Extent of the Problem

• Approximately 10% of couples are infertile.• Nearly half of all pregnancies do not result in the

birth of a normal child.• One in 33 babies is born with a major birth defect.• An additional 15-25% of babies have minor

defects or functional defects.• The effects of environmental agents are largely

unknown, but may have some interaction with 3-50% of birth defects.

Causes of Reproductive Toxicity

• Inhibition of spermatogenesis or oogenesis, maturation or motility.

• Hormonal imbalance• Behavioral toxicity• Developmental toxicity

Male Reproductive Toxicity

• Male germ cells are continuously produced, but take weeks to mature.

• Toxicity to a single stage of developing sperm will only be picked up if breeding is followed over the period of maturation.

• The number of sperm in rodents is much greater than in humans. Rodents can successfully breed with 70-90% decreases in sperm.

• Humans have much less reserve and can suffer from infertility with smaller decreases,

Testis Wt. (g)Testis Wt. (g) 3434 4949 33..77 66..44

Efficiency of Sperm Efficiency of Sperm Production (10 Production (10 / g )/ g ) 4.44.4 2323 2424 2525

Sperm Production Per Sperm Production Per Male (10 )Male (10 ) 125125 11001100 8686 160160

Sperm in Caudae Sperm in Caudae Epididymis (10Epididymis (10 ) ) 420420 57005700 440440 16001600

66

66

66

Sertoli cellsABPLEYDIG

CELLS

BLOODVESSEL

SEMINIFEROUSTUBULE

ABPANDROGEN

ANTERIORPITUITARY

GnRH

HYPOTHALMUS

LH

FSH

Stimulates synthesis of ABP and E

Stimulatessynthesis of T

Negative feedbackof T and E on the hypothalmus

T and E

T E

ABP

PROXIMAL CAUDAPROXIMAL CAUDA( First site of Fertilizing Ability )( First site of Fertilizing Ability )

DISTAL CAUDADISTAL CAUDA

CORPUSCORPUS

CAPUTCAPUT

TRANSIT TIMETRANSIT TIME= 4 DAYS= 4 DAYS

INTACT ( EDS, CEMS, EPI )INTACT ( EDS, CEMS, EPI )CASTRATED + T ( HFLUT )CASTRATED + T ( HFLUT )

EPIDIDYMISEPIDIDYMIS

TRANSPORTTRANSPORTSTORAGESTORAGE

MATURATIONMATURATION

MOTILITYMOTILITY

FERTILIZINGFERTILIZINGABILITYABILITY

NORMALNORMALDEVELOPMENTDEVELOPMENT

Female Reproductive Toxicity

• Females have all their germ cells at birth.• The ovulatory cycle is under hypothalamic

control.• Reproductive senescence in humans arises

from a lack of oocytes, whereas in rodents it is due to hypothalamic-controlled constant estrus or pseudopregnancy.

Reproductive Toxicity• Chemicals and drugs are tested for their ability to

cause reproductive or developmental toxicity.– Segment I: Tests for effects on fertilization and

implantation– Segment II: Evaluates effects on developmental

toxicity– Segment III: Evaluates effects on parturation, birth,

lactation and early development• Two Generation Study

– Evaluates fertilization through early development of two generations

Developmental Toxicology• Altered survival (death)

– Prenatal– Postnatal

• Morphological alterations– Malformations– Variations

• Developmental delays– Growth– Skeletal development– Neurodevelopment– Acquisition of developmental landmarks

• Functional deficits– Biochemical– Sexual development– Behaviorial