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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
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