Elsevier

Toxicology

Volume 465, 15 January 2022, 153056
Toxicology

The role of mouse and human peroxisome proliferator-activated receptor-α in modulating the hepatic effects of perfluorooctane sulfonate in mice

https://doi.org/10.1016/j.tox.2021.153056Get rights and content

Abstract

Perfluorooctane sulfonate (PFOS) is a stable environmental contaminant that can activate peroxisome proliferator-activated receptor alpha (PPARα). In the present work, the specific role of mouse and human PPARα in mediating the hepatic effects of PFOS was examined in short-term studies using wild type, Ppara-null and PPARA-humanized mice. Mice fed 0.006 % PFOS for seven days (∼10 mg/kg/day), or 0.003 % PFOS for twenty-eight days (∼5 mg/kg/day), exhibited higher liver and serum PFOS concentrations compared to controls. Relative liver weights were also higher following exposure to dietary PFOS in all three genotypes as compared vehicle fed control groups. Histopathological examination of liver sections from mice treated for twenty-eight days with 0.003 % PFOS revealed a phenotype consistent with peroxisome proliferation, in wild-type and PPARA-humanized mice that was not observed in Ppara-null mice. With both exposures, expression of the PPARα target genes, Acox1, Cyp4a10, was significantly increased in wild type mice but not in Ppara-null or PPARA-humanized mice. By contrast, expression of the constitutive androstane receptor (CAR) target gene, Cyp2b10, and the pregnane X receptor (PXR) target gene, Cyp3a11, were higher in response to PFOS administration in all three genotypes compared to controls for both exposure periods. These results indicate that mouse PPARα can be activated in the liver by PFOS causing increased expression of Acox1, Cyp4a10 and histopathological changes in the liver. While histopathological analyses indicated the presence of mouse PPARα-dependent hepatic peroxisome proliferation in wild-type (a response associated with activation of PPARα) and a similar phenotype in PPARA-humanized mice, the lack of increased Acox1 and Cyp4a10 mRNA by PFOS in PPARA-humanized mice indicates that the human PPARα was not as responsive to PFOS as mouse PPARα with this dose regimen. Moreover, results indicate that hepatomegaly caused by PFOS does not require mouse or human PPARα and could be due to effects induced by activation of CAR and/or PXR.

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.

Section snippets

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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