The Role of Mouse and Human Peroxisome Proliferator-Activated Receptor- α in Modulating the Hepatic Effects of Perflourohexane Sulfonate (PFHxS) in Mice
Open Access
- Author:
- Khan, Yahya
- Area of Honors:
- Biomedical Engineering
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Jeffrey Maurice Peters, Thesis Supervisor
Meghan Vidt, Thesis Honors Advisor - Keywords:
- Nuclear Receptors
Species differences
Perfluorohexanesulfonic acid
Peroxisome proliferator-activated receptor alpha
Constitutive androstane receptor
Pregnane X receptor - Abstract:
- Perfluorohexane sulfonate (PFHxS) is a short-chain perfluorinated alkylated substance (PFAS) used in various industrial processes. PFAS chemicals, including PFHxS, have been detected in the general human population. In rodents, PFAS exposure is associated with liver toxicity and liver cancer through mechanisms that may require nuclear receptors like peroxisome proliferator-activated receptor-α (PPARα), constitutive androstane dione receptor (CAR), or pregnane X receptor (PXR). This study tested the hypothesis that PFHxS causes changes in liver by activating PPARα, CAR or PXR. Wild-type, Ppara-null, and PPARA-humanized mice were fed either a control diet or one containing 3 mg/kg, or 30 mg/kg PFHxS diets for either 7 or 28 days. Relative liver weight was higher in wild-type, Ppara-null, and PPARA-humanized mice fed PFHxS in a dose-dependent manner compared to controls. The concentration of PFHxS in serum and liver was increased dose-dependently in all three genotypes and reached levels well above typical levels in humans. PFHxS exposure caused an increase in mRNA levels of the PPARα target genes Cyp4a10 and Acox1 after twenty-eight days in wild-type mice and PPARA-humanized mice compared to controls. This effect was not observed in similarly treated Ppara-null mice. PFHxS exposure did not alter expression of the CAR target gene Cyp2b10 in wild-type mice after either seven or twenty-eight days. By contrast, expression of Cyp2b10 was increased by PFHxS in Ppara-null and PPARA-humanized mice compared to controls. PFHxS exposure did not alter expression of the PXR target gene Cyp3a11 in wild-type or Ppara-null mice after either seven or twenty-eight days. By contrast, expression of Cyp3a11 was increased by PFHxS in PPARA-humanized mice compared to controls. Results from these studies demonstrate that exposure to PFHxS causes an increase in liver weight that is due in part to activation of PPARa, but activation of CAR and PXR also contribute to this phenotype. Ppara-null mice had increased relative liver weights despite no PPARa activation, suggesting that CAR and PXR were responsible for increased weights. A dietary concentration of 30 mg/kg but not 3 mg/kg PFHxS was able to achieve liver and serum concentrations in the range required to activate PPARα, CAR, or PXR. While PPARA-humanized mice and wild-type mice both had receptor activation, differences between rodents and humans in terms of CAR/PXR activation and PPARα sensitivity suggest that tumors would not form in humans.