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首页> 外文期刊>Archives of Toxicology >Hepatocellular hypertrophy and cell proliferation in Sprague–Dawley rats following dietary exposure to ammonium perfluorooctanoate occurs through increased activation of the xenosensor nuclear receptors PPARα and CAR/PXR
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Hepatocellular hypertrophy and cell proliferation in Sprague–Dawley rats following dietary exposure to ammonium perfluorooctanoate occurs through increased activation of the xenosensor nuclear receptors PPARα and CAR/PXR

机译：饮食中暴露于全氟辛酸铵后，Sprague-Dawley大鼠的肝细胞肥大和细胞增殖是通过异种传感器核受体PPARα和CAR / PXR的激活增加而发生的

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Ammonium perfluorooctanoate (APFO), a processing aid used in the production of fluoropolymers, produces hepatomegaly and hepatocellular hypertrophy in rodents. In mice, APFO-induced hepatomegaly is associated with increased activation of the xenosensor nuclear receptors, PPARα and CAR/PXR. Although non-genotoxic, chronic dietary treatment of Sprague–Dawley (S–D) rats with APFO produced an increase in benign tumours of the liver, acinar pancreas, and testicular Leydig cells. Most of the criteria for establishing a PPARα-mediated mode of action for the observed hepatocellular tumours have been previously established with the exception of the demonstration of increased hepatocellular proliferation. The present study evaluates the potential roles for APFO-induced activation of PPARα and CAR/PXR with respect to liver tumour production in the S-D rat and when compared to the specific PPARα agonist, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy 14,643). Male S-D rats were fed APFO (300 ppm in diet) or Wy 14,643 (50 ppm in diet) for either 1, 7, or 28 days. Effects of treatment with APFO included: decreased body weight; hepatomegaly, hepatocellular hypertrophy, hepatocellular hyperplasia (microscopically and by BrdU labelling index), and hepatocellular glycogen loss; increased activation of PPARα (peroxisomal β-oxidation and microsomal CYP4A1 protein); decreased plasma triglycerides, cholesterol, and glucose; increased activation of CAR (CYP2B1/2 protein) and CAR/PXR (CYP3A1 protein). Responses to treatment with Wy 14,643 were consistent with increased activation of PPARα, specifically: increased CYP4A1 and peroxisomal β-oxidation; increased hepatocellular hypertrophy and cell proliferation; decreased apoptosis; and hypolipidaemia. With the exception of decreased apoptosis, the effects observed with Wy 14,643 were noted with APFO, and APFO was less potent. These data clearly demonstrate an early hepatocellular proliferative response to APFO treatment and suggest that the hepatomegaly and tumours observed after chronic dietary exposure of S-D rats to APFO likely are due to a proliferative response to combined activation of PPARα and CAR/PXR. This mode of action is unlikely to pose a human hepatocarcinogenic hazard.
机译：全氟辛酸铵（APFO）是一种用于生产含氟聚合物的加工助剂，可在啮齿动物中产生肝肿大和肝细胞肥大。在小鼠中，APFO诱导的肝肿大与异种传感器核受体PPARα和CAR / PXR的活化增加有关。尽管用APFO对Sprague-Dawley（S-D）大鼠进行非遗传毒性的慢性饮食治疗，肝脏，腺泡胰腺和睾丸Leydig细胞的良性肿瘤增加。除已证明增加肝细胞增殖的证据外，大多数已经建立了建立针对观察到的肝细胞肿瘤的PPARα介导的作用方式的标准。本研究评估了SDFO中APFO诱导的PPARα和CAR / PXR激活对肝脏肿瘤产生的潜在作用，并且与特定的PPARα激动剂4-氯-6-（2,3-xylidino）进行了比较-2-嘧啶基硫代乙酸（Wy 14,643）。雄性S-D大鼠被喂APFO（饮食中300 ppm）或Wy 14,643（饮食中50 ppm）持续1、7或28天。 APFO治疗的效果包括：体重减轻；肝肿大，肝细胞肥大，肝细胞增生（在显微镜下和通过BrdU标记指数）和肝细胞糖原丢失； PPARα的激活增加（过氧化物酶体β-氧化和微粒体CYP4A1蛋白）;降低血浆甘油三酸酯，胆固醇和葡萄糖；增加了CAR（CYP2B1 / 2蛋白）和CAR / PXR（CYP3A1蛋白）的激活。对Wy 14,643治疗的反应与PPARα活化的增加相一致，特别是：CYP4A1的增加和过氧化物酶体β-氧化；肝细胞肥大和细胞增殖增加；凋亡减少；和低血脂症。除了凋亡减少外，APFO还记录了Wy 14,643所观察到的作用，而APFO的作用较弱。这些数据清楚地表明了对APFO治疗的早期肝细胞增殖反应，并表明在S-D大鼠长期饮食中接触APFO后观察到的肝肿大和肿瘤可能是由于对PPARα和CAR / PXR联合激活的增殖反应所致。这种作用方式不太可能造成人类肝癌的危害。

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