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 crucial time

Male Reproduction Sperm count decrease? –1951 – 44% subjects > 100x10 6 /mL – -- 5% < 20x10 6 /mL –1975 – 24% subjects > 100x10 6 /mL – -- 7% < 20x10 6 /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 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