Time-course of low dose effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin in female Sprague-Dawley rats

To define the dose- and time-response of CYP1A1 induction after the administration of TCDD and HxCDD at kinetic steady state, CYP1A1 mRNA, protein and EROD activity were measured. Low doses of both TCDD and HxCDD slightly increased body weight, whereas the highest dose of each compound consistently decreased body weight. Higher doses of both TCDD and HxCDD dose-dependently increased relative and absolute liver weights with a time-dependence only at the highest dose of each compound administered. Hepatic CYP1A1 mRNA, protein and EROD activity were dose-dependently induced with both TCDD and HxCDD. A LOEL of 0.0125/0.3125 mug/kg TCDD/HxCDD loading dose rate was determined for CYP1A1 mRNA and EROD activity. There was no effect of time on hepatic CYP1A1 mRNA, protein, or EROD activity with either TCDD or HxCDD administration, with the exception of the group receiving 0.05 mug/kg TCDD as a loading dose rate.; A half-life of 21 and 69 days for TCDD and HxCDD, respectively, was calculated from GC-MS analysis of livers after administration of the final dose of the two dioxins. Body weights of TCDD- and HxCDD-treated rats gradually increased 64 days after cessation of dosing. Reversibility of CYP1A1 induction following cessation of dosing of TCDD and HxCDD was driven by both kinetics and dynamics. There was a 16--32 day lag period during the initial phase of recovery that was driven by kinetics. However, after the lag period, the reversibility of the effects was decoupled from kinetics and was driven by dynamics. The slopes of the reversibility of CYP1A1 induction at the levels of mRNA, protein and activity were very similar (half-life of 60--80 days) for both TCDD and HxCDD.; In addition to enzyme induction, TCDD and related congeners are also known to have effects on intermediary metabolism. Low doses of TCDD and HxCDD (3.2 and 80 mug/kg loading dose rates, respectively) decreased circulating total thyroxine and insulin-like growth factor-I, began to inhibit hepatic phosphoenolpyruvate carboxykinase activity and increased hepatic p-AMP kinase protein, while not affecting circulating insulin or glucose. At a dose which decreased body weight, the life of female rats was prolonged and reproductive capacity was reduced due to reduced IGF-I signaling.