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INFLUENCE OF TYPE II DIABETES, OBESITY, AND EXPOSURE TO 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) EXPOSURE ON THE EXPRESSION OF HEPATIC CYP1A2 IN A MURIN MODEL OF TYPE II DIABETES
Citation:
Godin, S. J., V. M. Richardson, J J. Diliberto, L S. Birnbaum, AND M J. DeVito. INFLUENCE OF TYPE II DIABETES, OBESITY, AND EXPOSURE TO 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) EXPOSURE ON THE EXPRESSION OF HEPATIC CYP1A2 IN A MURIN MODEL OF TYPE II DIABETES. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.
Description:
Influence of type II diabetes, obesity and exposure 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on the expression of hepatic CYPIA2 in a murine model of type II diabetes. SJ Godin', VM Richardson2, JJ Diliberto2, LS Birnbaum', MJ DeVito2; 'Curriculum In Toxicology, UNC-CH, Chapel Hill NC, USA; 'ETD, NHEERL, ORD, US EPA, RTP, NC, 27711, USA.
Recent epidemiology studies indicate an association between TCDD exposure and an increased incidence of type II diabetes. One criticism of these results is that diabetes or body fat composition may influence the disposition and/or elimination of TCDD. In the present study the influence of body fat composition and type II diabetes was examined on the expression of CYPIA2, a major determinant of the disposition of TCDD. In this study a high fat, high simple carbohydrate (HFHSC) diet was used to develop murine models of type II diabetes and obesity. After exposure to the HFHSC diet for 13 weeks, C57BL/6J mice develop obesity, hyperinsulinemia and hyperglucosenemia, consistent with signs of type II diabetes. Following 13 weeks on the HFHSC diet AJ mice develop greater body fat mass without developing hyperinsulinemia or hyperglucosenemia. These models have allowed us to compare the influence of diabetes, body fat composition and TCDD exposure on the expression of CYP 1A2. Following 13 weeks on either a normal or HFHSC diet animals were exposed to 0, 0.1 or 5 ug/kg of 3H-TCDD by oral gavage and killed 1, 30 and 40 days later. Hepatic CYP 1 A2 was determined using western blot analysis. Initial results indicate that on day 1, animals on the normal diet have a greater fold induction of CYPIA2 than those on the HFHSC diet. This effect is more pronounced at the higher dose. For example in C57 mice on the normal diet, CYPIA2 is induced 3 and 43 fold by 0.1 and 5 ug/kg TCDD while in C57 mice on the HFHSC diet CYPIA2 is induced 2 and 13 fold at these same doses. On days 30 and 40, fold induction of CYP 1 A2 by 5 ug/kg TCDD is approximately 7-10 fold greater in the animals on the HFHSC diet. These data suggest that diet can influence the response to TCDD. This influence may be related to alterations in body fat composition. (This abstract does not represent USEPA policy).