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Reproductive Toxicology - PowerPoint PPT Presentation
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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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Presentation Transcript
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
