Extent of the Problem
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Transcript of Extent of the Problem
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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.
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Causes of Reproductive Toxicity
• Inhibition of spermatogenesis or oogenesis, maturation or motility.
• Hormonal imbalance• Behavioral toxicity• Developmental toxicity
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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,
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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
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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
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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
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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.
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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
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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
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