BACKGROUND Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced impacts on enterohepatic circulation may play a critical role in cardiovascular risk. OBJECTIVES Using a mouse model with high levels of low-density and very low-density lipoprotein (LDL and VLDL, respectively) cholesterol and aortic lesion development similar to humans, the present study investigated mechanisms linking exposure to a PFAS mixture with increased cholesterol. METHODS Male and female Ldlr-/- mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFHxS, PFNA, GenX), each at a concentration of 2mg/L, for 7 wk. Blood was collected longitudinally for cholesterol measurements, and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA sequencing. RESULTS After 7 wk of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and 1.5μg/mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7μg/mL in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. Total circulating cholesterol levels were higher in PFAS-exposed mice after 7 wk (352mg/dL vs. 415mg/dL in female mice and 392mg/dL vs. 488mg/dL in male mice exposed to vehicle or PFAS, respectively). Total circulating bile acid levels were higher in PFAS-exposed mice (2,978 pg/μL vs. 8,496 pg/μL in female mice and 1,960 pg/μL vs. 4,452 pg/μL in male mice exposed to vehicle or PFAS, respectively). In addition, total fecal bile acid levels were lower in PFAS-exposed mice (1,797 ng/mg vs. 682 ng/mg in females and 1,622 ng/mg vs. 670 ng/mg in males exposed to vehicle or PFAS, respectively). In the ileum, expression levels of the apical sodium-dependent bile acid transporter (ASBT) were higher in PFAS-exposed mice. DISCUSSION Mice exposed to a PFAS mixture displayed higher circulating cholesterol and bile acids perhaps due to impacts on enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk following PFAS exposure. https://doi.org/10.1289/EHP14339.

中文翻译：

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Ldlr - / - 小鼠暴露于 PFAS 混合物以及与循环脂质、胆汁酸排泄和肠道转运蛋白 ASBT 相关的结果。


背景 以前的流行病学研究一再发现，全氟烷基和多氟烷基物质 （PFAS） 暴露与较高的循环胆固醇有关，而循环胆固醇是冠状动脉疾病发展的最大风险因素之一。胆固醇分解代谢的主要途径是转化为胆汁酸，胆汁酸通过肠肝循环在肝脏和回肠之间循环。冠状动脉疾病患者的胆汁酸排泄减少，表明 PFAS 诱导的对肠肝循环的影响可能在心血管风险中起关键作用。目的 使用具有高水平低密度和极低密度脂蛋白 （分别为 LDL 和 VLDL） 胆固醇和与人类相似的主动脉病变发展的小鼠模型，本研究调查了将暴露于 PFAS 混合物与胆固醇升高联系起来的机制。方法 雄性和雌性 Ldlr-/- 小鼠喂食致动脉粥样硬化饮食 （Clinton/Cybulsky 低脂肪，0.15% 胆固醇） 并暴露于 5 种代表遗留、替代和新出现的亚型 （即 PFOA、PFOS、PFHxS、PFNA、GenX） 的混合物，每种浓度为 2mg/L，持续 7 周。纵向采集血液用于测量胆固醇，质谱法用于测量循环和粪便胆汁酸。通过 RNA 测序对回肠样本进行转录组学分析。结果 PFAS 暴露 7 周后，PFAS 暴露女性的平均循环 PFAS 水平分别为 21.6、20.1、31.2、23.5 和 1.5 μg/mL，PFAS 暴露男性的平均循环 PFAS 水平分别为 12.9、9.7、23、14.3 和 1.7 μg/mL。7 周后，暴露于 PFAS 的小鼠的总循环胆固醇水平较高（352mg/dL vs. 雌性小鼠为 415mg/dL，392mg/dL vs. 暴露于载体或 PFAS 的雄性小鼠分别为 488mg/dL）。暴露于 PFAS 的小鼠的总循环胆汁酸水平较高（暴露于载体或 PFAS 的雄性小鼠分别为 2,978 pg/μL vs. 8,496 pg/μL，雄性小鼠分别为 1,960 pg/μL vs. 4,452 pg/μL）。此外，暴露于 PFAS 的小鼠的总粪便胆汁酸水平较低（雌性分别为 1,797 ng/mg vs. 682 ng/mg，暴露于载体或 PFAS 的雄性分别为 1,622 ng/mg 和 670 ng/mg）。在回肠中，PFAS 暴露小鼠顶端钠依赖性胆汁酸转运蛋白 （ASBT） 的表达水平较高。讨论 暴露于 PFAS 混合物的小鼠表现出较高的循环胆固醇和胆汁酸，这可能是由于对肠肝循环的影响。这项研究表明 PFAS 介导的回肠部位作用可能是 PFAS 暴露后心血管风险增加的关键介质。https://doi.org/10.1289/EHP14339。