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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 2 mg=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 1:5 [micro]g/mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1:7 [micro]g/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 (352 mg/dL vs. 415 mg/dL in female mice and 392 mg/dL vs. 488 mg/dL in male mice exposed to vehicle or PFAS, respectively). Total circulating bile acid levels were higher in PFAS-exposed mice (2,978 pg/[micro]L vs. 8,496 pg/[micro]L in female mice and 1,960 pg/[micro]L vs. 4,452 pg/[micro]L 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, Introduction Per- and polyfluoroalkyl substances (PFAS) are a large family of synthetically manufactured chemicals used for their surfactant properties in industrial and consumer products, including nonstick cookware and food storage, [...]

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 2 mg/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 1.5 μg/mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7 μg/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 (352 mg/dL vs. 415 mg/dL in female mice and 392 mg/dL vs. 488 mg/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. [ABSTRACT FROM AUTHOR]

Continental large igneous provinces are among the largest magmatic events on Earth, characteristically manifesting at the surface as stacks of monotonous flood basalt lavas that form through a dynamic pattern of eruptive pulses separated by hiatuses. Such dynamic patterns may be difficult to detect from the composition of the lavas. Instead, lava crystal cargoes can be used to study how the eruption cycles inherent to continental large igneous provinces are moderated by episodic recharge and evacuation at multiple crustal levels. Here, we present a stratigraphically well-constrained series of 56 flood basalt flows from the Eocene Initial Phase of magmatic activity in East Africa. These flows and their crystal cargo permit temporal insight into the development of one of the youngest and best-preserved continental large igneous provinces. The stratiform mafic lavas exposed in northern Kenya consist of alternating aphyric and plagioclase-phyric lava packages consistent with periods of eruption punctuated by volcanic hiatus, where magmas stall and crystallize plagioclase at medium to shallow crustal levels. Plagioclase compositions (n  = 541) exhibit little intra-crystal or intra-sample compositional diversity. Intra-crystal equilibrium calculations for Sr and Ti indicate internal chemical equilibrium, requiring storage at high temperatures over a prolonged time interval (10 000–100 000 years). Using a series of seven interlinked partial crystal fractionation models under equilibrium conditions, we replicate the observed stratigraphic patterns in plagioclase composition. We find that the balance between recharge, evacuation, and diffusive equilibration within a shallow magmatic system controls the composition of plagioclase in these flood basalts. We conclude that the shallow fractionation system modulates eruptive cycles and thus constitutes a critical component in studies of continental large igneous provinces. [ABSTRACT FROM AUTHOR]