Perfluorooctane sulfonate (PFOS) is bioaccumulative and prevalent in the human population. PFOS induces hepatic steatosis in male rats at dietary exposures of 100 ppm via an unknown mechanism. In vitro, PFOS creates a choline ion complex. Choline deficiency induces hepatic steatosis in rats by decreasing VLDL secretion. The primary hypothesis was that a hepatic PFOS:choline ion complex causes steatosis that could be prevented by dietary choline supplementation. PFOS activation of steatosis related nuclear receptors (i.e., LXR, PXR, CAR, and PPAR-gamma) was investigated as a secondary hypothesis. To identify a choline dietary concentration, Sprague Dawley rats (5-6/sex/group) were fed control diet or 5X, 10X, or 15X basal choline diets for four weeks. The 5X diet was selected based on decreased body weights and body weight gains in the 10X (females only) and 15X groups. Sprague Dawley rats (12/sex/group) were fed control, choline supplemented (CS), 100 ppm PFOS, or 100 ppm PFOS + CS diets for three weeks. The male PFOS (±CS) rats developed hepatic steatosis, decreased mean serum cholesterol, and increased liver choline concentrations; the supplemented diet did not prevent hepatic steatosis. Female rats did not have these findings, even though serum and liver PFOS concentrations were similar to the males. In vitro, 400 µM PFOS did not inhibit choline kinase activity, which does not support the primary hypothesis. Regarding the secondary hypothesis, there was no activation (LXR, PXR, and CAR) or very weak activation (PPAR-gamma) by PFOS in a luciferase-linked assay. Also, liver mRNA activated by these nuclear receptors were not upregulated in rats fed PFOS. There are no clear data from this project that support the primary or secondary hypothesis. However, increased hepatic choline concentrations in the male PFOS rats correlates with the primary hypothesis. This finding and the sex-related difference in PFOS-induced hepatic steatosis warrant further investigation.
University of Minnesota Ph.D. dissertation. May 2017. Major: Toxicology. Advisor: Kendall Wallace. 1 computer file (PDF); xi, 150 pages.
The Effect of Perfluorooctane Sulfonate (PFOS) and Choline Supplementation on Hepatic Steatosis in Sprague Dawley Rats.
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