Effects of thyroid hormones on the induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6N mice.

The induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administered with thyroid hormones triiodothyronine (T3) or thyroxine (T4) was investigated in C57BL/6N mice. Timed-pregnant mice were treated with vehicle, TCDD, T3, T4, TCDD plus T3, or TCDD plus T4 on Days 10 to 13 of gestation. No cleft palates were observed in any control fetuses in this study, nor have there been any cleft palates in 1193 fetuses or 154 control litters in the past 24 months. TCDD (3 micrograms/kg/day) caused about 8% cleft palates per litter, while T3 (120, 240, 480 micrograms/kg/day) and T4 (625, 1250, 2500 micrograms/kg/day) resulted in no more than 1.2% cleft palates per litter in any of the treatment groups and the incidence was not dose related. The combination of TCDD (3 micrograms/kg/day) plus T3 at 120, 240, and 480 micrograms/kg/day resulted in 15.9, 20.6, and 31.4% cleft palates per litter, respectively. TCDD plus T4 at 625, 1250 and 2500 micrograms/kg/day caused 15.1, 22.9, and 27.2% cleft palates per litter. No cleft palates were observed when large doses of T3 were given in combination with T4. These data demonstrated that coadministration of T3 or T4 with TCDD increased the incidence of cleft palate to incidences greater than expected from the separate administration of the hormones plus TCDD.