NMR analyses show TCDD elicits differences in hepatic metabolism in female C57BL/6 mice and Sprague-Dawley rats

by Makley, Meghan Katherine

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) elicits tissue-, sex-, and species-specific effects. This study compares the hepatic response to an oral dose of TCDD in immature ovariectomized (i.o.) C57BL/6 mice (30 ug/kg) and i.o. Sprague-Dawley rats (10 ug/kg), at 72, 120, and 168 h post-dose. Hepatic lipid extracts were analyzed by 13C and 31P NMR, and aqueous extracts by 1H and 31P NMR. Consistent with increased lipid content in mice (p?0.05), TCDD induced increases in hepatic triacylglycerides (TAG), cholesterol, and fatty acids. Principal component analysis of 13C spectra show treatment groups separate in mice, but not rats. Mice showed decreases in the lactate/pyruvate ratio and dihydroxyacetone phosphate, consistent with decreased cytosolic NADH/NAD+ ratio and upregulated TAG synthesis. TCDD-treated rats exhibited decreased levels of sphingomyelin, and three-fold increase in phosphocholine, suggesting TCDD activates sphingomyelinase. Both species showed similar decreases in cardiolipin, indicating oxidative stress. These observations are compared with hepatic histopathology and gene expression findings.