{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:17:58Z","timestamp":1788585478787,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto Nacional de Cardiolog\u00eda, Ignacio Ch\u00e1vez"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: For a long time, it was thought that estrogen degradation metabolites (EDMs) had no role in the female body, but this view has changed. Despite the progress, there are still unknowns about EDMs and the heart. We found that EDMs affect isolated cardiac mitochondria, which may impact heart function. Therefore, our objective was to explore the effect of two EDMs, Met A (2-hydroxyestrone) and Met D (17\u03b2-estradiol-3-methyl-ether), on two experimental models: rat H9c2 cardiomyoblast cells exposed for increasing times to different concentrations of each EDM, and, also, the effects of each metabolite on heart function in intact and oophorectomized (Oopho) rats. Methods: The cell viability, mitochondrial potential, and oxidative stress were assayed in H9c2 cells. Echocardiographic analyses, histological analyses, and an assessment of cardiac damage and oxidative stress in intact and Oopho rats were tested. Results: The strongest negative effects were seen with Met D, where antioxidant capacity decreased and oxidative stress increased significantly. Upon further analysis of the effects of each metabolite on heart function, echocardiographic analysis revealed that cardiac function had not changed in either group, although clear signs of cardiac hypertrophy and fibrosis were observed. Conclusions: Our results suggest EDMs have specific effects on female rats. This study emphasizes the need to thoroughly investigate EDMs\u2019 side effects and impact on the heart.<\/jats:p>","DOI":"10.3390\/metabo16090647","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:10:33Z","timestamp":1788430233000},"page":"647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Exploratory Study on Two Exogenous Estrogenic Metabolites (EDMs): Their Effects In Vitro and on Oophorectomized Female Rats"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8409-7967","authenticated-orcid":false,"given":"Alejandro","family":"Silva-Palacios","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Gabriela","family":"Navarrete-Anastasio","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8261-0010","authenticated-orcid":false,"given":"Elizabeth","family":"Lira-Silva","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"del Valle-Mondrag\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4865-6933","authenticated-orcid":false,"given":"Willy Rams\u00e9s","family":"Garc\u00eda-Ni\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4439-2598","authenticated-orcid":false,"given":"Ang\u00e9lica","family":"Ruiz-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4243-6019","authenticated-orcid":false,"given":"Francisco","family":"Correa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4726-0048","authenticated-orcid":false,"given":"Francisco Javier","family":"Rold\u00e1n-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Outpatient Department, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Vargas-Barr\u00f3n","sequence":"additional","affiliation":[{"name":"Research Coordination, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Aranda","sequence":"additional","affiliation":[{"name":"Department of Pathological Anatomy, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-8121","authenticated-orcid":false,"given":"Salvador","family":"Uribe-Carvajal","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Institute of Cellular Physiology, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8520-5077","authenticated-orcid":false,"given":"Natalia","family":"Pav\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jsbmb.2012.12.014","article-title":"The Structural Biology of Oestrogen Metabolism","volume":"137","author":"Thomas","year":"2013","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Uribe-Alvarez, C., Lira-Silva, E., Morales-Garc\u00eda, L., Chiquete-Felix, N., Rold\u00e1n-G\u00f3mez, F.J., Vargas-Barr\u00f3n, J., Garc\u00eda-Trejo, J.J., Silva-Palacios, A., Uribe-Carvajal, S., and Pav\u00f3n, N. (2025). Estrogen Degradation Metabolites: Some Effects on Heart Mitochondria. J. Xenobiotics, 15.","DOI":"10.3390\/jox15050170"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.biopha.2018.03.078","article-title":"Estrogen: The Necessary Evil for Human Health, and Ways to Tame It","volume":"102","author":"Patel","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114649","DOI":"10.1016\/j.biopha.2023.114649","article-title":"Possible Implication of Estrogenic Compounds on Heart Disease in Menopausal