{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:06:07Z","timestamp":1790683567833,"version":"4.1.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H01880"],"award-info":[{"award-number":["17H01880"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H04619"],"award-info":[{"award-number":["18H04619"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP 26340038"],"award-info":[{"award-number":["JP 26340038"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Yoshindo"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process remains unclear. By Cap Analysis of Gene Expression method, we found that neonatal DES exposure up-regulated inflammatory <jats:italic>Cxcl<\/jats:italic> chemokines 2, 3, 5, and 7 located in the 5qE1 region in the vaginal epithelium of mice 70 days after birth. When we examined the gene expressions of these genes much earlier stages, we found that neonatal DES exposure increased these <jats:italic>Cxcl<\/jats:italic> chemokine genes expression even after 17 days after birth. It implies the DES-mediated persistent activation of inflammatory genes. Intriguingly, we also detected DES-induced non-coding RNAs from a region approximately 100 kb far from the <jats:italic>Cxcl<\/jats:italic>5 gene. The non-coding RNA up-regulation by DES exposure was confirmed on the 17-day vagina and continued throughout life, which may responsible for the activation of Cxcl chemokines located in the same region, 5qE1. This study shows that neonatal administration of DES to mice causes long-lasting up-regulation of inflammatory <jats:italic>Cxcl<\/jats:italic> chemokines in the vaginal epithelium. DES-mediated inflammation may be associated with the carcinogenic process.<\/jats:p>","DOI":"10.1371\/journal.pone.0280421","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T18:03:11Z","timestamp":1678989791000},"page":"e0280421","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Neonatal administration of synthetic estrogen, diethylstilbestrol to mice up-regulates inflammatory Cxclchemokines located in the 5qE1 region in the vaginal epithelium"],"prefix":"10.1371","volume":"18","author":[{"given":"Ayaka","family":"Kitamura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Jiayue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Suwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiko","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Wada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9657-6554","authenticated-orcid":true,"given":"Hajime","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"pone.0280421.ref001","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3390\/cells9010013","article-title":"Perturbation of nuclear hormone receptors by endocrine disrupting chemicals: mechanisms and pathological consequences of exposure","volume":"9","author":"J. M. Hall","year":"2020","journal-title":"Cells"},{"key":"pone.0280421.ref002","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1111\/andr.12206","article-title":"Environmental signaling: from environmental estrogens to endocrine-disrupting chemicals and beyond","volume":"4","author":"J. A. McLachlan","year":"2016","journal-title":"Andrology"},{"key":"pone.0280421.ref003","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1001\/jama.1976.03270110011002","article-title":"Exposure in utero to diethylstilbestrol and related synthetic hormones","volume":"236","author":"E Adam","year":"1976","journal-title":"JAMA"},{"key":"pone.0280421.ref004","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1056\/NEJM197104222841604","article-title":"Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women","volume":"284","author":"A. L. Herbst","year":"1971","journal-title":"N Engl J Med"},{"key":"pone.0280421.ref005","unstructured":"International Agency for Research on Cancer (IARC). Summaries & Evaluations. DIETHYLSTILBOESTROL (Group 1), Supplement 7, 273 (1987)."},{"key":"pone.0280421.ref006","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1006\/dbio.2001.0413","article-title":"Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract","volume":"238","author":"J. F. Couse","year":"2001","journal-title":"Dev Biol."