{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:25:36Z","timestamp":1790612736891,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T00:00:00Z","timestamp":1685145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FORICA","award":["2021-PFAS-HT"],"award-info":[{"award-number":["2021-PFAS-HT"]}]},{"name":"European Union\u2014NextGenerationEU and Supporting TAlent in ReSearch@University of Padua","award":["2021-PFAS-HT"],"award-info":[{"award-number":["2021-PFAS-HT"]}]},{"name":"University of Padua","award":["2021-PFAS-HT"],"award-info":[{"award-number":["2021-PFAS-HT"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The large environmental contamination of drinking water by perfluoroalkyl substances (PFAS) markedly increased the plasma levels of pentadecafluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in a Northern Italy population with a high prevalence of arterial hypertension and cardiovascular disease. As the link between PFAS and arterial hypertension is unknown, we investigated if they enhance the biosynthesis of the well-known pressor hormone aldosterone. We found that PFAS increased aldosterone synthase (CYP11B2) gene expression by three-fold and doubled aldosterone secretion and cell and mitochondria reactive oxygen species (ROS) production over controls (p &lt; 0.01 for all) in human adrenocortical carcinoma cells HAC15. They also enhanced the effects of Ang II on CYP11B2 mRNA and aldosterone secretion (p &lt; 0.01 for all). Moreover, when added 1 h before, the ROS scavenger tempol abolished the effect of PFAS on CYP11B2 gene expression. These results indicate that at concentrations mimicking those found in human plasma of exposed individuals, PFAS are potent disruptors of human adrenocortical cell function, and might act as causative factors of human arterial hypertension via increased aldosterone production.<\/jats:p>","DOI":"10.3390\/ijms24119376","type":"journal-article","created":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T16:19:37Z","timestamp":1685204377000},"page":"9376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Aldosterone Biosynthesis Is Potently Stimulated by Perfluoroalkyl Acids: A Link between Common Environmental Pollutants and Arterial Hypertension"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3775-0011","authenticated-orcid":false,"given":"Brasilina","family":"Caroccia","sequence":"first","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3639-4086","authenticated-orcid":false,"given":"Teresa Maria","family":"Seccia","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9766-5970","authenticated-orcid":false,"given":"Giorgia","family":"Pallafacchina","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences\u2014DSB, University of Padua, 35131 Padua, Italy"},{"name":"Neuroscience Institute, Italian National Research Council (CNR), 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6640-5401","authenticated-orcid":false,"given":"Maria","family":"Piazza","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Caputo","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4362-4342","authenticated-orcid":false,"given":"Stefania","family":"Zamberlan","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Rizzuto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences\u2014DSB, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7963-0931","authenticated-orcid":false,"given":"Gian Paolo","family":"Rossi","sequence":"additional","affiliation":[{"name":"Internal Emergency Medicine Unit, Specialized Center for Blood Pressure Disorders-Regione Veneto, Department of Medicine\u2014DIMED, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1210\/en.2012-1422","article-title":"Endocrine-Disrupting Chemicals and Public Health Protection: A Statement of Principles from the Endocrine Society","volume":"153","author":"Brown","year":"2012","journal-title":"Endocrinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1210\/er.2015-1010","article-title":"EDC-2: The Endocrine Society\u2019s Second Scientific Statement on Endocrine-Disrupting Chemicals","volume":"36","author":"Gore","year":"2015","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S2213-8587(20)30129-7","article-title":"Endocrine-Disrupting Chemicals: Implications for Human Health","volume":"8","author":"Kahn","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.envpol.2019.06.033","article-title":"Associations between Long-Term Exposure to Ambient Air Pollution and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis","volume":"252","author":"Liu","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.envint.2019.05.027","article-title":"Per- and Polyfluoroalkyl Substances and Blood Lipid Levels in Pre-Diabetic Adults\u2014Longitudinal Analysis of the Diabetes Prevention Program Outcomes Study","volume":"129","author":"Lin","year":"2019","journal-title":"Environ. