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Reproductive Toxicology

Reproductive Toxicology. Effects Amplified. Lower doses  toxic effects Repro system more sensitive to ~33% toxicants evaluated Tox evaluation in males, nonpregnant females. Female Reproduction. Three structures Hypothalamic-pituitary-gonadal axis Ovary Fallopian tube.

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Reproductive Toxicology

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  1. Reproductive Toxicology

  2. Effects Amplified • Lower doses  toxic effects • Repro system more sensitive to ~33% toxicants evaluated • Tox evaluation in males, nonpregnant females

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

  4. Hypothalamic-Pituitary-Gonadal Axis • Signals ovulation • Disrupted by • Xenobiotics • Excess hormones • Insufficient hormones

  5. Cyclic production of gonadotropins • Urgent for reproduction • 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

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

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

  8. Primary oocytes during suspended meiosis • Susceptible to drugs, environmental agents • PAH’s toxic to ovary, oocytes • Dose toxic to mouse oocytes sim to mutagenic/carcinogenic dose • Dependent on strain, species, age, dose, metabolism • Some agents act indirectly • DES, DDT structural analogs of endogenous substances

  9. Metabolic enzymes found within ovary • Microsomal monoxygenases • Epoxide hydrases • Transferases

  10. Activation of some toxins  reactive intermediates • Ex: DES activation • Harmful to developing fetus •  infertility in mature females • Ex: Benzo(a)pyrene • Systemic and ovarian metabolism • Some metabolites ootoxic • Cigarette smoking linked to disruption reproduction

  11. Fallopian Tube, Uterus • Gamete propulsion, fertilization, implantation of embryo • Congenital structural problems • May be linked to xenobiotic exposure • Ex: DES

  12. 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

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

  14. Other indicators decreasing following repro toxicants • Libido • Impotence • Forms fertile sperm, deliver to female tract • Must be functional

  15. Ex: Nematocide 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 • Extrapolation from animal to human unfortunate • Recovery w/in 18-21 mos

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

  17. 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

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

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

  20. Testosterone • Spermatogenesis progression, maturation, maintenance • Accessory sex glands • Negative feedback to anterior pituitary • Alterations • Anesthetics, stimulants, drugs of abuse • Alter hypothal-pit-gonadal axis (so GnRH, FSH, LH) • Exogenous steroids, alcohol • Interfere w/ steroid metabolism • May affect hormonal balance

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

  22. Cd • Testicular necrosis • Concentrates in interstitial tissues • Polyaromatic Hydrocarbons • Metabolized in testes • Cyt P450’s, GSH transferase, other enz’s found • Metabolites may be toxic

  23. DES • Hypoplastic testes • Microphallus • Cryptorchidism • Oligospermia • Azoospermia

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