Reproductive Toxicology - PowerPoint PPT Presentation

Reproductive Toxicology

• Lower doses  toxic effects
• Repro system more sensitive to ~33% toxicants evaluated
• Tox evaluation in males, nonpregnant females

• Three structures
• Hypothalamic-pituitary-gonadal axis
• Ovary
• Fallopian tube

• Signals ovulation
• Disrupted by
• Xenobiotics
• Excess hormones
• Insufficient hormones

• 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

• Site of gamete maturation
• Controls proliferation
• Endometrium
• Oviductal function
• Uterus

• Suspended meiosis (birth to maturity)
• Recruitment at maturity
• Meiosis
• Release at ovulation

• 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

• Microsomal monoxygenases
• Epoxide hydrases
• Transferases

• 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

• Gamete propulsion, fertilization, implantation of embryo
• Congenital structural problems
• May be linked to xenobiotic exposure
• Ex: DES

• Xenobiotics??
• Unexplained infertility
• Preimplantation embryo in oviduct
• Signals endometrium biochemically
• Site for interruption 
• Disruption implantation
• Improper hormones
• Improper hormone levels @ crucial time

• Sperm count decrease?
• 1951 – 44% subjects > 100x106/mL
• -- 5% < 20x106/mL
• 1975 – 24% subjects > 100x106/mL
• -- 7% < 20x106/mL

• Libido
• Impotence
• Forms fertile sperm, deliver to female tract
• Must be functional

• 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

• Convoluted seminiferous tubules arranged in lobules
• Surrounded by interstitial cells (Leydig cells)

• 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

• Flagellum develops
• Nucleus condenses
• Acrosomal cap w/ digestive enzymes develops

• 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

• 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

• Toxicants selective for sperm dev’t stage(s)
• DNA repair mech’s stage-specific
• Sperm metabolism alteration may affect fertilizing capacity

• Testicular necrosis
• Concentrates in interstitial tissues
• Polyaromatic Hydrocarbons
• Metabolized in testes
• Cyt P450’s, GSH transferase, other enz’s found
• Metabolites may be toxic

• Hypoplastic testes
• Microphallus
• Cryptorchidism
• Oligospermia
• Azoospermia