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1093\/toxsci\/kfm128","article-title":"Perfluoroalkyl Acids: A Review of Monitoring and Toxicological Findings","volume":"99","author":"Lau","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eabg9065","DOI":"10.1126\/science.abg9065","article-title":"Per- and Polyfluoroalkyl Substances in the Environment","volume":"375","author":"Evich","year":"2022","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1021\/es102769t","article-title":"Environmental Fate and Transport Modeling for Perfluorooctanoic Acid Emitted from the Washington Works Facility in West Virginia","volume":"45","author":"Shin","year":"2011","journal-title":"Environ. Sci. Technol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1136\/oemed-2017-104651","article-title":"Half-Lives of PFOS, PFHxS and PFOA after End of Exposure to Contaminated Drinking Water","volume":"75","author":"Li","year":"2018","journal-title":"Occup. Environ. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1289\/ehp.10009","article-title":"Half-Life of Serum Elimination of Perfluorooctanesulfonate, Perfluorohexanesulfonate, and Perfluorooctanoate in Retired Fluorochemical Production Workers","volume":"115","author":"Olsen","year":"2007","journal-title":"Environ. Health Perspect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.envint.2017.10.026","article-title":"Biomonitoring of Perfluorinated Compounds in Adults Exposed to Contaminated Drinking Water in the Veneto Region, Italy","volume":"110","author":"Ingelido","year":"2018","journal-title":"Environ. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"027007","DOI":"10.1289\/EHP5337","article-title":"Serum Levels of Perfluoroalkyl Substances (PFAS) in Adolescents and Young Adults Exposed to Contaminated Drinking Water in the Veneto Region, Italy: A Cross-Sectional Study Based on a Health Surveillance Program","volume":"128","author":"Pitter","year":"2020","journal-title":"Environ. Health Perspect."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1093\/eurpub\/ckx066","article-title":"Drinking Water Contamination from Perfluoroalkyl Substances (PFAS): An Ecological Mortality Study in the Veneto Region, Italy","volume":"28","author":"Mastrantonio","year":"2018","journal-title":"Eur. J. Public Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12940-020-00656-0","article-title":"Perfluoroalkyl Substances Are Associated with Elevated Blood Pressure and Hypertension in Highly Exposed Young Adults","volume":"19","author":"Pitter","year":"2020","journal-title":"Environ. Health"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.chemosphere.2013.01.012","article-title":"Endocrine-Related Effects of Perfluorooctanoic Acid (PFOA) in Zebrafish, H295R Steroidogenesis and Receptor Reporter Gene Assays","volume":"91","author":"Du","year":"2013","journal-title":"Chemosphere"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.chemosphere.2016.04.070","article-title":"Transcriptional Changes in Steroidogenesis by Perfluoroalkyl Acids (PFOA and PFOS) Regulate the Synthesis of Sex Hormones in H295R Cells","volume":"155","author":"Kang","year":"2016","journal-title":"Chemosphere"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1152\/jappl.1995.78.5.1625","article-title":"O2 Dependence of Pregnenolone and Aldosterone Synthesis in Mitochondria from Bovine Zona Glomerulosa Cells","volume":"78","author":"Raff","year":"1995","journal-title":"J. Appl. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.chemosphere.2014.10.014","article-title":"Perfluoroalkylated Substances (PFAS) Affect Oxidative Stress Biomarkers in Vitro","volume":"129","author":"Long","year":"2015","journal-title":"Chemosphere"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1055\/s-0031-1298019","article-title":"Comparison of Aldosterone Production among Human Adrenocortical Cell Lines","volume":"44","author":"Wang","year":"2012","journal-title":"Horm. Metab. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/s41418-018-0113-8","article-title":"MICU3 Is a Tissue-Specific Enhancer of Mitochondrial Calcium Uptake","volume":"26","author":"Patron","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117322","DOI":"10.1016\/j.lfs.2020.117322","article-title":"Parkin Overexpression Attenuates A\u03b2-Induced Mitochondrial Dysfunction in HEK293 Cells by Restoring Impaired Mitophagy","volume":"244","author":"Wang","year":"2020","journal-title":"Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1210\/endrev\/bnac011","article-title":"Peptidergic G Protein-Coupled Receptor Regulation of Adrenal Function: Bench to Bedside and Back","volume":"43","author":"Lenzini","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_23","first-page":"1029","article-title":"The Biology of Normal Zona Glomerulosa And Aldosterone-Producing Adenoma: Pathological Implications","volume":"39","author":"Seccia","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1089\/ars.2011.4176","article-title":"NADPH Oxidase-Derived H2O2 Contributes to Angiotensin II-Induced Aldosterone Synthesis in Human and Rat Adrenal Cortical Cells","volume":"17","author":"Rajamohan","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1289\/ehp.0800379","article-title":"The C8 Health Project: Design, Methods, and