{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:31:04Z","timestamp":1790850664585,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Erectile dysfunction (ED) is increasingly prevalent worldwide, arising from complex interactions between genetic susceptibility and environmental exposure. Real-world exposure involves complex chemical mixtures that may induce synergistic toxicity, which traditional methods struggle to elucidate. This study integrates multi-omics data with reverse network toxicology to systematically identify causal molecular targets and environmental pollutants underlying ED risk, thereby clarifying their mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed summary data-based Mendelian randomization (SMR) integrating proteomic (pQTL), transcriptomic (eQTL), and DNA methylation (mQTL) data to identify plasma proteins, gene expression levels, and methylation sites causally linked to ED, with false positives excluded\n                      <jats:italic>via<\/jats:italic>\n                      HEIDI tests. The identified targets were used to screen environmental pollutants in the Comparative Toxicogenomics Database Toxicity was predicted using ADMETlab 3.0 and ProTox-III, followed by molecular docking to validate interactions. Functional assays in HUVECs assessed the role of FIS1 and the effects of benzo[a]pyrene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      pQTL-SMR analysis identified 28 plasma proteins significantly associated with ED risk, with consistent effects in both discovery and validation cohorts. Integrated eQTL and mQTL analyses further prioritized FIS1, TNFSF12, and CNP as core targets linked to ED at the protein, gene expression, and methylation. Multi-omics evidence revealed that distinct methylation sites within these genes differentially regulate transcription and translation, exerting different impacts on ED. Using these targets, we screened four environmental pollutants\u2014bisphenol F, tetrabromobisphenol A, benzo[a]pyrene, and chlorpyrifos\u2014as potential regulators. Toxicity predictions indicated mutagenic, cytotoxic, or endocrine-disrupting potential for these compounds. Molecular docking confirmed stable binding to the target proteins (binding free energy \u0394G &amp;lt; \u22125.0\u00a0kcal\/mol).\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments showed that inhibition of\n                      <jats:italic>FIS1<\/jats:italic>\n                      expression suppressed HUVEC proliferation and mitochondrial function, and exposure to benzo[a]pyrene similarly impaired these processes and reduced\n                      <jats:italic>FIS1<\/jats:italic>\n                      expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study delineates a potential \u201cenvironmental pollutant\u2013molecular target\u2013ED\u201d mechanistic pathway, offering new insights into the environmental etiology of ED and establishing a theoretical basis for risk assessment and targeted prevention strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1802191","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:26:13Z","timestamp":1775107573000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrating multi-omics, EWAS, and reverse network toxicology to explore environmental pollutant risks in erectile dysfunction"],"prefix":"10.3389","volume":"14","author":[{"given":"Qingtao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]},{"name":"Department of Reproductive Center, Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changshi","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fa","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, the Affiliated Hospital of Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"C1428","DOI":"10.1152\/ajpcell.00006.2009","article-title":"Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2\u2032,3\u2032-cyclic nucleotides and 2\u2032,3\u2032-cyclic nucleotide 3\u2032-phosphodiesterase","volume":"296","author":"Azarashvili","year":"2009","journal-title":"Am. 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