Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-function
Perfluoro-alkyl substances (PFAS) are pollutants, whose exposure was associated with altered levels of low-density lipoproteins (LDL) in humans. Here we investigated this clinical outcome in two groups of young male adults residing in areas of respectively low and high environmental exposure to perf...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Toxicology Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750023001087 |
| _version_ | 1797386779497594880 |
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| author | Iva Sabovic Maria Giovanna Lupo Ilaria Rossi Federica Pedrucci Andrea Di Nisio Stefano Dall’Acqua Nicola Ferri Alberto Ferlin Carlo Foresta Luca De Toni |
| author_facet | Iva Sabovic Maria Giovanna Lupo Ilaria Rossi Federica Pedrucci Andrea Di Nisio Stefano Dall’Acqua Nicola Ferri Alberto Ferlin Carlo Foresta Luca De Toni |
| author_sort | Iva Sabovic |
| collection | DOAJ |
| description | Perfluoro-alkyl substances (PFAS) are pollutants, whose exposure was associated with altered levels of low-density lipoproteins (LDL) in humans. Here we investigated this clinical outcome in two groups of young male adults residing in areas of respectively low and high environmental exposure to perfluoro-octanoic-acid (PFOA). From the Regional Authority data on pollution areas, 38 not-exposed and 59 exposed age-matched participants were evaluated for serum levels of total cholesterol (Total-Chol), LDL-Chol, high-density lipoprotein cholesterol (HDL-Chol), triglycerides (Tgl) and chromatography quantified PFOA. Human hepato-carcinoma cell line HepG2 was exposed to PFOA or perfluoro-octane-sulfonate (PFOS), as legacy PFAAs, and C6O4 as new generation compound. Fluorimetry was used to evaluate the cell-uptake of labelled-LDL. Proprotein Convertase Subtilisin/Kexin 9 (PCSK9)-mediated LDL-receptor (LDL-R) degradation and sub-cellular localization of LDL-R were evaluated by western blot analysis. Serum levels of PFOA, were positively and significantly correlated with Total-Chol (ρ = 0.312, P = 0.002), LDL-Chol (ρ = 0.333, P = 0.001) and Tgl (ρ = 0.375, P < 0.001). Participants with high serum LDL-Chol and Tgl levels, according to the cardiovascular risk, were more prevalent in exposed compared to not-exposed subjects (respectively: 23.7% vs 5.3%, P = 0.023 and 18,6% vs 0%, P = 0.006). Exposure of HepG2 cells to PFOA or C6O4 100 ng/mL was associated with a significantly lower LDL uptake than controls but no major impact of any PFAAs on PCSK9-mediated LDL-R degradation was observed. Compared to controls, exposure to PFAS showed an unbalanced LDL-R partition between membrane and cytoplasm. Endocytosis inducer sphingosine restored LDL-R partition only in samples exposed to C6O4. These data suggest a novel endocytosis-based mechanism of altered lipid trafficking associated with the exposure to legacy PFAS. |
| first_indexed | 2024-03-08T22:14:17Z |
| format | Article |
| id | doaj.art-79b10326b4ff4e23ab7f976e558b5de0 |
| institution | Directory Open Access Journal |
| issn | 2214-7500 |
| language | English |
| last_indexed | 2024-03-08T22:14:17Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Toxicology Reports |
| spelling | doaj.art-79b10326b4ff4e23ab7f976e558b5de02023-12-19T04:16:59ZengElsevierToxicology Reports2214-75002023-12-0111288294Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-functionIva Sabovic0Maria Giovanna Lupo1Ilaria Rossi2Federica Pedrucci3Andrea Di Nisio4Stefano Dall’Acqua5Nicola Ferri6Alberto Ferlin7Carlo Foresta8Luca De Toni9Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, ItalyDepartment of Medicine, University of Padova, Padova, ItalyDepartment of Medicine, University of Padova, Padova, ItalyUnit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, ItalyUnit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, ItalyDepartment of Pharmacological Sciences, University of Padova, Padova, ItalyDepartment of Medicine, University of Padova, Padova, Italy; Veneto Institute of Molecular Medicine, Padova, ItalyUnit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, ItalyUnit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy; Correspondence to: Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, ItalyPerfluoro-alkyl substances (PFAS) are pollutants, whose exposure was associated with altered levels of low-density lipoproteins (LDL) in humans. Here we investigated this clinical outcome in two groups of young male adults residing in areas of respectively low and high environmental exposure to perfluoro-octanoic-acid (PFOA). From the Regional Authority data on pollution areas, 38 not-exposed and 59 exposed age-matched participants were evaluated for serum levels of total cholesterol (Total-Chol), LDL-Chol, high-density lipoprotein cholesterol (HDL-Chol), triglycerides (Tgl) and chromatography quantified PFOA. Human hepato-carcinoma cell line HepG2 was exposed to PFOA or perfluoro-octane-sulfonate (PFOS), as legacy PFAAs, and C6O4 as new generation compound. Fluorimetry was used to evaluate the cell-uptake of labelled-LDL. Proprotein Convertase Subtilisin/Kexin 9 (PCSK9)-mediated LDL-receptor (LDL-R) degradation and sub-cellular localization of LDL-R were evaluated by western blot analysis. Serum levels of PFOA, were positively and significantly correlated with Total-Chol (ρ = 0.312, P = 0.002), LDL-Chol (ρ = 0.333, P = 0.001) and Tgl (ρ = 0.375, P < 0.001). Participants with high serum LDL-Chol and Tgl levels, according to the cardiovascular risk, were more prevalent in exposed compared to not-exposed subjects (respectively: 23.7% vs 5.3%, P = 0.023 and 18,6% vs 0%, P = 0.006). Exposure of HepG2 cells to PFOA or C6O4 100 ng/mL was associated with a significantly lower LDL uptake than controls but no major impact of any PFAAs on PCSK9-mediated LDL-R degradation was observed. Compared to controls, exposure to PFAS showed an unbalanced LDL-R partition between membrane and cytoplasm. Endocytosis inducer sphingosine restored LDL-R partition only in samples exposed to C6O4. These data suggest a novel endocytosis-based mechanism of altered lipid trafficking associated with the exposure to legacy PFAS.http://www.sciencedirect.com/science/article/pii/S2214750023001087Environmental exposureEndocytosisSphingosineLDL-receptorTriglycerides |
| spellingShingle | Iva Sabovic Maria Giovanna Lupo Ilaria Rossi Federica Pedrucci Andrea Di Nisio Stefano Dall’Acqua Nicola Ferri Alberto Ferlin Carlo Foresta Luca De Toni Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-function Toxicology Reports Environmental exposure Endocytosis Sphingosine LDL-receptor Triglycerides |
| title | Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-function |
| title_full | Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-function |
| title_fullStr | Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-function |
| title_full_unstemmed | Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-function |
| title_short | Legacy perfluoro-alkyl substances impair LDL-cholesterol uptake independently from PCSK9-function |
| title_sort | legacy perfluoro alkyl substances impair ldl cholesterol uptake independently from pcsk9 function |
| topic | Environmental exposure Endocytosis Sphingosine LDL-receptor Triglycerides |
| url | http://www.sciencedirect.com/science/article/pii/S2214750023001087 |
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