ToxSci Advance Access originally published online on February 9, 2005
Toxicological Sciences 2005 85(1):560-571; doi:10.1093/toxsci/kfi106
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2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and 1,2,3,4,7,8-Hexachlorodibenzo-p-Dioxin (HxCDD) Alter Body Weight by Decreasing Insulin-Like Growth Factor I (IGF-I) Signaling
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* Department of Pharmacology, Toxicology and Experimental Therapeutics; GSF- Institute of Ecological Chemistry, Neuherberg, Germany; Center for Reproductive Sciences and Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160 USA; Section of Environmental Toxicology, GSF-Institut für Toxikologie, Neuherberg, Germany
Received November 18, 2004; accepted January 27, 2005
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) affects glycemia due to reduced gluconeogenesis; when combined with a reduction in feed intake, this culminates in decreased body weight. We investigated the effects of steady-state levels of TCDD (loading dose rates of 0.0125, 0.05, 0.2, 0.8, and 3.2 µg/kg) or approximately isoeffective dose rates of 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD) (loading dose rates of 0.3125, 1.25, 5, 20, and 80 µg/kg) on body weight, phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and activity, and circulating concentrations of insulin, glucose, and insulin-like growth factor-I (IGF-I), and expression of hepatic phosphorylated AMP kinase-
(p-AMPK) protein in female Sprague-Dawley rats (
250 gm) at 2, 4, 8, 16, 32, 64, and 128 days after commencement of treatment. At the 0.05 and 1.25 µg/kg loading dose rates of TCDD and HxCDD, respectively, there was a slight increase in body weight as compared to controls, whereas at the 3.2 and 80 µg/kg loading dose rates of TCDD and HxCDD, respectively, body weight of the rats was significantly decreased. TCDD and HxCDD also inhibited PEPCK activity in a dose-dependent fashion, as demonstrated by reductions in PEPCK mRNA and protein. Serum IGF-I levels of rats treated initially with 3.2 µg/kg TCDD or 80 µg/kg HxCDD started to decline at day 4 and decreased to about 40% of levels seen in controls after day 16, remaining low for the duration of the study. Eight days after initial dosing, hepatic p-AMPK protein was increased in a dose-dependent manner with higher doses of TCDD and HxCDD. There was no effect with any dose of TCDD or HxCDD on circulating insulin or glucose levels. In conclusion, doses of TCDD or HxCDD that began to inhibit body weight in female rats also started to inhibit PEPCK, inhibited IGF-I, while at the same time inducing p-AMPK.
Key Words: TCDD; HxCDD; insulin-like growth factor I; IGF-I.
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