},{"key":"pone.0280421.ref007","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/sj.onc.1207207","article-title":"Estrogen-independent activation of erbBs signaling and estrogen receptor alpha in the mouse vagina exposed neonatally to diethylstilbestrol","volume":"23","author":"S. Miyagawa","year":"2004","journal-title":"Oncogene"},{"key":"pone.0280421.ref008","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1677\/jme.0.0320663","article-title":"Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol","volume":"32","author":"S. Miyagawa","year":"2004","journal-title":"J Mol Endocrinol"},{"key":"pone.0280421.ref009","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1073\/pnas.80.12.3743","article-title":"Growth of normal mouse vaginal epithelial cells in and on collagen gels","volume":"80","author":"T. Iguchi","year":"1983","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0280421.ref010","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.tox.2012.02.010","article-title":"Wnt family genes and their modulation in the ovary-independent and persistent vaginal epithelial cell proliferation and keratinization induced by neonatal diethylstilbestrol exposure in mice","volume":"296","author":"T. Nakamura","year":"2012","journal-title":"Toxicology"},{"key":"pone.0280421.ref011","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s00441-011-1161-2","article-title":"Involvement of activin signaling in abnormalities of mouse vagina exposed neonatally to diethylstilbestrol","volume":"344","author":"T. Nakajima","year":"2011","journal-title":"Cell Tissue Res."},{"key":"pone.0280421.ref012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.114.125724","article-title":"Neonatal uterine and vaginal cell proliferation and adenogenesis are independent of estrogen receptor 1 (ESR1) in the mouse","volume":"92","author":"M. K. Nanjappa","year":"2015","journal-title":"Biol Reprod"},{"key":"pone.0280421.ref013","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.270.5241.1491","article-title":"Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase","volume":"270","author":"S. Kato","year":"1995","journal-title":"Science"},{"key":"pone.0280421.ref014","doi-asserted-by":"crossref","first-page":"12986","DOI":"10.1073\/pnas.1513550112","article-title":"Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina","volume":"112","author":"S. Miyagawa","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0280421.ref015","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s11845-016-1464-0","article-title":"From inflammation to cancer","volume":"186","author":"A. Korniluk","year":"2016","journal-title":"Ir J Med Sci."},{"key":"pone.0280421.ref016","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s00281-019-00744-5","article-title":"CD8+ T cell exhaustion","volume":"41","author":"M. Kurachi","year":"2019","journal-title":"Semin Immunopathol"},{"key":"pone.0280421.ref017","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1677\/erc.1.01301","article-title":"CXC chemokines located in the 4q21 region are up-regulated in breast cancer","volume":"14","author":"I. Bi\u00e8che","year":"2007","journal-title":"Endocr Relat Cancer"},{"key":"pone.0280421.ref018","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature09033","article-title":"Widespread transcription at neuronal activity-regulated enhancers","volume":"465","author":"T. K. Kim","year":"2010","journal-title":"Nature"},{"key":"pone.0280421.ref019","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nature11884","article-title":"Activating RNAs associate with Mediator to enhance chromatin architecture and transcription","volume":"494","author":"F. Lai","year":"2013","journal-title":"Nature"},{"key":"pone.0280421.ref020","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.molcel.2014.08.023","article-title":"Enhancer RNA facilitates NELF release from immediate early genes","volume":"56","author":"K. Schaukowitch","year":"2014","journal-title":"Mol Cell"},{"key":"pone.0280421.ref021","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cell.2016.12.020","article-title":"RNA binding to CBP stimulates histone acetylation and transcription","volume":"168","author":"D. A. Bose","year":"2017","journal-title":"Cell"},{"key":"pone.0280421.ref022","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/nature12210","article-title":"Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation","volume":"498","author":"W. Li","year":"2013","journal-title":"Nature"},{"key":"pone.0280421.ref023","doi-asserted-by":"crossref","first-page":"e28658","DOI":"10.4161\/trns.28658","article-title":"lncRNA and gene looping: what\u2019s the connection?.","volume":"5","author":"Y. Shibayama","year":"2014","journal-title":"Transcription"},{"key":"pone.0280421.ref024","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3389\/fcell.2019.00377","article-title":"Diversity and emerging roles of enhancer RNA in regulation of gene expression and cell fate","volume":"7","author":"P. R. Arnold","year":"2019","journal-title":"Front Cell Dev Biol"},{"key":"pone.0280421.ref025","doi-asserted-by":"crossref","first-page":"15776","DOI":"10.1073\/pnas.2136655100","article-title":"Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage","volume":"100","author":"T. Shiraki","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0280421.ref026","doi-asserted-by":"crossref","first-page":"R183","DOI":"10.1186\/gb-2007-8-9-r183","article-title":"The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists","volume":"8","author":"D. W. Huang","year":"2007","journal-title":"Genome Biol."