1 / 35

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.

ulric-baker
Télécharger la présentation

Reproductive Toxicology

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related