reproductive toxicology. effects amplified lower doses toxic effects –repro system more sensitive...

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