{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:20:45Z","timestamp":1792167645778,"version":"4.4.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019971","name":"Luzhou Science and Technology Bureau","doi-asserted-by":"publisher","award":["15197"],"award-info":[{"award-number":["15197"]}],"id":[{"id":"10.13039\/501100019971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      In recent years, heavy metal exposure has been increasingly implicated in the onset and progression of various diseases. However, the relationship between heavy metal exposure and male erectile function remains insufficiently understood. This study aimed to investigate the association between cadmium chloride (CdCl\n                      <jats:sub>2<\/jats:sub>\n                      ) and erectile dysfunction (ED), and to explore the underlying molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An integrated analytical framework was established to elucidate the potential link between cadmium chloride and ED. Key cadmium-ED related genes were first identified through comprehensive analyses using multiple databases, including PubChem, TargetNet, GeneCards, and STRING. Subsequently, Mendelian randomization (MR) analysis was conducted to assess the causal relationship between cadmium associated genes and ED. Finally,\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments were carried out to examine the effects of varying concentrations of CdCl\n                      <jats:sub>2<\/jats:sub>\n                      on human umbilical vein endothelial cells (HUVECs), focusing on alterations in cell viability and gene expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Network toxicology analysis identified estrogen receptor 2 (\n                      <jats:italic>ESR2<\/jats:italic>\n                      ) as a key gene mediating the link between cadmium chloride and ED. MR analysis demonstrated that increased\n                      <jats:italic>ESR2<\/jats:italic>\n                      expression was causally associated with a higher risk of ED.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments further showed that CdCl\n                      <jats:sub>2<\/jats:sub>\n                      exposure led to a concentration- and time-dependent reduction in HUVEC viability, accompanied by upregulation of\n                      <jats:italic>ESR2<\/jats:italic>\n                      expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      CdCl\n                      <jats:sub>2<\/jats:sub>\n                      exposure may be associated with the onset and progression of erectile dysfunction, and its potential effects may involve multiple aspects, including vascular endothelial dysfunction, disruption of endocrine homeostasis, and abnormal\n                      <jats:italic>ESR2<\/jats:italic>\n                      related signaling.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1798494","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T04:45:23Z","timestamp":1776228323000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Cadmium chloride and erectile dysfunction: integrative evidence from network toxicology, Mendelian randomization, and in vitro validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuqi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qilong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyang","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College","place":["Mianyang, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfu","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Urology, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2021.106406","article-title":"Cadmium exposure impairs pancreatic \u03b2-cell function and exaggerates diabetes by disrupting lipid metabolism","volume":"149","author":"Hong","year":"2021","journal-title":"Environ Int"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2020.105879","article-title":"Cadmium exposure and risk of breast cancer: A dose-response meta-analysis of cohort studies","volume":"142","author":"Filippini","year":"2020","journal-title":"Environ Int"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2017.05.224","article-title":"The role of cadmium in obesity and diabetes","author":"Tinkov","year":"2017","journal-title":"Sci Total Environ"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2024.153787","article-title":"Reproductive toxicity of cadmium stress in male animals","volume":"504","author":"Zhang","year":"2024","journal-title":"Toxicology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13350","article-title":"Review of cadmium exposure and smoking-independent effects on atherosclerotic cardiovascular disease in the general population","volume":"290","author":"Fagerberg","year":"2021","journal-title":"J Intern Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.111027","article-title":"Roflumilast extenuates inflammation and oxidative stress in cadmium-induced hepatic and testicular injury in rats","volume":"124","author":"Sulayman Aboulqassim","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/toxics11040322","article-title":"Effects of endocrine-disrupting heavy metals on human health","volume":"11","author":"Liu","year":"2023","journal-title":"Toxics"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2024.118966","article-title":"Plastic-related endocrine disrupting chemicals significantly related to the increased risk of estrogen-dependent diseases in