■先前的流行病学研究一再发现全氟烷基物质和多氟烷基物质(PFAS)暴露与较高的循环胆固醇有关,冠状动脉疾病发展的最大危险因素之一。胆固醇分解代谢的主要途径是通过其转化为胆汁酸,通过肝肠循环在肝脏和回肠之间循环。冠心病患者胆汁酸排泄减少,这表明PFAS对肝肠循环的影响可能在心血管风险中起关键作用。
■使用具有高水平低密度和极低密度脂蛋白(LDL和VLDL,分别)胆固醇和主动脉病变发育与人类相似,本研究调查了PFAS混合物暴露与胆固醇升高之间的关联机制.
■对雄性和雌性Ldlr-/-小鼠进行致动脉粥样硬化饮食(Clinton/Cybulsky低脂肪,0.15%的胆固醇),并暴露于代表遗产的5种PFAS的混合物中,replacement,和新兴的亚型(即,PFOA,全氟辛烷磺酸,PFHxS,PFNA,GenX),每个浓度为2mg/L,7周纵向收集血液用于胆固醇测量,和质谱法用于测量循环和粪便胆汁酸。通过RNA测序进行回肠样品的转录组学分析。
■PFAS暴露7周后,在PFAS暴露的女性中,平均循环PFAS水平为21.6、20.1、31.2、23.5和1.5μg/mL,在PFAS暴露的男性中,PFOA的平均循环PFAS水平为12.9、9.7、23、14.3和1.7μg/mL,全氟辛烷磺酸,PFHxS,PFNA,和GenX,分别。7周后,暴露于PFAS的小鼠的总循环胆固醇水平更高(352mg/dL与雌性小鼠415mg/dL和392mg/dLvs.488mg/dL的雄性小鼠暴露于载体或PFAS,分别)。暴露于PFAS的小鼠的总循环胆汁酸水平较高(2,978pg/μL与雌性小鼠中的8,496pg/μL和1,960pg/μL与暴露于媒介物或PFAS的雄性小鼠中的4,452pg/μL,分别)。此外,暴露于PFAS的小鼠的总粪便胆汁酸水平较低(1,797ng/mgvs.女性682ng/mg和1,622ng/mgvs.暴露于车辆或PFAS的男性为670ng/mg,分别)。在回肠,在PFAS暴露的小鼠中,顶端钠依赖性胆汁酸转运蛋白(ASBT)的表达水平较高。
■暴露于PFAS混合物的小鼠表现出更高的循环胆固醇和胆汁酸,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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.