Reproductive Toxicology Effects Amplified Lower doses toxic effects

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 > 100 x 106/m. L – -- 5% < 20 x 106/m. L – 1975 – 24% subjects > 100 x 106/m. L – -- 7% < 20 x 106/m. L

• 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 • Gn. RH (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 Gn. RH, 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 P 450’s, GSH transferase, other enz’s found – Metabolites may be toxic

• DES – Hypoplastic testes – Microphallus – Cryptorchidism – Oligospermia – Azoospermia