2,3,7,8-Tetrachlorodibenzo-p-dioxin in Pregnant Long Evans Rats: Disposition to Maternal and Embryo/Fetal Tissues

Abstract

Prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interferes with fetal development at doses lower than those causing overt toxicity in adult animals. In a multigeneration study (Murray et al., 1979), female rats that were administered 0.01 microgram TCDD/kg/day in their diet did not experience reduced fertility; however, reduced fertility was seen in the F1 and F2 generations. Exposure to TCDD during development produces alterations in the reproductive system of the developing pups, such as delayed puberty and reduced sperm counts in males (Mably et al., 1992a; Gray et al., 1995) and malformations in the external genitalia of females (Gray and Ostby, 1995). Therefore, the objectives of this study were to determine maternal and fetal tissue concentrations of TCDD that are associated with the adverse reproductive effects seen by Gray and co-workers. Pregnant Long Evans rats received a single oral dose of 1.15 micrograms [3H]TCDD/kg on Gestation Day (GD) 8 and maternal as well as fetal tissue concentrations of TCDD were measured on GD9, GD16, and GD21. On GD9, the highest level of TCDD localized in the maternal liver (25.1% dose). In addition, the amount reaching all the embryos on GD9 was 0.01% of the administered dose, which resulted in a concentration of 0.02% dose/g. The amount of TCDD reaching the fetal compartment (fetuses + placentas) increased to 0.12% dose/tissue on GD16 and 0.71% by GD21. The concentration of TCDD within the fetal compartment (0.01% dose/g) on GD16 was comparable to that found in the maternal blood and spleen. Concentrations of TCDD in a single embryo/fetus were 39.6, 18.1, and 22.1 pg/g on GD9, GD16, and GD21, respectively. Estimates of hepatic half-life of elimination in pregnant rats suggested that TCDD may be eliminated faster in pregnant LE rats. Therefore, measurements of biliary elimination were made in pregnant and nonpregnant LE rats to compare rates of metabolism; however, biliary elimination of TCDD is not affected by pregnancy. In conclusion, this dose administered during a critical period of organogenesis causes adverse effects on the developing reproductive system of rodents. This dose produced a body burden of 22.1 pg TCDD/g within a single fetus on GD21. This indicates that low-level TCDD exposure during the perinatal stage of life can produce adverse effects within the developing pups.