women","volume":"252","author":"Chitakwa","year":"2024","journal-title":"Environ Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"16003","DOI":"10.1038\/nrdp.2016.3","article-title":"Erectile dysfunction","volume":"2","author":"Yafi","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/bf02332973","article-title":"Neurogenic erectile dysfunction","volume":"11","author":"Lue","year":"2001","journal-title":"Clin Auton Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2009.01356.x","article-title":"The endothelial-erectile dysfunction connection: an essential update","volume":"6","author":"Costa","year":"2009","journal-title":"J Sex Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/3.5.455","article-title":"Erectile dysfunction: an overview","volume":"3","author":"Fabbri","year":"1997","journal-title":"Hum Reprod Update"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-022-20910-x","article-title":"Associations between exposure to different heavy metals and self-reported erectile dysfunction: a population-based study using data from the 2001\u20132004 National Health and Nutrition Examination Survey","volume":"29","author":"Liu","year":"2022","journal-title":"Environ Sci pollut Res Int"},{"key":"B14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.tox.2015.12.004","article-title":"Different mechanisms for lead acetate, aluminum and cadmium sulfate in rat corpus cavernosum","volume":"340","author":"Senbel","year":"2016","journal-title":"Toxicology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9384(94)90332-8","article-title":"Cadmium-induced sexual dysfunction does not involve increased hepatic metabolism of testosterone nor increased circulating levels of corticosterone","volume":"56","author":"Clark","year":"1994","journal-title":"Physiol Behav"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2025.117911","article-title":"Exploring the mechanisms of lithium neurotoxicity based on network toxicology and molecular docking","volume":"292","author":"Wei","year":"2025","journal-title":"Ecotoxicol Environ Saf"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2025.108918","article-title":"Integrating network toxicology and Mendelian randomization to uncover the role of AHR in linking air pollution to male reproductive health","volume":"135","author":"Li","year":"2025","journal-title":"Reprod Toxicol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2025.154139","article-title":"Cadmium treatment induces oxidative damage and apoptosis in vitro skeletal muscle cells","volume":"515","author":"Wenhong","year":"2025","journal-title":"Toxicology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2025.109026","article-title":"Identification of key genes involved in phthalate-induced male erectile dysfunction: Insights from network toxicology and bioinformatics analyses","volume":"137","author":"Li","year":"2025","journal-title":"Reprod Toxicol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1038\/s41598-025-85799-1","article-title":"Combining machine learning and single-cell sequencing to identify key immune genes in sepsis","volume":"15","author":"Wang","year":"2025","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.21037\/tau-24-365","article-title":"Causal relationship between serum uric acid levels and male infertility: a bidirectional two-sample Mendelian randomization study","volume":"13","author":"Li","year":"2024","journal-title":"Transl Androl Urol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"V\u00f5sa","year":"2021","journal-title":"Nat Genet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.11.004","article-title":"GWAS identifies risk locus for erectile dysfunction and implicates hypothalamic neurobiology and diabetes in etiology","volume":"104","author":"Bovijn","year":"2019","journal-title":"Am J Hum Genet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1186\/s13098-025-01700-0","article-title":"Protective effect of antidiabetic drugs against male infertility: evidence from Mendelian randomization","volume":"17","author":"Li","year":"2025","journal-title":"Diabetol Metab Syndr"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.16927","article-title":"Knockdown of miR-423-5p simultaneously upgrades the eNOS and VEGFa pathways in ADSCs and improves erectile function in diabetic rats","volume":"25","author":"Zhou","year":"2021","journal-title":"J Cell Mol Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.90354.2008","article-title":"Transcriptional profiling of human cavernosal endothelial cells reveals distinctive cell adhesion phenotype and role for claudin 11 in vascular barrier function","volume":"39","author":"Wessells","year":"2009","journal-title":"Physiol Genomics"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00404.x","article-title":"NS11021, a novel opener of large-conductance Ca(2+)-activated K(+) channels, enhances erectile responses in rats","volume":"158","author":"Kun","year":"2009","journal-title":"Br J Pharmacol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/tox.23866","article-title":"ROS-mediated PERK-CHOP pathway plays an important role in cadmium-induced HepG2 cells apoptosis","volume":"38","author":"Zhaohui","year":"2023","journal-title":"Environ Toxicol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2025.154046","article-title":"Cadmium exposure induces inflammation, oxidative stress and DNA damage in HUVEC and promotes THP-1 adhesion: A possible mechanism on the formation of atherosclerotic