{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:49:07Z","timestamp":1778546947300,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T00:00:00Z","timestamp":1731888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Preeclampsia (PE) is a severe hypertensive pregnancy disorder characterized by endothelial dysfunction, placental ischemia and oxidative stress; however, reliable non-invasive biomarkers for early detection are limited. In this study, untargeted solid-phase microextraction with gas chromatography\u2013mass spectrometry (SPME-GC-MS) was used to analyze volatile organic compounds in the urine of 45 women with PE and 46 healthy controls. Among the 29 metabolites identified, hexadecanal\u2014a product of lipid peroxidation and sphingolipid metabolism\u2014was found to be the most significant, with an area under the receiver operating characteristic (ROC) curve of 0.618, highlighting its diagnostic potential. This result emphasizes the role of hexadecanal in oxidative stress and placental dysfunction, which are central to the pathophysiology of PE. The results support hexadecanal as a potential non-invasive biomarker while demonstrating the efficacy of SPME-GC-MS in identifying metabolic disorders associated with PE, paving the way for further research to confirm its clinical utility for early diagnosis and risk assessment.<\/jats:p>","DOI":"10.3390\/ijms252212371","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T07:45:27Z","timestamp":1731915927000},"page":"12371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Untargeted Urinary Volatilomics Reveals Hexadecanal as a Potential Biomarker for Preeclampsia"],"prefix":"10.3390","volume":"25","author":[{"given":"Marina","family":"Pehli\u0107","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4005-5394","authenticated-orcid":false,"given":"Stipe","family":"Duman\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7932-5817","authenticated-orcid":false,"given":"Mila","family":"Radan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Chemistry and Technology, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jelena","family":"Gali\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Chemistry and Technology, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Branimir","family":"Gruica","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Chemistry and Technology, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2259-2871","authenticated-orcid":false,"given":"Sandra","family":"Marijan","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, University of Split School of Medicine, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marko","family":"Vuli\u0107","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41572-023-00417-6","article-title":"Pre-eclampsia","volume":"9","author":"Dimitriadis","year":"2023","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Afrose, D., Chen, H., Ranashinghe, A., Liu, C.C., Henessy, A., Hansbro, P.M., and McClements, L. (2022). The diagnostic potential of oxidative stress biomarkers for preeclampsia: Systematic review and meta-analysis. Biol. Sex Differ., 13.","DOI":"10.1186\/s13293-022-00436-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preghy.2017.01.004","article-title":"Oxidative stress in pre-eclampsia; have we been looking in the wrong place?","volume":"8","author":"Williamson","year":"2017","journal-title":"Pregnancy Hypertens."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3892\/ijmm.2023.5292","article-title":"Predictive value of the sFlt-1\/PlGF ratio in women with suspected preeclampsia: An update (Review)","volume":"52","author":"Velegrakis","year":"2023","journal-title":"Int. J. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1161\/01.HYP.0000141085.98320.01","article-title":"Poston, Oxidative stress and preeclampsia: Rationale for antioxidant clinical trials","volume":"44","author":"Raijmakers","year":"2004","journal-title":"Hypertension"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1080\/19396368.2018.1482968","article-title":"Application of metabolomics to preeclampsia diagnosis","volume":"64","author":"Gh","year":"2018","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pathmasiri, W., Rushing, B.R., McRitchie, S., Choudhari, M., Du, X., Smirnov, A., Pelleigrini, M., Thompson, M.J., Sakaguchi, C.A., and Nieman, D.C. (2024). Untargeted metabolomics reveal signatures of a healthy lifestyle. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-64561-z"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100143","DOI":"10.1016\/j.medidd.2022.100143","article-title":"Metabolic profiling of serum and urine in preeclampsia and gestational diabetes in early pregnancy","volume":"16","author":"Agarwal","year":"2022","journal-title":"Med. