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. 2025 May 1;205(1):47-52.
doi: 10.1093/toxsci/kfaf026.

Differential hepatic activation of mouse and human peroxisome proliferator-activated receptor-α by perfluorohexane sulfonate

Yahya Khan  1   2 , Annalee M Schmidt  1   2 , Kyle J Oldro  1   2 , Xiaoyang Zhu  1   2 , Angelina R Kramer  1   2 , Sarah R Hamilton  1   2 , Katherine O Bleil  1   2 , Ryan M Krisko  3 , Jeremiah D Zitzow  3 , Yuan Tian  1   2 , Shu-Ching Chang  3 , Vonn Walter  4   5 , Samuel M Cohen  6   7 , Frank J Gonzalez  8 , Andrew D Patterson  1   2 , Jeffrey M Peters  1   2
Affiliations

Differential hepatic activation of mouse and human peroxisome proliferator-activated receptor-α by perfluorohexane sulfonate

Yahya Khan et al. Toxicol Sci. .

Abstract

Exposure of perfluorohexane sulfonate (PFHxS) is associated with hepatomegaly and accumulation of lipids that may be mediated by nuclear receptors like peroxisome proliferator-activated receptor-α (PPARα), constitutive androstane receptor (CAR), or pregnane X receptor (PXR). This study tested the hypotheses that: (i) PFHxS causes changes in liver by activating PPARα, CAR, or PXR, and (ii) there is a species difference in PPARα activity by PFHxS. Wild-type, Ppara-null, and PPARA-humanized mice were fed either a control diet, or one containing 2.2 mg PFHxS/kg diet or 25.8 mg PFHxS/kg diet for either 7 or 28 days, and target gene expression was examined. Relative liver weights were similar after 7 days with either 2.2 or 25.8 mg PFHxS/kg dietary exposure compared with controls. Relative liver weights were higher after treatment for 28 days in all 3 genotypes fed 25.8 mg PFHxS/kg diet compared with controls. The concentration of PFHxS was dose-dependently increased in serum and liver compared with controls. PFHxS exposure of 2.2 and 25.8 mg PFHxS/kg diet caused an increase in expression of PPARα target genes in wild-type mice and this effect was not observed in similarly treated Ppara-null mice or PPARA-humanized mice. Administration of PFHxS caused increased expression of the CAR target gene Cyp2b10 in all 3 genotypes at both timepoints, and the PXR target gene Cyp3a11 in all 3 genotypes after 28 days. Exposure to PFHxS can increase liver weight due in part to the activation of mouse, but not human, PPARα. Activation of CAR and PXR by PFHxS also likely contributes to the observed hepatomegaly in all 3 genotypes.

Keywords: liver; perfluorohexane sulfonate; peroxisome proliferator-activated receptor-α; species difference.

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Figures

Fig. 1.
Fig. 1.
Average relative liver weight in wild-type (Ppara+/+), Ppara-null (Ppara−/−), or PPARA-humanized (PPARA) mice after (A) 7 days, or (B) 28 days of dietary PFHxS (2.2 mg/kg diet or 25.8 mg/kg diet). Untransformed and Log2 transformed values represent the mean ± SD. N = 5 mice per group. Values with different letters are significantly different at P ≤ 0.05.
Fig. 2.
Fig. 2.
Relative hepatic expression of the PPARα (Acox1, Cyp4a10), CAR (Cyp2b10), and PXR (Cyp3a11) target genes in wild-type (Ppara+/+), Ppara-null (Ppara−/−), or PPARA-humanized (PPARA) mice after 7 days of dietary PFHxS (2.2 mg/kg diet or 25.8 mg/kg diet). Square root transformed values represent the mean ± SD. N = 3 unique biological replicate liver mRNA samples per group. Values with different letters are significantly different at P ≤ 0.05.
Fig. 3.
Fig. 3.
Relative hepatic expression of the PPARα (Acox1, Cyp4a10), CAR (Cyp2b10), and PXR (Cyp3a11) target genes in wild-type (Ppara+/+), Ppara-null (Ppara−/−) or PPARA-humanized (PPARA) mice after 28 days of dietary PFHxS (2.2 mg/kg diet or 25.8 mg/kg diet). Square root transformed values represent the mean ± SD. N = 2 to 3 unique biological replicate liver mRNA samples per group. Values with different letters are significantly different at P ≤ 0.05.
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