plaque","volume":"511","author":"Liu","year":"2025","journal-title":"Toxicology"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.70115","article-title":"Cadmium reduces VE-cadherin expression in endothelial cells through activation of the Notch signaling pathway","volume":"39","author":"Zhang","year":"2025","journal-title":"J Biochem Mol Toxicol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"355","DOI":"10.3892\/etm.2022.11282","article-title":"Cadmium exposure enhances VE-cadherin expression in endothelial cells via suppression of ROCK signaling","volume":"23","author":"Li","year":"2022","journal-title":"Exp Ther Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2009.01.011","article-title":"Mechanisms of cadmium carcinogenesis","volume":"238","author":"Joseph","year":"2009","journal-title":"Toxicol Appl Pharmacol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2017.07.021","article-title":"The environment and male reproduction: The effect of cadmium exposure on reproductive function and its implication in fertility","volume":"73","author":"de Angelis","year":"2017","journal-title":"Reprod Toxicol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.0260189","article-title":"Sexual behaviour of male rats sterilized by cadmium","volume":"26","author":"Madlafousek","year":"1971","journal-title":"J Reprod Fertil"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/and.12866","article-title":"Effect of quercetin on cadmium chloride-induced impairments in sexual behaviour and steroidogenesis in male Wistar rats","volume":"50","author":"Ujah","year":"2018","journal-title":"Andrologia"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr304","article-title":"Nitric oxide synthases: regulation and function","volume":"33","author":"F\u00f6rstermann","year":"2012","journal-title":"Eur Heart J"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20123022","article-title":"The role of endothelial dysfunction in peripheral blood nerve barrier: Molecular mechanisms and pathophysiological implications","volume":"20","author":"Maiuolo","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.240126","article-title":"Yes-associated protein promotes endothelial-mesenchymal transition to mediate diabetes mellitus erectile dysfunction by phosphorylating Smad3","author":"Xiao","year":"2024","journal-title":"World J Mens Health"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2020.128346","article-title":"Cadmium induced BEAS-2B cells apoptosis and mitochondria damage via MAPK signaling pathway","volume":"263","author":"Cao","year":"2021","journal-title":"Chemosphere"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cbi.2005.12.009","article-title":"Free radicals, metals and antioxidants in oxidative stress-induced cancer","volume":"160","author":"Valko","year":"2006","journal-title":"Chem Biol Interact"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.123.323617","article-title":"Heavy metal exposure and cardiovascular disease","volume":"134","author":"Pan","year":"2024","journal-title":"Circ Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1080\/09603123.2013.835032","article-title":"Cellular mechanisms of cadmium-induced toxicity: a review","volume":"24","author":"Rani","year":"2014","journal-title":"Int J Environ Health Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1177\/014107689909200402","article-title":"Nitric oxide: discovery and impact on clinical medicine","volume":"92","author":"Moncada","year":"1999","journal-title":"J R Soc Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2007.05.003","article-title":"Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis","volume":"43","author":"Biagioli","year":"2008","journal-title":"Cell Calcium"},{"key":"B45","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.niox.2020.05.003","article-title":"Estrogen receptor (ESR1 and ESR2)-mediated activation of eNOS-NO-cGMP pathway facilitates high altitude acclimatization","volume":"102","author":"Pooja","year":"2020","journal-title":"Nitric Oxide"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gah023","article-title":"Augmented endothelial nitric oxide synthase (eNOS) protein expression in human pregnant myometrium: possible involvement of eNOS promoter activation by estrogen via both estrogen receptor (ER)alpha and ERbeta","volume":"10","author":"Kakui","year":"2004","journal-title":"Mol Hum Reprod"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2025.177598","article-title":"FKBP5 mediates glucocorticoid signaling in estrogen deficiency-associated endothelial dysfunction","volume":"996","author":"Zhu","year":"2025","journal-title":"Eur J Pharmacol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1210\/er.2015-1010","article-title":"EDC-2: the endocrine society's second scientific statement on endocrine-disrupting chemicals","volume":"36","author":"Gore","year":"2015","journal-title":"Endocr Rev"},{"key":"B49","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1152\/physrev.00018.2016","article-title":"Estrogens in male physiology","volume":"97","author":"Cooke","year":"2017","journal-title":"Physiol Rev"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1798494\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T04:45:36Z","timestamp":1776228336000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1798494\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":49,"alternative-id":["10.3389\/fendo.2026.1798494"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1798494","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]},"article-number":"1798494"}}