reproductive toxicology n.
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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
Effects Amplified
  • Lower doses  toxic effects
    • Repro system more sensitive to ~33% toxicants evaluated
  • Tox evaluation in males, nonpregnant females
female reproduction
Female Reproduction
  • Three structures
    • Hypothalamic-pituitary-gonadal axis
    • Ovary
    • Fallopian tube
hypothalamic pituitary gonadal axis
Hypothalamic-Pituitary-Gonadal Axis
  • Signals ovulation
  • Disrupted by
    • Xenobiotics
    • Excess hormones
    • Insufficient hormones
slide7
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
Ovary
  • Site of gamete maturation
  • Controls proliferation
    • Endometrium
    • Oviductal function
    • Uterus
slide12
Oocytes at birth
    • Suspended meiosis (birth to maturity)
  • Recruitment at maturity
  • Meiosis
  • Release at ovulation
slide13
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
slide14
Metabolic enzymes found within ovary
    • Microsomal monoxygenases
    • Epoxide hydrases
    • Transferases
slide15
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
Fallopian Tube, Uterus
  • Gamete propulsion, fertilization, implantation of embryo
  • Congenital structural problems
    • May be linked to xenobiotic exposure
    • Ex: DES
slide17
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
Male Reproduction
  • Sperm count decrease?
    • 1951 – 44% subjects > 100x106/mL
    • -- 5% < 20x106/mL
    • 1975 – 24% subjects > 100x106/mL
    • -- 7% < 20x106/mL
slide20
Other indicators decreasing following repro toxicants
    • Libido
    • Impotence
  • Forms fertile sperm, deliver to female tract
    • Must be functional
slide21
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
Testes
  • Convoluted seminiferous tubules arranged in lobules
  • Surrounded by interstitial cells (Leydig cells)
slide23
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
slide27
Sperm dev’t prior to release from Sertoli cells
    • Flagellum develops
    • Nucleus condenses
    • Acrosomal cap w/ digestive enzymes develops
hormones regulate testicular activity
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
slide32
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
Xenobiotics Affect Spermatogenesis
  • Toxicants selective for sperm dev’t stage(s)
  • DNA repair mech’s stage-specific
  • Sperm metabolism alteration may affect fertilizing capacity
slide34
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
slide35
DES
    • Hypoplastic testes
    • Microphallus
    • Cryptorchidism
    • Oligospermia
    • Azoospermia