Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
Toxicology. 2022 Jan 15;465:153056. doi: 10.1016/j.tox.2021.153056. Epub 2021 Nov 30.
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.
全氟辛烷磺酸 (PFOS) 是一种稳定的环境污染物，能够激活过氧化物酶体增殖物激活受体α (PPARα)。在本研究中，使用野生型、Ppara 基因敲除型和人源化 PPARA 型小鼠进行了短期研究，以检验 PFOS 对肝脏的作用是否通过小鼠和人 PPARα 介导。喂食 0.006%PFOS 七天（约 10mg/kg/天）或 0.003%PFOS 二十八天（约 5mg/kg/天）的小鼠，其肝脏和血清中的 PFOS 浓度明显高于对照组。与对照组相比，三种基因型的小鼠在喂食 PFOS 后相对肝脏重量也更高。喂食 0.003%PFOS 二十八天的小鼠肝脏切片的组织病理学检查显示，在野生型和人源化 PPARA 型小鼠中观察到的与过氧化物酶体增殖一致的表型，在 Ppara 基因敲除型小鼠中并未观察到。在这两种暴露情况下，PPARα 靶基因 Acox1 和 Cyp4a10 的表达在野生型小鼠中显著增加，但在 Ppara 基因敲除型或人源化 PPARA 型小鼠中没有增加。相反，在两种暴露情况下，与对照组相比，所有三种基因型的 CAR 靶基因 Cyp2b10 和 PXR 靶基因 Cyp3a11 的表达均升高。这些结果表明，PFOS 可在肝脏中激活小鼠 PPARα，导致 Acox1、Cyp4a10 表达增加，并导致肝脏组织病理学改变。虽然组织病理学分析表明，在野生型（与 PPARα 激活相关的反应）和人源化 PPARA 型小鼠中存在依赖于小鼠 PPARα 的肝过氧化物酶体增殖，但人源化 PPARA 型小鼠中 PFOS 并未导致 Acox1 和 Cyp4a10 mRNA 增加，这表明在该剂量方案下，人源 PPARα 对 PFOS 的反应不如小鼠 PPARα 敏感。此外，结果表明，PFOS 引起的肝肿大不需要小鼠或人 PPARα，可能是由于 CAR 和/或 PXR 激活引起的作用。
