Ldlr-/- 小鼠暴露于全氟辛烷磺酸混合物以及与循环脂质、胆汁酸排泄和肠道转运体 ASBT 相关的结果。

IF 10.1 1区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES
Environmental Health Perspectives Pub Date : 2024-08-01 Epub Date: 2024-08-23 DOI:10.1289/EHP14339
Katherine Roth, Zhao Yang, Manisha Agarwal, Johnna Birbeck, Judy Westrick, Todd Lydic, Katherine Gurdziel, Michael C Petriello
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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.</p><p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>Male and female <math><mrow><mi>L</mi><mi>d</mi><mi>l</mi><mrow><msup><mrow><mi>r</mi></mrow><mrow><mrow><mo>-</mo><mo>/</mo><mo>-</mo></mrow></mrow></msup></mrow></mrow></math> 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 <math><mrow><mn>2</mn><mspace></mspace><mi>mg</mi><mo>/</mo><mi>L</mi></mrow></math>, 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.</p><p><strong>Results: </strong>After 7 wk of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and <math><mrow><mn>1.5</mn><mspace></mspace><mi>μ</mi><mi>g</mi><mo>/</mo><mi>mL</mi></mrow></math> in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and <math><mrow><mn>1.7</mn><mspace></mspace><mi>μ</mi><mi>g</mi><mo>/</mo><mi>mL</mi></mrow></math> in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. 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引用次数: 0

摘要

背景:以往的流行病学研究多次发现,接触全氟和多氟烷基物质(PFAS)与循环胆固醇升高有关,而循环胆固醇升高是冠心病发病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,这表明全氟辛烷磺酸对肠肝循环的影响可能在心血管风险中起到关键作用:本研究利用一种低密度和极低密度脂蛋白(分别为 LDL 和 VLDL)胆固醇水平较高且主动脉病变发展与人类相似的小鼠模型,调查了暴露于 PFAS 混合物与胆固醇升高之间的关联机制:给雌雄 Ldlr-/- 小鼠喂食致动脉粥样硬化饮食(Clinton/Cybulsky 低脂饮食,胆固醇含量为 0.15%),并将其暴露于 5 种全氟辛烷磺酸混合物(分别代表遗留、替代和新兴亚型,即 PFOA、PFOS、PFHxS、PFNA、GenX)中,每种混合物的浓度为 2 毫克/升,持续 7 周。纵向收集血液以测量胆固醇,并使用质谱法测量循环胆汁酸和粪便胆汁酸。通过 RNA 测序对回肠样本进行转录组分析:结果:暴露于 PFAS 7 周后,PFOA、PFOS、PFHxS、PFNA 和 GenX 在暴露于 PFAS 的女性体内的平均循环 PFAS 含量分别为 21.6、20.1、31.2、23.5 和 1.5 微克/毫升,在暴露于 PFAS 的男性体内的平均循环 PFAS 含量分别为 12.9、9.7、23、14.3 和 1.7 微克/毫升。暴露于 PFAS 的小鼠在 7 周后的总循环胆固醇水平较高(雌性小鼠为 352 毫克/分升,雄性小鼠为 415 毫克/分升;暴露于车辆或 PFAS 的小鼠为 392 毫克/分升,雄性小鼠为 488 毫克/分升)。暴露于 PFAS 的小鼠的总循环胆汁酸水平更高(暴露于车辆或 PFAS 的雌性小鼠分别为 2,978 pg/μL 对 8,496 pg/μL,雄性小鼠分别为 1,960 pg/μL 对 4,452 pg/μL)。此外,暴露于 PFAS 的小鼠粪便总胆汁酸水平较低(暴露于车辆或 PFAS 的雌性小鼠为 1,797 纳克/毫克,雄性小鼠为 682 纳克/毫克;暴露于车辆或 PFAS 的雄性小鼠为 1,622 纳克/毫克,雄性小鼠为 670 纳克/毫克)。在回肠中,暴露于 PFAS 的小鼠顶端钠依赖性胆汁酸转运体 (ASBT) 的表达水平较高:讨论:暴露于全氟辛烷磺酸混合物的小鼠体内循环胆固醇和胆汁酸含量较高,这可能是由于肠肝循环受到了影响。这项研究表明,PFAS 在回肠部位介导的效应可能是暴露于 PFAS 后心血管风险增加的关键介质。https://doi.org/10.1289/EHP14339。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Exposure of Ldlr-/- Mice to a PFAS Mixture and Outcomes Related to Circulating Lipids, Bile Acid Excretion, and the Intestinal Transporter ASBT.

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.

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来源期刊
Environmental Health Perspectives
Environmental Health Perspectives 环境科学-公共卫生、环境卫生与职业卫生
CiteScore
14.40
自引率
2.90%
发文量
388
审稿时长
6 months
期刊介绍: Environmental Health Perspectives (EHP) is a monthly peer-reviewed journal supported by the National Institute of Environmental Health Sciences, part of the National Institutes of Health under the U.S. Department of Health and Human Services. Its mission is to facilitate discussions on the connections between the environment and human health by publishing top-notch research and news. EHP ranks third in Public, Environmental, and Occupational Health, fourth in Toxicology, and fifth in Environmental Sciences.
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