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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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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
Hypothalamic-Pituitary-Gonadal Axis • Signals ovulation • Disrupted by • Xenobiotics • Excess hormones • Insufficient hormones
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
Ovary • Site of gamete maturation • Controls proliferation • Endometrium • Oviductal function • Uterus
Oocytes at birth • Suspended meiosis (birth to maturity) • Recruitment at maturity • Meiosis • Release at ovulation
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
Metabolic enzymes found within ovary • Microsomal monoxygenases • Epoxide hydrases • Transferases
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
Fallopian Tube, Uterus • Gamete propulsion, fertilization, implantation of embryo • Congenital structural problems • May be linked to xenobiotic exposure • Ex: DES
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
Male Reproduction • Sperm count decrease? • 1951 – 44% subjects > 100x106/mL • -- 5% < 20x106/mL • 1975 – 24% subjects > 100x106/mL • -- 7% < 20x106/mL
Other indicators decreasing following repro toxicants • Libido • Impotence • Forms fertile sperm, deliver to female tract • Must be functional
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
Testes • Convoluted seminiferous tubules arranged in lobules • Surrounded by interstitial cells (Leydig cells)
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
Sperm dev’t prior to release from Sertoli cells • Flagellum develops • Nucleus condenses • Acrosomal cap w/ digestive enzymes develops
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
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
Xenobiotics Affect Spermatogenesis • Toxicants selective for sperm dev’t stage(s) • DNA repair mech’s stage-specific • Sperm metabolism alteration may affect fertilizing capacity
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
DES • Hypoplastic testes • Microphallus • Cryptorchidism • Oligospermia • Azoospermia