The role of mouse and human peroxisome proliferator-activated receptor-α in modulating the hepatic effects of perfluorooctane sulfonate in mice
Introduction
Perfluorooctanesulfonyl-based chemistry has been used in many specialized applications. Perfluorooctane sulfonate (C8F17SO3−, PFOS) is the end-stage metabolite for PFOS-based compounds. Due to its strong electronegativity, PFOS is resistant to environmental and metabolic degradation and thus has been found in different environmental biota. PFOS has been detected in either serum or plasma in the general United State population (Kato et al., 2011; Olsen et al., 2017) with an estimated serum elimination half-life for PFOS of approximately three to five years (Li et al., 2018; Olsen et al., 2007; Xu et al., 2020). Because of its ubiquitous environmental presence and slow rates of excretion after absorption, PFOS has been subject to different human health regulatory decisions and has been designated as a persistent organic pollutant under the Stockholm Convention (http://chm.pops.int/TheConvention/ThePOPs/ListingofPOPs).
In laboratory studies with rodents, it was shown that liver is the primary target organ of PFOS exposure and that the hallmark biological responses included hepatomegaly and hepatosteatosis (Lau et al., 2007). Moreover, chronic administration of PFOS in rats can also lead to an increased incidence of hepatocellular adenoma (Butenhoff et al., 2012). These hepatic effects are thought to be influenced by activation of hepatic nuclear receptors such as peroxisome proliferator-activated receptor-α (PPARα), constitutive androstane receptor (CAR) and pregnane X receptor (PXR) (Bijland et al., 2011; Chang et al., 2009; Elcombe et al., 2012a, b). While these nuclear receptors are critical in regulating general physiological metabolic pathways in the liver (Hakkola et al., 2016; Wada et al., 2009; Wang et al., 2020), the observation of hepatocellular adenomas in rats after chronic PFOS exposure has also led to question whether such findings are relevant to human health.
For example, activation of the peroxisome proliferator-activated receptor alpha (PPARα) is central for maintaining daily variations in expression of genes that regulate lipid homeostasis to facilitate the release, transport, and enzymatic degradation of lipids to generate high energy phosphate (e.g. ATP) for cells to survive (Dubois et al., 2017). Given the central role of PPARα in lipid homeostasis it is not surprising that these critical functions are conserved between species. Previous in vitro studies showed that PFOS can differentially activate mouse or human PPARα based on either reporter assays or examination of expression of PPARα target genes in primary hepatic cells (Bjork et al., 2011; Bjork and Wallace, 2009; Janssen et al., 2015; Takacs and Abbott, 2007; Vanden Heuvel et al., 2006; Wolf et al., 2008). Further, long-term activation of PPARα can also increase signaling for proliferation of hepatocytes and cause liver cancer in rodents (Corton et al., 2018; Klaunig et al., 2003; Peters et al., 2005). This is of interest because PPARα has critical functional roles in lipid metabolism required to maintain normal lipid homeostasis in both rodents and humans, whereas hepatocarcinogenesis appears to result from pharmacological activation of PPARα only in rodents. There is compelling evidence for a species difference between rodents and humans with respect to hepatocarcinogenesis caused by PPARα activation (Corton et al., 2018; Klaunig et al., 2003; Peters et al., 2005). For example, recent evidence indicates that hepatocarcinogenesis caused by ligand activation of PPARα with a potent human PPARα agonist (GW7647) is altered in Ppara-null and PPARA-humanized mice compared to similarly treated wild-type controls (Foreman et al., 2021a, b).
Given these observations, there is strong interest to delineate the role of nuclear receptors in modulating the effects of PFOS as this chemical could impact human health through these mechanisms. Whether there is a species difference in the effects of PFOS in the liver mediated by either the mouse or human PPARα has not been evaluated to date in vivo. Thus, in the present study, the specific role of mouse and human PPARα in mediating the hepatic effects of PFOS was examined using wild-type, Ppara-null and PPARA-humanized mice.
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Animals and treatments
Male wild-type, Ppara-null and PPARA-humanized mice on an Sv/129 genetic background were used for these studies (Akiyama et al., 2001; Cheung et al., 2004; Lee et al., 1995). Age and weight matched mice were maintained in a temperature and light controlled environment (25 °C, with a 12-h light/12-h dark cycle). The potassium PFOS (K+PFOS; FC-95, Lot 217, 87 % purity) was provided by the 3 M Company (St. Paul, MN). Impurities in PFOS have been previously described and consisted primarily of
The role of PPARα in regulating the acute hepatic effects of PFOS
Administration of 0.006 % dietary PFOS for seven days did not influence average body weight in either wild-type or Ppara-null mice as compared to respective controls (Table 1). The average concentration of PFOS in liver and serum PFOS was markedly higher in both wild-type and Ppara-null mice, and this change was similar between genotypes (Table 2). Relative liver weight was increased after seven days of dietary administration of 0.006 % PFOS, and this effect was similar between wild-type or
Discussion
One important finding from these studies is the dosimetry of tissue PFOS concentration after administration of dietary PFOS in wild-type, Ppara-null and PPARA-humanized mice. These dosimetry data allow for a direct comparison with previous published studies in terms of relative tissue exposure. For example, hepatic PFOS was similar in concentration in the present study after either seven or twenty-eight days of dietary administration of either 0.006 % or 0.003 %, respectively, as compared to
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors gratefully acknowledge the expert histopathological analyses provided by Dr. George Parker. This work supported in part by an unrestricted gift from The 3M Company, and the USDA National Institute of Food and Federal Appropriations under Project PEN04607and Accession number 1009993 (J.M.P, A.D.P.).
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2022, ToxicologyCitation Excerpt :It is known to be hazardous for both environment and human beings (EFSA, 2020) due to its long half-life (from four to five years) and its ability to significantly bioaccumulate not only in the wildlife but also in the human body (Olsen et al. 2007; Saikat et al. 2013; Tsuda, 2016; Sunderland et al. 2019; Glüge et al. 2020). Indeed, PFOS accumulation was reported to cause damage in particular areas of specific organs, like histopathological changes in the liver (Su et al., 2022) and in the marginal area of the heart (Li et al. 2021), and tocause neurotoxicity due to its ability to cross the blood-brain-barrier and enter the brain (Li et al. 2021). PFOS was detected in drinking waterin different areas, such as the Constance Lake in Germany (3 ng/L) (Lange et al. 2007) or in Osaka (13.7 ng/L) (Takagi et al. 2011) and levels of PFOS ranging from 0.39 to 0.87 ng/L were also reported in tap water in Spain (Ericson et al. 2008).