},{"key":"pone.0280421.ref027","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1006\/dbio.2001.0458","article-title":"Epithelial-stromal tissue interaction in paramesonephric (M\u00fcllerian) epithelial differentiation","volume":"240","author":"T. Kurita","year":"2001","journal-title":"Dev Biol."},{"key":"pone.0280421.ref028","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.mam.2005.12.003","article-title":"RNA integrity and the effect on the real-time qRT-PCR performance","volume":"27","author":"S. Fleige","year":"2006","journal-title":"Mol Aspects Med."},{"key":"pone.0280421.ref029","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1158\/0008-5472.CAN-07-2017","article-title":"Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype","volume":"68","author":"D. Sarri\u00f3","year":"2017","journal-title":"Cancer Res."},{"key":"pone.0280421.ref030","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.tcb.2015.07.012","article-title":"Epithelial-Mesenchymal Plasticity: A Central Regulator of Cancer Progression","volume":"25","author":"X. Ye","year":"2015","journal-title":"Trends Cell Biol."},{"key":"pone.0280421.ref031","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.mce.2006.04.002","article-title":"-S. & Bourguignon, J-P. Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data","volume":"254\u2013255","author":"G. Rasier","year":"2006","journal-title":"Mol Cell Endocrinol."},{"key":"pone.0280421.ref032","volume-title":"Environmental Impacts on Reproductive Health and Fertility","author":"M. V. Maffini","year":"2010"},{"key":"pone.0280421.ref033","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1074\/jbc.M111.292946","article-title":"Membrane estrogen signaling enhances tumorigenesis and metastatic potential of breast cancer cells via estrogen receptor-\u03b136 (ER\u03b136).","volume":"287","author":"R. A. Chaudhri","year":"2012","journal-title":"J Biol Chem."},{"key":"pone.0280421.ref034","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1200\/JCO.1992.10.3.438","article-title":"Aromatase activity and estradiol in human breast cancer: its relationship to estradiol and epidermal growth factor receptors and to tumor-node-metastasis staging","volume":"10","author":"P. Bolufer","year":"1992","journal-title":"J Clin Oncol."},{"key":"pone.0280421.ref035","doi-asserted-by":"crossref","first-page":"483","DOI":"10.2217\/epi-2017-0157","article-title":"Enhancer talk.","volume":"10","author":"V. Snetkova","year":"2018","journal-title":"Epigenomics"},{"key":"pone.0280421.ref036","doi-asserted-by":"crossref","first-page":"BSR20160183","DOI":"10.1042\/BSR20160183","article-title":"-W. Enhancers and chromatin structures: regulatory hubs in gene expression and diseases","volume":"37","author":"Z. Hu","year":"2017","journal-title":"Biosci Rep."},{"key":"pone.0280421.ref037","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nature12787","article-title":"An atlas of active enhancers across human cell types and tissues","volume":"507","author":"R. Andersson","year":"2014","journal-title":"Nature"},{"key":"pone.0280421.ref038","doi-asserted-by":"crossref","first-page":"D876","DOI":"10.1093\/nar\/gkq963","article-title":"The UCSC Genome Browser database: update 2011","volume":"39","author":"P. A. Fujita","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"pone.0280421.ref039","doi-asserted-by":"crossref","first-page":"5988","DOI":"10.1038\/s41598-018-24363-6","article-title":"A murine model of atopic dermatitis can be generated by painting the dorsal skin with hapten twice 14 days apart","volume":"8","author":"A. Kitamura","year":"2018","journal-title":"Sci Rep."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0280421","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T18:04:00Z","timestamp":1678989840000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0280421"}},"subtitle":[],"editor":[{"given":"Giovanni","family":"Nassa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,16]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0280421","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,16]]}}}