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Transport of perfluoroalkyl substances across human induced pluripotent stem cell-derived intestinal epithelial cells in comparison with primary human intestinal epithelial cells and Caco-2 cells

ABSTRACT: Humans can be exposed to per- and polyfluoroalkyl substances (PFASs) via many exposure routes, including diet, which may lead to several adverse health effects. So far, little is known about PFAS transport across the human intestinal barrier. In the current study, we aimed to assess the transport of 5 PFASs (PFOS, PFOA, PFNA, PFHxS and HFPO-DA) in a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cell (IEC) model. This model was extensively characterized and compared with the widely applied human colonic adenocarcinoma cell line Caco-2 and a human primary IEC-based model, described to most closely resemble in vivo tissue. The hiPSC-derived IEC layers demonstrated polarized monolayers with tight junctions and a mucus layer. The monolayers consisted of enterocytes, stem cells, goblet cells, enteroendocrine cells, and Paneth cells that are also present in native tissue. Transcriptomics analysis revealed distinct differences in gene expression profiles where the hiPSC-derived IECs showed highest expression of intestinal tissue-specific genes relative to the primary IEC-based model, whereas the Caco-2 cells clustered closer to the primary IEC-based model than the hiPSC-derived IECs. The order of PFAS transport was largely similar between the models and the apparent permeability (Papp) values of PFAS in apical to basolateral direction in the hiPSC-derived IEC model were in the following order: PFHxS>PFOA>HFPO-DA>PFNA>PFOS. In conclusion, the hiPSC-derived IEC model highly resembles human intestinal physiology and is therefore a promising novel in vitro model to study transport of chemicals across the intestinal barrier for risk assessment of chemicals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268603 | GEO | 2024/06/05

REPOSITORIES: GEO

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Project description: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 changes of enterohepatic circulation may play a critical role in cardiovascular risk. Objectives: Using a mouse model with high LDL-VLDL cholesterol and aortic lesion development similar to humans, the current study investigates 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, PFNA, PFHxS, GenX), each at a concentration of 2 mg/L, for 7 weeks. 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 weeks 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. PFAS exposure led to elevated circulating cholesterol levels after 7 weeks compared to vehicle mice, with females increasing 18% and males increasing 24%. Total circulating bile acid levels were elevated in PFAS-exposed mice by 230% in males and 290% in females compared to vehicle. PFAS decreased fecal bile acid levels by 62% in females and 59% in males. In the ileum, expression levels of the bile acid reuptake transporter ASBT were increased due to PFAS exposure. Discussion: Mice exposed to a PFAS mixture display increased circulating cholesterol and bile acids perhaps due to changes in enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk due to PFAS.

Project description:PFAS are widely used in commercial products, and so humans have consistent exposure to them via oil- and water-resistant consumer products, fire- fighting foam, and industrial surfactants 1,2. The four PFASs commonly detected in blood, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS) 3,4, are present in drinking water supplies both in northern New England as well as in 27 states nationally 5-8. Animal models shows that PFASs have can have effects on both the endocrine system and on adiposity 9-12. Epidemiological evidence shows that the presence of PFASs in maternal serum is associated with changes in maternal serum lipid and cholesterol composition 13,14. Similarly, serum levels of PFAS in adolescents have been associated with increases in serum cholesterol 15. These findings raise interesting questions about the association of PFAS and lipids in human milk. Research has shown the PFASs are present in human milk 16-18, and human milk is composed primarily of lipids 19. However, the relation between PFAS in milk and milk composition is unclear. The chemical and compositional profiles of breast milk are important because of the potential effects on the developing infant. The developmental origins of health and disease hypothesis suggests that early life exposures, such as toxins and nutrients via breast milk, have lasting effects on health, particularly obesity outcomes 20. In fact, some studies have shown associations between PFAS in maternal serum and infant birth weight and later childhood BMI 14,21. Our study will help to better illuminate the potential effects of maternal exposure to PFASs on infant exposure, both through direct transmission into breast milk and indirectly via influence on the lipid profiles of milk. To investigate how early life exposure to perfluoroalkyl substances (PFAS) may affect childhood health outcomes as mediated through breast milk, we propose the following specific aims: 1. Characterize the levels of PFAS in breast milk samples (n=495) in the NHBCS; 2. Characterize the lipid profiles of breast milk samples (n=495) in the NHBCS; 3. Test the relation between PFAS concentration and breast milk lipid profiles; and 4. Test the association between PFAS concentrations in maternal plasma collected during pregnancy with paired breast milk samples (n=100).

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Transport of perfluoroalkyl substances across human induced pluripotent stem cell-derived intestinal epithelial cells in comparison with primary human intestinal epithelial cells and Caco-2 cells

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