Women","volume":"162","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9220","DOI":"10.1073\/pnas.92.20.9220","article-title":"4-Hydroxylation of Estradiol by Human Uterine Myometrium and Myoma Microsomes: Implications for the Mechanism of Uterine Tumorigenesis","volume":"92","author":"Liehr","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1073\/pnas.93.8.3294","article-title":"4-Hydroxylation of Estrogens as Marker of Human Mammary Tumors","volume":"93","author":"Liehr","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gaikwad, N.W., Yang, L., Pruthi, S., Ingle, J.N., Sandhu, N., Rogan, E.G., and Cavalieri, E.L. (2009). Urine Biomarkers of Risk in the Molecular Etiology of Breast Cancer. Breast Cancer Basic Clin. Res., 3.","DOI":"10.4137\/BCBCR.S2112"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1080\/10715760400013805","article-title":"Effect of Catecholestrogen Administration during Adriamycin-Induced Cardiomyopathy in Ovariectomized Rat","volume":"39","author":"Bujalance","year":"2005","journal-title":"Free Radic. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4840","DOI":"10.1016\/S0021-9258(17)42922-X","article-title":"Antiestrogen Action of 2-Hydroxyestrone on MCF-7 Human Breast Cancer Cells","volume":"259","author":"Schneider","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111754","DOI":"10.1016\/j.ecoenv.2020.111754","article-title":"Opposite Estrogen Effects of Estrone and 2-Hydroxyestrone on MCF-7 Sensitivity to the Cytotoxic Action of Cell Growth, Oxidative Stress and Inflammation Activity","volume":"209","author":"Xu","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kim, H., and Xue, X. (2020). Detection of Total Reactive Oxygen Species in Adherent Cells by 2\u2032,7\u2032-Dichlorodihydrofluorescein Diacetate Staining. J. Vis. Exp.","DOI":"10.3791\/60682-v"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"106595","DOI":"10.1016\/j.jsbmb.2024.106595","article-title":"Cross-Sex Hormonal Replacement: Some Effects over Mitochondria","volume":"244","author":"Cardenas","year":"2024","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1530\/JOE-16-0161","article-title":"In Female Rat Heart Mitochondria, Oophorectomy Results in Loss of Oxidative Phosphorylation","volume":"232","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Prieto-Carrasco, R., Silva-Palacios, A., Rojas-Morales, P., Aparicio-Trejo, O.E., Medina-Reyes, E.I., Hern\u00e1ndez-Cruz, E.Y., S\u00e1nchez-Garibay, C., Salinas-Lara, C., Pav\u00f3n, N., and Rold\u00e1n, F.J. (2021). Unilateral Ureteral Obstruction for 28 Days in Rats Is Not Associated with Changes in Cardiac Function or Alterations in Mitochondrial Function. Biology, 10.","DOI":"10.3390\/biology10070671"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109923","DOI":"10.1016\/j.jnutbio.2025.109923","article-title":"Cardioprotective Effect of Senotherapy in Chronically Obese Middle-Aged Female Rats May Be Mediated by a MERCSs\/Nrf2 Interaction","volume":"142","author":"Nieto","year":"2025","journal-title":"J. Nutr. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1080\/10715760500210145","article-title":"Total Antioxidant Capacity Assay of Human Serum Using Copper(II)-Neocuproine as Chromogenic Oxidant: The CUPRAC Method","volume":"39","author":"Apak","year":"2005","journal-title":"Free Radic. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0378-4347(00)00030-X","article-title":"Free Malondialdehyde Determination in Rat Brain Tissue by Capillary Zone Electrophoresis: Evaluation of Two Protein Removal Procedures","volume":"740","author":"Claeson","year":"2000","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0021-9673(02)01527-3","article-title":"Determination of 8-Hydroxy-2\u2032-Deoxyguanosine in Untreated Urine by Capillary Electrophoresis with UV Detection","volume":"985","year":"2003","journal-title":"J. Chromatogr. A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0039-128X(96)00014-1","article-title":"Modulation of Hypertensive Heart Disease by Estrogen","volume":"61","author":"Grohe","year":"1996","journal-title":"Steroids"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100050","DOI":"10.1016\/j.jpet.2024.100050","article-title":"Protective Effect of 2-Hydroxyestrone and 2-Hydroxyestradiol against Chemically Induced Hepatotoxicity in Vitro and in Vivo","volume":"392","author":"Sun","year":"2025","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yan, S., Chen, Y., Dong, M., Song, W., Belcher, S.M., and Wang, H.-S. (2011). Bisphenol A and 17\u03b2-Estradiol Promote Arrhythmia in the Female Heart via Alteration of Calcium Handling. