Dose-response and time course of hypothyroxinemia and hypoinsulinemia and characterization of insulin hypersensitivity in 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)-treated rats

Male Sprague-Dawley rats were administered i.p. various doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in corn oil. At several time points thyroid stimulating hormone (TSH), total thyroxine (TT 4), free thyroxine (FT 4), total triiodothyronine (TT 3), reverse triiodothyronine (rT 3) and insulin were determined in serum using radioimmunoassays, and glucose was measured by the glucose oxidase method. TSH and TT 3 were not affected by any dose at any time point of measurement. TT 4 and FT 4 were decreased in a somewhat dose-dependent manner by days 2 to 4 after dosing. Return of TT 4 and FT 4 to normal values by day 32 after TCDD dosage also occurred in a dose-dependent manner, except in rats that died later. rT 3 was also decreased at each dose level early and returned to normal levels in a somewhat dose-dependent fashion. Rats in the 2 highest dose groups became hypoinsulinemic and in the highest dose group also hypoglycemic by day 8 after dosing. Serum insulin and glucose remained suppressed in non-survivors of TCDD until death ensued. In survivors, serum insulin returned to normal values by day 32 after dosing. The hypoinsulinemic state was further characterized by hypersensitivity towards insulin, i.e. injection of an otherwise non-toxic dose of insulin 3 days after administration of 125 μg/kg TCDD was lethal to 80% of the rats within 24 h. Insulin hypersensitivity preceded both hypoglycemia and hypoinsulinemia. These findings suggest that hypothyroxinemia and hypoinsulinemia may be part of an adaptive process whereby rats attempt to diminish the toxic insult of TCDD.