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Here, a biomarker\u2010integrated, fluorescent reporter\u2010based reproductive organ\u2010on\u2010a\u2010chip platform that recapitulates the multicellular composition, 3D architecture, endocrine signaling, and cyclic dynamics of the human menstrual cycle, is presented. The system is constructed using primary human theca, granulosa, endometrial stromal and stem cells, vascular endothelial cells, uterine macrophages, and myometrial smooth muscle cells, compartmentalized within collagen\u2013hyaluronic acid hydrogels. Early\u2010response toxicity biomarkers\u2014ANGPTL4 (ovary) and SERPINB2 (endometrium)\u2014are genetically linked to mCherry or GFP fluorescent reporters, enabling real\u2010time, cell\u2010type\u2010specific visualization of toxicant\u2010induced stress. Transcriptomic profiling, KEGG pathway enrichment, and gene knockdown studies confirm ANGPTL4 and SERPINB2 as functional mediators of toxic injury, not just passive indicators. Upon exposure to dioxin and other reproductive toxicants, the platform shows strong, region\u2010specific fluorescent responses that preceded changes detected by conventional cytotoxicity assays. This system demonstrates high sensitivity, temporal precision, and mechanistic insight, offering a scalable and physiologically relevant tool for high\u2010content reproductive toxicology screening. Furthermore, it supports endocrine crosstalk between the ovary and uterus, and dynamic responses across the menstrual cycle, enabling future applications in personalized toxicity prediction and preclinical safety evaluation.<\/jats:p>","DOI":"10.1002\/advs.202511098","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:30:48Z","timestamp":1768469448000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Biomarker\u2010Driven Ovary\u2013Endometrium Organ\u2010on\u2010a\u2010Chip Mimicking 3D Multicellular Complexity and Menstrual Cyclicity for Predicting Reproductive Toxicity"],"prefix":"10.1002","volume":"13","author":[{"given":"Soo\u2010Rim","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Health Sciences and Technology GAIHST Gachon University  Incheon 21999 Republic of Korea"},{"name":"Department of Molecular Medicine School of Medicine Gachon University  Incheon 406\u2013840 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u2010kyung","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology GAIHST Gachon University  Incheon 21999 Republic of Korea"},{"name":"Department of Molecular Medicine School of Medicine Gachon University  Incheon 406\u2013840 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choon\u2010Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology GAIHST Gachon University  Incheon 21999 Republic of Korea"},{"name":"Department of Molecular Medicine School of Medicine Gachon University  Incheon 406\u2013840 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Hum","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Chuncheon Sacred Heart Hospital Hallym University College of Medicine  Chuncheon 24252 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung\u2010Chul","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Physiology Lee Gil Ya Cancer and Diabetes Institute Gachon University College of Medicine  Incheon 21999 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YunJae","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology GAIHST Gachon University  Incheon 21999 Republic of Korea"},{"name":"Department of Microbiology College of Medicine Gachon University  Incheon 21999 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3267-0127","authenticated-orcid":false,"given":"In\u2010Sun","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology GAIHST Gachon University  Incheon 21999 Republic of Korea"},{"name":"Department of Molecular Medicine School of Medicine Gachon University  Incheon 406\u2013840 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1088\/1758-5090\/abbd29"},{"key":"e_1_2_10_2_1","volume":"39","author":"Wu J. 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