more sensitive to ~33% toxicants evaluated

  16. Female Reproduction • Three structures • Hypothalamic-pituitary-gonadal axis • Ovary • Fallopian tube

  17. Hypothalamic-Pituitary-GonadalAxis Signals ovulation Disrupted by Xenobiotics Excess hormones Insufficient hormones

  18. Cyclic production of gonadotropins • FSH, LH, prolactin produced, released • Feedback loops controlled by endogenous hormones • BUT environmental chemicals can influence feedback loops Neuronal influences • Affected by anesthetics, cannabinols, sedatives

  19. Ovary • Site of gamete maturation • Controls proliferation • Endometrium • Oviductal function • Uterus

  20. Oocytes at birth • Suspended meiosis (birth to maturity) • Recruitment at maturity • Meiosis • Release at ovulation

  21. Primary oocytes during suspended meiosis • Susceptible to drugs, environmental agents • PAH’s toxic to ovary, oocytes • Dose toxic to mouse oocytessim to mutagenic/carcinogenic dose • Dependent on strain, species, age, dose, metabolism • Some agents act indirectly • DES, DDT • PAH= Polycyclic aromatic hydrocarbons

  22. Activation of some toxins  reactive intermediates Ex: DES- Diethylstilbestrolactivation • Harmful to developing fetus •  infertility in mature females Ex: Benzopyrene • Systemic and ovarian metabolism • Some metabolites ootoxic • Cigarette smoking linked to disruption reproduction

  23. Fallopian Tube, Uterus • Gamete propulsion, fertilization, implantation of embryo • Congenital structural problems • May be linked to xenobiotic exposure • DES- Diethylstilbestrol

  24. Hormonal imbalance, immunologic alterations • Xenobiotics?? • Unexplained infertility • Preimplantation embryo in oviduct • Signals endometrium biochemically • Site for interruption  • Disruption implantation • Improper hormones • Improper hormone levels @ crucial time

  25. Male Reproduction • Sperm count decrease? • 1951 – 44% subjects > 100x106/mL • -- 5% < 20x106/mL • 1975 – 24% subjects > 100x106/mL • -- 7% < 20x106/mL

  26. Other indicators decreasing following repro toxicants • Libido • Impotence FORMSfertile sperm, deliver to female tract • Must be functional

  27. DiBromoChloroPropane (DBCP) (1970’s) • Azoospermia • Oligospermia • Incr’d plasma LH, FSH • Atrophy seminiferous tubular epithelium • Human testes affected • Sim in lab animals, but to lesser extent • Recovery w/in 18-21 mos

  28. Testes • Convoluted seminiferous tubules arranged in lobules • Surrounded by interstitial cells (Leydig cells)

  29. Lined w/ • Germ cells • Proliferative • Mature to spermatozoa • Migrate basement membr  tubule lumen w/ maturation • Sertoli cells • “Hold” sperm • Form blood-testis barrier • Help protect sperm from some toxicants

  30. Sperm dev’t prior to release from Sertoli cells • Flagellum develops • Nucleus condenses • Acrosomal cap w/ digestive enzymes develops

  31. Hormones Regulate Testicular Activity • GnRH (hypothalamus) • FSH • From anterior pituitary • Required to initiate spermatogenesis • LH • From anterior pituitary • Stim’s testosterone synth/release from Leydig cells

  32. Testosterone • Spermatogenesis progression, maturation, maintenance • Accessory sex glands • Negative feedback to anterior pituitary • Alterations • Anesthetics, Stimulants, Drugs of Abuse • Alter hypothal-pit-gonadal(so GnRH, FSH, LH) • Exogenous Steroids, Alcohol • Interfere w/ steroid metabolism • May affect hormonal balance

  33. Xenobiotics Affect Spermatogenesis • Toxicants selective for sperm dev’t stage(s) • DNA repair mech’s stage-specific • Sperm metabolism alteration may affect fertilizing capacity

  34. Cd • Testicular necrosis • Concentrates in interstitial tissues • Polyaromatic Hydrocarbons • Metabolized in testes • CytP450’s. • Metabolites may be toxic

  35. DES -Diethylstilbestrol • Hypoplastic testes • Microphallus • Cryptorchidism • Oligospermia • Azoospermia

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