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025455"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1161\/CIRCULATIONAHA.123.066542","article-title":"Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function","volume":"149","author":"Xu","year":"2024","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.freeradbiomed.2020.06.013","article-title":"Improvement in Cardiac Function of Ovariectomized Rats by Antioxidant Tempol","volume":"160","author":"Phungphong","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1007\/s00424-025-03092-6","article-title":"Targeting NLRP3 Inflammasome Attenuates Cardiac Pyroptosis and Fibrosis in Estrogen-Deficient Diabetic Rats","volume":"477","author":"Phungphong","year":"2025","journal-title":"Pflug. Arch.-Eur. J. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Du, J., Liu, J., Wang, X., Wang, X., Ma, Y., Zhang, S., Li, Z., Ma, J., and Liu, J. (2025). The Role of Estrogen in the Sex Difference for the Risk Factors of Heart Failure with Preserved Ejection Fraction. Biol. Direct, 20.","DOI":"10.1186\/s13062-025-00618-x"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"H1459","DOI":"10.1152\/ajpheart.00247.2020","article-title":"Estrogen Receptor-\u03b1 Prevents Right Ventricular Diastolic Dysfunction and Fibrosis in Female Rats","volume":"319","author":"Cheng","year":"2020","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1161\/CIRCULATIONAHA.119.042267","article-title":"Female Sex Is Protective in a Preclinical Model of Heart Failure With Preserved Ejection Fraction","volume":"140","author":"Tong","year":"2019","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1038\/s41467-022-31544-5","article-title":"Sex Differences in Heart Mitochondria Regulate Diastolic Dysfunction","volume":"13","author":"Cao","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R1599","DOI":"10.1152\/ajpregu.2000.279.5.R1599","article-title":"17\u03b2-Estradiol Prevents Oxidative Stress and Decreases Blood Pressure in Ovariectomized Rats","volume":"279","author":"Delgado","year":"2000","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ngo, V., and Duennwald, M.L. (2022). Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease. Antioxidants, 11.","DOI":"10.3390\/antiox11122345"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Janaszak-Jasiecka, A., P\u0142oska, A., Wiero\u0144ska, J.M., Dobrucki, L.W., and Kalinowski, L. (2023). Endothelial Dysfunction Due to eNOS Uncoupling: Molecular Mechanisms as Potential Therapeutic Targets. Cell. Mol. Biol. Lett., 28.","DOI":"10.1186\/s11658-023-00423-2"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.freeradbiomed.2019.08.012","article-title":"Sulforaphane Protects from Myocardial Ischemia-Reperfusion Damage through the Balanced Activation of Nrf2\/AhR","volume":"143","author":"Zazueta","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"474","DOI":"10.37349\/edd.2024.00062","article-title":"Mitochondrial ROS, a Trigger for Mitochondrial Dysfunction and Inflammasome Activation and a Therapeutic Target in Liver Diseases","volume":"3","author":"Jaara","year":"2024","journal-title":"Explor. Dig. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"72","DOI":"10.4103\/cjp.cjp_102_20","article-title":"Deficit of Female Sex Hormones Desensitizes Rat Cardiac Mitophagy","volume":"64","author":"Kampaengsri","year":"2021","journal-title":"Chin. J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhao, W., Hou, Y., Song, X., Wang, L., Zhang, F., Zhang, H., Yu, H., and Zhou, Y. (2021). Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.713819"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Yan, X., Ma, D., Li, R., Xu, J., Zou, Y., and He, M. (2025). The Role of Mitochondrial Dysfunction in Ovarian Granulosa Cells in Polycystic Ovary Syndrome. Endocr. Connect., 14.","DOI":"10.1530\/EC-25-0186"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yamada, K., Ito, M., Nunomura, H., Nishigori, T., Furuta, A., Yoshida, M., Yamaki, A., Shozu, K., Yasuda, I., and Tsuda, S. (2025). Interplay of Oxidative Stress, Autophagy, and Rubicon in Ovarian Follicle Dynamics: Orchestrating Ovarian Aging. Antioxidants, 14.","DOI":"10.20944\/preprints202507.0406.v1"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1139\/cjpp-2023-0412","article-title":"The Influence of Estrogen on Myocardial Post-Translational Modifications and Cardiac Function in Women","volume":"102","author":"Shorthill","year":"2024","journal-title":"Can. J. Physiol. Pharmacol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/647\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:55:10Z","timestamp":1788584110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/647"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["metabo16090647"],"URL":"https:\/\/doi.org\/10.3390\/metabo16090647","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]}}}