Acute administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in pregnant Long Evans rats: association of measured tissue concentrations with developmental effects.
Prenatal exposure to TCDD interferes with fetal development at doses lower than those causing overt toxicity in adult animals. Exposure to TCDD during development produces alterations in the reproductive system of the developing pups- delayed puberty and reduced sperm counts in males and malformations in the external genitalia of females. The objectives of this study were to determine maternal and fetal tissue concentrations of TCDD after acute exposure and whether these tissue concentrations can be used to estimate the intensity of the developmental abnormalities reported by other laboratories. Pregnant Long Evans rats received a single, oral dose of 0.05, 0.20, 0.80, or 1.0 microg [3H]-TCDD/kg on gestation day (GD) 15, and maternal and fetal tissue concentrations of TCDD were measured on GD16 and GD21. On GD16, maternal liver contained the greatest amount of TCDD (30-47% administered dose). One day after administration of 0.20 microg TCDD/kg on GD15, there were 13.2 pg TCDD/g present in an individual fetus. This concentration is associated with delayed puberty and decreased epididymal sperm counts in male pups as well as malformations in the external genitalia of females. For the responses studied, tissue concentration measured during a critical period of gestation adequately predicts the intensity of the response. In addition, there was a strong correlation between fetal body burden and maternal body burden on GD16. A dose of 0.05 microg TCDD/kg resulted in maternal body burdens of 30.6+/-3.1 and 26.6+/-3.1 ng TCDD/kg on GD16 and GD21, respectively. In conclusion, low-level TCDD exposure during the perinatal stage of life can produce adverse effects within the developing pups and that tissue concentration measured during a critical period is the appropriate dose metric to predict adverse reproductive and developmental effects.
Hurst
C H
CH
Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599-7270, USA. hurst.christopher@epamail.epa.gov
DeVito
M J
MJ
Setzer
R W
RW
Birnbaum
L S
LS
D000818:Animals; D001822:Body Burden; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development; D005260:Female; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics* / Q000633:toxicity; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D013076:Sperm Count / Q000187:drug effects; D013723:Teratogens / Q000493:pharmacokinetics* / Q000633:toxicity; D013737:Testis / Q000187:drug effects / Q000196:embryology; D014018:Tissue Distribution; D014521:Urethra / Q000187:drug effects / Q000196:embryology; D014621:Vagina / Q000187:drug effects / Q000196:embryology
D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens