Reproductive

Toxicology

Developmental Toxicity

Occurrence of adverse effects on the developing organism occurring anytime during the lifetime of the organism that may result from exposure to environmental agents prior to conception (either parent), during prenatal development, or postnatally until the time of puberty.

Sequence of Human Development

1 2 3 4 5 6 7 8 12 16 20 38

ImplantationPrenatal

Death

Emryonic period

Major Morphological abnormalities

Fetal PeriodPhysiological and Functional

Defects

Central Nervous System

Heart

Ears

Eyes

Limbs

Palate

External Genetalia

Red - most sensitive, Gray - Less

Reproduction – issues associated with the egg and sperm

Pregnancy – the critical environment of early development

Development of the infant.

Three Areas

Many ancient cultures had fertility goddess

Many ancient documentation of malformations

Malformations rich aspect of mythology 6500 BC – Turkey - figurine of

conjoined twins 4000-5000 BC – Australia drawings of

twins 2000 BC - Tablet of Nineveh –

describes 62 malformations and predicts the future

Ancient Awareness

15th-16th centuries malformations caused by the Devil, mother and child killed

1830’s - Etienne Geoffroy Saint-Hilaire experimented with chicken eggs

1900’s began acceptance of malformations related to genetics

1940’s - Josef Warkany – environmental factors affect rat development

Historical Awareness

1941 – Human malformations linked to rubella virus

1960’s – Thalidomide (a sedative and anti-nausea drug) found to cause human malformations

1950’s – Methylmercury recognized as developmental toxicant

1970’s – Alcohol related to developmental effects – Fetal Alcohol Syndrome (FAS)

Historical Events

• Approximately 80,000 chemicals listed by EPA

• Most of these chemicals have not been tested for developmental toxicity

• For example, High Production Volume (HPV) Chemicals

• Chemicals produced at >1 million lbs/year• Approximately 3,000 chemicals

identified internationally• Few tested for both reproductive and

developmental toxicity

Current Chemical Facts

• 50% of pregnancies end in miscarriage or spontaneous abortion often before pregnancy is recognized

• 15% of couples of reproductive age are infertile

Human Reproductive Facts

• The occurrence of biologically adverse effects on the reproductive systems of females or males that may result from exposure to environmental agents.

• The toxicity may be expressed as alterations to the female or male reproductive organs, the related endocrine system, or pregnancy outcomes.

Reproductive Toxicity

Reproductive EndpointsREPRODUCTIVE ToxicityReproductive toxicity involves toxic damage to either male or female reproductive system. Toxic effects may causeDecrease LIBIDO and IMPOTENCEINFERTILITYInterrupted pregnancy ( abortion, fatal death, or premature delivery)Infant death or childhood morbidityAltered sex ratio and multiple birthChromosome abnormalities and birth defectsChildhood cancer.

Endocrine disruptorsDDT, Dioxin, Phthalates

Heavy metalsLead (decreased sperm)

Organic SolventsToluene, benzene

DrugsAlcohol

Reproductive Toxicants

• Cardiovascular• Increased - cardiac output heart rate,

blood pressure, blood volume expands • Oxygen consumption increases by

15-20%• Urine volume increases• Gut absorption changes

• Increases in iron and calcium (toxic lead substitutes for calcium)

• Liver metabolism decreases for some drugs or chemicals (caffeine)

Pregnancy Effects the Women

Teratology (physical malformations)

Birth weight Growth Neurobehavioral

Decreased intelligence Decreases learning and

memory

Developmental Endpoints

Effects Amplified

Lower doses toxic effectsRepro system more sensitive to ~33%

toxicants evaluated

Female Reproduction

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

Hypothalamic-Pituitary-Gonadal Axis

Signals ovulationDisrupted by

XenobioticsExcess hormonesInsufficient hormones

Cyclic production of gonadotropins

› 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

› PAH= Polycyclic aromatic hydrocarbons

Activation of some toxins reactive intermediates

Ex: DES- Diethylstilbestrol activation› Harmful to developing fetus› infertility in mature females

Ex: Benzopyrene› 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› DES- Diethylstilbestrol

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

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

› 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)› 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 (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.› Metabolites may be toxic

DES -Diethylstilbestrol

› Hypoplastic testes› Microphallus› Cryptorchidism› Oligospermia› Azoospermia