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  • The role of activation of xenosensor nuclear receptors such


    The role of activation of xenosensor nuclear receptors such as PPARα, CAR, and PXR in producing hepatomegaly and liver tumors in rodents has been well-established (Klaunig et al., 2003, Lake, 2009). In the case of PPARα, the increase in liver weight results from increased peroxisomal mass and expansion of the smooth endoplasmic reticulum. CAR and PXR increase liver mass through induction of cytochromes with a consequent increase in cytochromal PLX4720 proteins. In addition, activation of PPARα, CAR, or PXR in rodents may stimulate replicative DNA synthesis, resulting in proliferation of hepatocytes, and may decrease apoptosis of hepatocytes, potentially leading to clonal expansion of preneoplastic foci and, ultimately, liver carcinogenesis. Although human liver may have some capacity to respond to the hepatocellular hypertrophic effects of activation of these xenosensor receptors, exposure of humans to agents known to activate these receptors has not been associated with increased risk of liver cancer. Furthermore, in recent years it has been demonstrated that, when the mouse forms of these receptors are replaced by the human forms, the human forms of the receptors appear incapable of supporting the hepatocellular hyperplastic response (Cheung et al., 2004, Gonzalez and Shah, 2008, Hirose et al., 2009, Ross et al., 2010, Shah et al., 2007). In addition to the increase in liver tumors observed in the chronic dietary study with K+PFOS in Sprague Dawley rats, there was a statistically significant increase in thyroid follicular cell adenoma in male rats who received one year of 20ppm dietary K+PFOS and switched to control diet through termination of the study (stop-dose group) when compared to male control rats or male rats that were fed with 20ppm dietary K+PFOS through study termination at 104 weeks (Butenhoff et al., 2012). The etiological basis of the increase in thyroid follicular tumors in the stop-dose group males has remained recondite and may possibly have been due to a chance occurrence. In the 28-day dietary study mentioned above (Elcombe et al., 2012), we further evaluated the apoptotic, proliferative, and histological responses in thyroid with K+PFOS treatment; however, there were no changes when compared to the controls. Following the completion of the 28-day study (Elcombe et al., 2012), a seven-day dietary study at the same K+PFOS dietary doses was conducted followed by an 84-day recovery observation PLX4720 in order to allow evaluation of recovery from K+PFOS-induced effects. The results of this recovery study are reported herein.
    Materials and methods
    Discussion In a 28-day dietary study reported in this issue (Elcombe et al., 2012), K+PFOS elicited responses characteristic of mixed activation of PPARα and CAR/PXR. The study reported herein evaluated resolution of K+PFOS-induced, liver-related effects in male rats during an 84-day period following a 7-day dietary exposure to K+PFOS at 20 or 100ppm (w/w) in diet. This study focused on endpoints related to hepatocellular hypertrophy and included the activities of key marker enzymes associated with hepatic xenosensor nuclear receptors PPARα (ACOX and CYP4A activities), CAR (CYP2B activity), and PXR (CYP3A activity) that exert ligand-specificity with PFOS (Ren et al., 2009, Rosen et al., 2009, Rosen et al., 2010, Shipley et al., 2004, Takacs and Abbott, 2007, Vanden Heuvel et al., 2006, Wolf et al., 2008). These receptors play vital roles in the regulation of both intermediary metabolism and xenobiotic metabolism, and in the regulation of liver growth (Waxman, 1999). In rodent liver, the activation of xenosensor nuclear receptors, PPARα, CAR, and PXR may increase liver size by increasing replicative DNA synthesis (cell proliferation) and, sometimes in addition, by decreasing apoptosis (Klaunig et al., 2003, Lake, 2009). Seven days of dietary treatment with either 20 or 100ppm K+PFOS were sufficient to result in hepatic hypertrophy. Rats fed both K+PFOS dietary concentrations and sacrificed on the first day of the recovery period following dietary treatment had increased relative liver weights as compared to controls. The latter finding was supported by microscopic observation of a dose-related increase in the incidence and severity of centrilobular hepatocellular hypertrophy. The decrease in hepatic DNA concentration and increase in hepatic P450 concentration also correlated well with hepatocellular hypertrophy observed on the first recovery day. In addition, the hepatic proliferative index was increased and the hepatic apoptotic index decreased in a dose-dependent manner, without a notable change in total DNA. Also at this time point, there was evidence in the 100ppm group for induction of acyl CoA oxidase, lauric acid 12-hyroylase, pentoxyresorufin-O-depentylase, and testosterone 6 β-hydroxylase, indicative of activation by PFOS of the xenosensor nuclear receptors PPARα and CAR/PXR. These changes were associated with mean serum PFOS concentrations of 39 and 140μg/mL in the 20 and 100ppm dose groups, respectively. Corresponding mean PFOS concentrations in liver and liver cytosol were 124 and 320μg/g for liver and 13 and 41μg/mL for liver cytosol.