Developmental Toxicity of 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) in the Most TCDD-Resistant and -Susceptible Rat Strains

Abstract

To gain insight into the relationship between TCDD acute toxicity and teratogenicity, developmental effects of TCDD were assessed in the most TCDD-resistant and -sensitive rat strains, Han/Wistar (Kuopio [H/W]; LD 50 > 7200 μg/kg) and Long-Evans (Turku AB [L-E]; LD 50 about 10 μg/kg), respectively. A single oral dose of 0, 1, or 10 μg/kg TCDD was given to mated female H/W rats on Gestation Day 8 or 12. In L-E rats, the doses were 0, 1, or 5 μg/kg TCDD and the exposure took place on Gestation Day 8. Fetuses were examined on Gestational Day 20 for external and soft tissue malformations. TCDD inhibited maternal body weight gain (corrected for weight of uterus with fetuses) at the 10 μg/kg dose in H/W rats and at 1 and 5 μg/kg in L-E rats. Absolute and relative thymus weights decreased dose-dependently in dams of both strains, but relative liver weights increased only in high-dose H/W dams and low-dose L-E dams. There was a striking interstrain difference in teratogenic outcomes. Over 70% of the live L-E fetuses at 5 μg/kg of TCDD exhibited cleft palate, while this effect did not occur in any H/W fetus. Conversely, hydronephrosis and gastrointestinal hemorrhaging appeared dose dependently in live H/W fetuses only. In L-E dams, the incidence of resorptions and late fetal deaths increased up to 75% at 5 μg/kg. Edematous dead fetuses and a slightly increased number of resorptions (together 35%) were found in H/W dams at 10 μg/kg. Fetal body weights and placental weights decreased at 5 μg/kg in L-E rats. In H/W rats, the weights of male placentas decreased at both doses of TCDD. Thus, sensitivity of adult rats to the acute lethal effect of TCDD does not correlate with susceptibility to its developmental toxicity.