Participants","volume":"117","author":"Frisbee","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1161\/HYPERTENSIONAHA.106.086116","article-title":"Is There an Unrecognized Epidemic of Primary Aldosteronism? (Pro)","volume":"50","author":"Calhoun","year":"2007","journal-title":"Hypertension"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10","DOI":"10.7326\/M20-0065","article-title":"The Unrecognized Prevalence of Primary Aldosteronism: A Cross-Sectional Study","volume":"173","author":"Brown","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1172\/JCI117440","article-title":"Gene Expression, Localization, and Characterization of Endothelin A and B Receptors in the Human Adrenal Cortex","volume":"94","author":"Rossi","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.amjhyper.2004.12.005","article-title":"Clinical and Genetic Correlates of Serum Aldosterone in the Community: The Framingham Heart Study","volume":"18","author":"Kathiresan","year":"2005","journal-title":"Am. J. Hypertens."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa033263","article-title":"Serum Aldosterone and the Incidence of Hypertension in Nonhypertensive Persons","volume":"351","author":"Vasan","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1161\/HYPERTENSIONAHA.122.19134","article-title":"Cardiac Structure and Function Across the Spectrum of Aldosteronism: The Atherosclerosis Risk in Communities Study","volume":"79","author":"Brown","year":"2022","journal-title":"Hypertension"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1042\/CS20171593","article-title":"The Angiotensin Type 2 Receptor in the Human Adrenocortical Zona Glomerulosa and in Aldosterone-Producing Adenoma: Low Expression and No Functional Role","volume":"132","author":"Vanderriele","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1016\/j.jacc.2019.09.057","article-title":"Primary Aldosteronism: JACC State-of-the-Art Review","volume":"74","author":"Rossi","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1136\/oemed-2011-100288","article-title":"Perfluorooctanoic Acid Exposure Is Associated with Elevated Homocysteine and Hypertension in US Adults","volume":"69","author":"Min","year":"2012","journal-title":"Occup. Environ. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.scitotenv.2017.10.074","article-title":"Association of Serum Levels of Perfluoroalkyl Substances (PFASs) with the Metabolic Syndrome (MetS) in Chinese Male Adults: A Cross\u2013Sectional Study","volume":"621","author":"Yang","year":"2018","journal-title":"Sci. Total Environ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1161\/HYPERTENSIONAHA.121.18809","article-title":"Per- and Polyfluoroalkyl Substances and Incident Hypertension in Multi-Racial\/Ethnic Women: The Study of Women\u2019s Health Across the Nation","volume":"79","author":"Ding","year":"2022","journal-title":"Hypertension"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.envint.2016.03.012","article-title":"Perfluoroalkyl Substances in Older Male Anglers in Wisconsin","volume":"91","author":"Christensen","year":"2016","journal-title":"Environ. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1289\/ehp.1307943","article-title":"High Cholesterol in Community and Worker Cohorts","volume":"122","author":"Winquist","year":"2014","journal-title":"Environ. Health Perspect."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.envint.2019.01.007","article-title":"Associations between Repeated Measure of Plasma Perfluoroalkyl Substances and Cardiometabolic Risk Factors","volume":"124","author":"Bergdahl","year":"2019","journal-title":"Environ. Int."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Brase, R.A., Mullin, E.J., and Spink, D.C. (2021). Legacy and Emerging Per-and Polyfluoroalkyl Substances: Analytical Techniques, Environmental Fate, and Health Effects. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22030995"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"113225","DOI":"10.1016\/j.envres.2022.113225","article-title":"Perfluoroalkyl Substance Mixtures and Cardio-Metabolic Outcomes in Highly Exposed Male Workers in the Veneto Region: A Mixture-Based Approach","volume":"212","author":"Batzella","year":"2022","journal-title":"Environ. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108743","DOI":"10.1016\/j.envres.2019.108743","article-title":"A Mortality Study on Male Subjects Exposed to Polyfluoroalkyl Acids with High Internal Dose of Perfluorooctanoic Acid","volume":"179","author":"Girardi","year":"2019","journal-title":"Environ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1016\/j.celrep.2020.01.081","article-title":"A High-Throughput Screening Identifies MICU1 Targeting Compounds","volume":"30","author":"Vallese","year":"2020","journal-title":"Cell Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:43:35Z","timestamp":1760125415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,27]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24119376"],"URL":"https:\/\/doi.org\/10.3390\/ijms24119376","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,27]]}}}