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  • br Acknowledgements We would like to thank Dr Ron

    2020-02-08


    Acknowledgements We would like to thank Dr Ron Mason (NIEHS, Research Triangle Park, NC) for helpful discussion regarding the analysis of nox4 CCl4 metabolism, to Dr Karla Thrall and Dr Rick Corley (Battelle) for helpful discussions regarding study design and data interpretation, and to Jim Merdink and Karl Weitz (Battelle) for assistance in the analysis of chlorinated compounds by gas chromatography. Work performed by Pacific Northwest National Laboratory (PNNL) for Lovelace Respiratory Research Institute under Cooperative Agreement DE-FC04-96AL7604, Environmental Management Science Program, Office of Science and Technology, Office of Environmental Management, Department of Energy. PNNL is operated by Battelle for the US Department of Energy (DOE) under contract DE-ACO6-76RLO 1830. However, any opinions, findings, conclusions, or recommendations expressed herein are those of the authors and do not necessarily reflect the views of the DOE.
    Introduction Perfluorooctanesulfonate (PFOS) is a perfluorinated surfactant that has been used commercially in applications requiring exceptional stability and high surface tension reducing properties. Degradation of “precursor” compounds metabolically (Xu et al., 2004) or in the environment (D’Eon et al., 2006, Rhoads et al., 2008) may also lead to formation of PFOS. Quantitation of PFOS in biomonitoring samples from humans (Hansen et al., 2001) and wildlife (Giesy and Kannan, 2001) demonstrated broad dissemination in the environment, and, since that time, numerous environmental sampling and biomonitoring studies have confirmed the broad dissemination of PFOS in the environment (Butenhoff et al., 2006, Houde et al., 2006, Lau et al., 2007). Recent trend studies suggest that body burdens of PFOS in the general nox4 have been in decline since circa 2000–2002 (Calafat et al., 2007, Olsen et al., 2008, Sundström et al., 2011), when the major United States manufacturer ceased production (Renner, 2001). In repeat-dose toxicological studies in rodents (Bijland et al., 2011, Butenhoff et al., 2012, Curran et al., 2008, Qazi et al., 2009, Seacat et al., 2003, Sohlenius et al., 1993) and non-human primates (Seacat et al., 2002), PFOS has been shown to produce responses that are consistent with activation of the xenosensor nuclear receptor NR1C1 (peroxisome proliferator-activated receptor α, or PPARα). These responses include hepatomegaly and hepatocellular hypertrophy, expansion of the smooth endoplasmic reticulum, changes in lipid metabolism, notably increased peroxisomal fatty acid β-oxidation, fatty acid ω-hydroxylation of fatty acids, hypolipidemia, and, an increase in benign hepatocellular adenoma on chronic dietary dosing of Sprague Dawley rats (Butenhoff et al., 2012). Transactivation assays have confirmed PFOS as an agonist of PPARα (Shipley et al., 2004, Takacs and Abbott, 2007, Vanden Heuvel et al., 2006, Wolf et al., 2008). Although PPARα appears to be the primary target of PFOS, PFOS also has been shown to increase the expression of two other xenosensor nuclear receptors associated with hepatomegaly in rodents, NR1I3 (constitutive androstane receptor, or CAR) (Bjork et al., 2011, Elcombe et al., 2012, Ren et al., 2009, Rosen et al., 2010) and NR1I2 (pregnane X receptor, or PXR) (Bijland et al., 2011, Bjork et al., 2011, Elcombe et al., 2012). We recently confirmed in a 28-day dietary study that the activation of PPARα and CAR/PXR are etiological factors in K+PFOS-induced hepatomegaly and hepatic tumorigenesis in rats (Elcombe et al., 2012). In that study, two dietary levels of K+PFOS were used, 20 and 100ppm (w/w), and separate groups of male rats were given dietary 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY) at 50ppm (w/w) in diet and sodium phenobarbital (PB) at 500ppm (w/w) in diet as positive controls for the activation of PPARα and CAR/PXR, respectively. Treatment with K+PFOS elicited responses characteristic of mixed activation of PPARα and CAR/PXR, inducing the same changes as WY and PB, but to a lesser magnitude.