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41392-023-01399-3","article-title":"Small molecule metabolites: Discovery of biomarkers and therapeutic targets","volume":"8","author":"Qiu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-4939-1258-2_1","article-title":"Overview of mass spectrometry-based metabolomics: Opportunities and challenges","volume":"1198","author":"Gowda","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.molcel.2012.04.033","article-title":"The Sj\u00f6gren-Larsson Syndrome Gene Encodes a Hexadecenal Dehydrogenase of the Sphingosine 1-Phosphate Degradation Pathway","volume":"46","author":"Nakahara","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.freeradbiomed.2012.06.025","article-title":"An overview of the chemistry and biology of reactive aldehydes","volume":"59","author":"Fritz","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41573-021-00233-1","article-title":"Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy","volume":"20","author":"Forman","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jpba.2017.07.013","article-title":"GC\u2013MS based metabolomics used for the identification of cancer volatile organic compounds as biomarkers","volume":"147","author":"Lubes","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.trac.2014.07.005","article-title":"Solid-phase microextraction in metabolomics","volume":"61","author":"Bojko","year":"2014","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Aggarwal, P., Baker, J., Boyd, M.T., Coyle, S., Probert, C., and Chapman, E.A. (2020). Optimisation of urine sample preparation for headspace-solid phase microextraction gas chromatography-mass spectrometry: Altering sample ph, sulphuric acid concentration and phase ratio. Metabolites, 10.","DOI":"10.3390\/metabo10120482"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.trac.2019.01.009","article-title":"Recent developments and applications of solid phase microextraction as a sample preparation approach for mass-spectrometry-based metabolomics and lipidomics","volume":"113","author":"Gionfriddo","year":"2019","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"888","DOI":"10.4239\/wjd.v13.i10.888","article-title":"Metabonomics fingerprint of volatile organic compounds in serum and urine of pregnant women with gestational diabetes mellitus","volume":"13","author":"Sana","year":"2022","journal-title":"World J. Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Charkiewicz, K., Goscik, J., Blachnio-Zabielska, A., Raba, G., Sakowicz, A., Kalinka, J., Chabowski, A., and Laudanski, P. (2017). Sphingolipids as a new factor in the pathomechanism of preeclampsia\u2014Mass spectrometry analysis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177601"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chiarello, D.I., Abad, C., Rojas, D., Toledo, F., V\u00e1zquez, C.M., Mate, A., Sobrevia, L., and Mar\u00edn, R. (2020). Oxidative stress: Normal pregnancy versus preeclampsia. Biochim. Biophys. Acta Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2018.12.005"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.freeradbiomed.2015.10.422","article-title":"The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions","volume":"89","author":"OJovanovic","year":"2015","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Epizzimenti, S., Ciamporcero, E.S., Edaga, M., Epettazzoni, P., Earcaro, A., Ecetrangolo, G., Eminelli, R., Edianzani, C., Elepore, A., and Egentile, F. (2013). Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front. Physiol., 4.","DOI":"10.3389\/fphys.2013.00242"},{"key":"ref_23","first-page":"1395","article-title":"Substrate specificity, plasma membrane localization, and lipid modification of the aldehyde dehydrogenase ALDH3B1","volume":"1831","author":"Kitamura","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Cell Biol. Lipids"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mallela, S.K., Merscher, S., and Fornoni, A. (2022). Implications of Sphingolipid Metabolites in Kidney Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084244"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"534","DOI":"10.34067\/KID.0006322020","article-title":"Sphingolipids and Kidney Disease: Possible Role of Preeclampsia and Intrauterine Growth Restriction (IUGR)","volume":"2","author":"Yokota","year":"2021","journal-title":"Kidney360"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1161\/01.HYP.0000188408.49896.c5","article-title":"Preeclampsia: Recent insights","volume":"46","author":"Roberts","year":"2005","journal-title":"Hypertension"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1089\/ars.2020.8151","article-title":"Sulfur Metabolism Under Stress","volume":"33","author":"Miller","year":"2020","journal-title":"Antioxidants Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/S0140-6736(05)66350-7","article-title":"Screening for pre-eclampsia: The quest for the Holy Grail?","volume":"365","author":"Audibert","year":"2005","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.pedneo.2016.10.005","article-title":"The sFlt-1\/PlGF ratio as a predictor for poor pregnancy and neonatal outcomes","volume":"58","author":"Chang","year":"2017","journal-title":"Pediatr. Neonatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.preghy.2021.12.003","article-title":"Clinical interpretation and implementation of the sFlt-1\/PlGF ratio in the prediction, diagnosis and management of preeclampsia","volume":"27","author":"Verlohren","year":"2021","journal-title":"Pregnancy Hypertens."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nmeth.3393","article-title":"MS-DIAL: Data-independent MS\/MS deconvolution for comprehensive metabolome analysis","volume":"12","author":"Tsugawa","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chen, Y., Li, E.M., and Xu, L.Y. (2022). Guide to Metabolomics Analysis: A Bioinformatics Workflow. 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