Differential Hepatic Effects of Perfluorobutyrate Mediated by Mouse and Human PPAR-α

Abstract

Perfluorobutyrate (PFBA) is a short chain perfluoroalkyl carboxylate that is structurally similar to perfluorooctanoate. Administration of PFBA can cause peroxisome proliferation, induction of peroxisomal fatty acid oxidation and hepatomegaly, suggesting that PFBA activates the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In this study, the role of PPAR-alpha in mediating the effects of PFBA was examined using PPAR-alpha null mice and a mouse line expressing the human PPAR-alpha in the absence of mouse PPAR-alpha (PPAR-alpha humanized mice). PFBA caused upregulation of known PPAR-alpha target genes that modulate lipid metabolism in wild-type and PPAR-alpha humanized mice, and this effect was not found in PPAR-alpha null mice. Increased liver weight and hepatocyte hypertrophy were also found in wild-type and humanized PPAR-alpha mice treated with PFBA, but not in PPAR-alpha null mice. Interestingly, hepatocyte focal necrosis with inflammatory cell infiltrate was only found in wild-type mice administered PFBA; this effect was markedly diminished in both PPAR-alpha null and PPAR-alpha humanized mice. Results from these studies demonstrate that PFBA can modulate gene expression and cause mild hepatomegaly and hepatocyte hypertrophy through a mechanism that requires PPAR-alpha and that these effects do not exhibit a species difference. In contrast, the PPAR-alpha-dependent increase in PFBA-induced hepatocyte focal necrosis with inflammatory cell infiltrate was mediated by the mouse PPAR-alpha but not the human PPAR-alpha. Collectively, these findings demonstrate that PFBA can activate both the mouse and human PPAR-alpha, but there is a species difference in the hepatotoxic response to this chemical.

Dual action of peroxisome proliferator-activated receptor alpha in perfluorodecanoic acid-induced hepatotoxicity

“…This was unexpected because hepatomegaly and hepatocyte hypertrophy induced by PPARα agonists were considered related to a mechanism requiring PPARα. This result accorded with that reported for another perfluoroalkyl carboxylate perfluorobutryate (Foreman et al 2009). By histopathological examination, slight edema was observed in Pparα-null mice.…”

“…These results were quite similar to perfluorobutryate which causes focal necrosis with inflammatory cell infiltrate only in wild-type mice, but diminished in Pparα-null mice (Foreman et al 2009). Considering the disruption of bile acid homeostasis, this inflammation was a reaction to bile acid load, not a direct PPARα-dependent reaction.…”

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

“…The liver has been identified as a major target organ for PFAS compounds in rodents (Cui et al 2009;Foreman et al 2009;Qazi et al 2010;Tatum-Gibbs et al 2011;Botelho et al 2015) and in humans (Karrman et al 2010). Cui et al (2009) measured the concentration of PFOA and PFOS in the tissues of Sprague-Dawley rats; liver was one of the top two sites for bioaccumulation for both compounds.…”

“…Similarly, a single exposure to 0.1 mmol PFNA/kg (% 46 mg/kg) resulted in hepatomegaly in C57Bl/6 mice (Rockwell et al 2013). Heptatic histopathological and biological damage (immunological and non-immunological) have been observed following exposure to a variety of PFAS compounds in research animals, including peroxisome proliferation and activation of PPARa, peroxisomal b-oxidation, and liver tumors (DeWitt et al 2009;Foreman et al 2009;Qazi et al 2010;DeWitt et al 2012;OHAT 2016;Rockwell et al 2017). However, with its resident lymphocyte and Kupffer cell populations, the liver is also a sensitive immune organ, capable of generating acute-phase proteins and cytokines, and engaging in phagocytosis, host resistance, and antigen recognition, processing, and presentation (Sheth and Bankey 2001;Racanelli and Rehermann 2006).…”

Effect of prenatal peroxisome proliferator-activated receptor α (PPARα) agonism on postnatal development

“…The mRNAs encoding the known PPAR␣ target genes, cytochrome P450 4a10 (Cyp4a10) and acyl-CoA oxidase 1 (Aco), were measured using qPCR analysis. The sequence for the forward and reverse primers used to quantify mRNAs for Cyp4a10, Aco and internal control, glyceraldehyde 3-phosphate dehydrogenase (Gapdh) are described previously (Foreman et al, 2009). PCR reactions were carried out using SYBR ® Green Supermix for IQ (Quanta Biosciences, Gaithersburg, MD) in the iCycler and detected using the MyiQ Real-Time PCR Detection System (Bio-Rad Laboratories, Hercules, CA).…”