{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:09:40Z","timestamp":1753877380583,"version":"3.41.2"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T00:00:00Z","timestamp":1686873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 173268"],"award-info":[{"award-number":["PJT 173268"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We have previously demonstrated spermicidal activity of LL-37 antimicrobial peptide on mouse\/human sperm and its contraceptive effects in female mice. With its microbicidal action against Neisseria gonorrhoeae, LL-37 warrants development into a multipurpose prevention technology (MPT) agent for administering into the female reproductive tract (FRT). However, it is important to verify that multiple administrations of LL-37 do not lead to damage of FRT tissues and\/or irreversible loss of fecundity. Herein, we transcervically injected LL-37 (36\u2009\u00b5M\u201310\u00d7 spermicidal dose) into female mice in estrus in three consecutive estrous cycles. A set of mice were sacrificed for histological assessment of the vagina\/cervix\/uterus 24\u2009h after the last injection, while the second set were artificially inseminated with sperm from fertile males 1\u00a0week afterwards, and then monitored for pregnancy. Mice injected with PBS in parallel were regarded as negative controls, whereas those injected with vaginal contraceptive foam (VCF, available over the counter), containing 12.5% nonoxynol-9, served as positive controls for vaginal epithelium disruption. We demonstrated that the vagina\/cervix\/uterus remained normal in both LL-37-injected and PBS-injected mice, which also showed 100% resumption of fecundity. In contrast, VCF-injected mice showed histological abnormalities in the vagina\/cervix\/uterus and only 50% of them resumed fecundity. Similarly, LL-37 multiply administered intravaginally caused no damage to FRT tissues. While our results indicate the safety of multiple treatments of LL-37 in the mouse model, similar studies have to be conducted in non-human primates and then humans. Regardless, our study provides an experimental model for studying in vivo safety of other vaginal MPT\/spermicide candidates.<\/jats:p>","DOI":"10.1093\/molehr\/gaad023","type":"journal-article","created":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T15:07:44Z","timestamp":1686928064000},"source":"Crossref","is-referenced-by-count":3,"title":["Safety of multiple administrations of spermicidal LL-37 antimicrobial peptide into the mouse female reproductive tract"],"prefix":"10.1093","volume":"29","author":[{"given":"Seung Gee","family":"Lee","sequence":"first","affiliation":[{"name":"Chronic Disease Program, Ottawa Hospital Research Institute , Ottawa, ON, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wongsakorn","family":"Kiattiburut","sequence":"additional","affiliation":[{"name":"Chronic Disease Program, Ottawa Hospital Research Institute , Ottawa, ON, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie C","family":"Burke Schinkel","sequence":"additional","affiliation":[{"name":"Chronic Disease Program, Ottawa Hospital Research Institute , Ottawa, ON, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Angel","sequence":"additional","affiliation":[{"name":"Chronic Disease Program, Ottawa Hospital Research Institute , Ottawa, ON, Canada"},{"name":"Department of Biochemistry, Microbiology, Immunology, Faculty of Medicine, University of Ottawa , Ottawa, ON, Canada"},{"name":"Division of Infectious Diseases, Department of Medicine, The Ottawa Hospital , Ottawa, ON, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8585-6670","authenticated-orcid":false,"given":"Nongnuj","family":"Tanphaichitr","sequence":"additional","affiliation":[{"name":"Chronic Disease Program, Ottawa Hospital Research Institute , Ottawa, ON, Canada"},{"name":"Department of Obstetrics\/Gynecology, Faculty of Medicine, University of Ottawa , Ottawa, ON, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,6,16]]},"reference":[{"key":"2023070605270607000_gaad023-B1","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1093\/biolre\/ioaa049","article-title":"Serine protease inhibitor disrupts sperm motility leading to reduced fertility in female mice","volume":"103","author":"Barton","year":"2020","journal-title":"Biol Reprod"},{"key":"2023070605270607000_gaad023-B2","doi-asserted-by":"crossref","first-page":"e35538","DOI":"10.1371\/journal.pone.0035538","article-title":"Mouse estrous cycle identification tool and images","volume":"7","author":"Byers","year":"2012","journal-title":"PLoS One"},{"key":"2023070605270607000_gaad023-B3","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/1471-2334-6-90","article-title":"Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission","volume":"6","author":"Cone","year":"2006","journal-title":"BMC Infect Dis"},{"key":"2023070605270607000_gaad023-B4","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0010-7824(03)00178-1","article-title":"Disruption of the upper female reproductive tract epithelium by nonoxynol-9","volume":"68","author":"Dayal","year":"2003","journal-title":"Contraception"},{"key":"2023070605270607000_gaad023-B5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/humupd\/dmi040","article-title":"Exploiting common targets in human fertilization and HIV infection: development of novel contraceptive microbicides","volume":"12","author":"Doncel","year":"2006","journal-title":"Hum Reprod Update"},{"key":"2023070605270607000_gaad023-B6","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1086\/322047","article-title":"The molecular basis of nonoxynol-9-induced vaginal inflammation and its possible relevance to human immunodeficiency virus type 1 transmission","volume":"184","author":"Fichorova","year":"2001","journal-title":"J Infect Dis"},{"key":"2023070605270607000_gaad023-B7","doi-asserted-by":"crossref","first-page":"e110980","DOI":"10.1371\/journal.pone.0110980","article-title":"New candidate biomarkers in the female genital tract to evaluate microbicide toxicity","volume":"9","author":"Fields","year":"2014","journal-title":"PLoS One"},{"key":"2023070605270607000_gaad023-B8","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.1574-695X.2009.00571.x","article-title":"Low concentrations of LL-37 alter IL-8 production by keratinocytes and bronchial epithelial cells in response to proinflammatory stimuli","volume":"56","author":"Filewod","year":"2009","journal-title":"FEMS Immunol Med Microbiol"},{"key":"2023070605270607000_gaad023-B9","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1086\/513279","article-title":"A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety","volume":"195","author":"Galen","year":"2007","journal-title":"J Infect Dis"},{"key":"2023070605270607000_gaad023-B10","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/biolre\/ioaa092","article-title":"Towards a roadmap to advance non-hormonal contraceptive multipurpose prevention technologies: strategic insights from key stakeholders","volume":"103","author":"Hemmerling","year":"2020","journal-title":"Biol Reprod"},{"key":"2023070605270607000_gaad023-B11","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1177\/1753425912454026","article-title":"Mouse estrous cycle regulation of vaginal versus uterine cytokines, chemokines, \u03b1-\/\u03b2-defensins and TLRs","volume":"19","author":"Hickey","year":"2013","journal-title":"Innate 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gonorrhoeae","volume":"37","author":"Lee","year":"2022","journal-title":"Hum Reprod"},{"key":"2023070605270607000_gaad023-B15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/2050-6511-13-9","article-title":"Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety","volume":"13","author":"Lozenski","year":"2012","journal-title":"BMC Pharmacol Toxicol"},{"key":"2023070605270607000_gaad023-B16","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/S0015-0282(16)55038-9","article-title":"The effect of contraceptives containing nonoxynol-9 on the genital transmission of simian immunodeficiency virus in Rhesus macaques","volume":"57","author":"Miller","year":"1992","journal-title":"Fertil Steril"},{"key":"2023070605270607000_gaad023-B17","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1097\/00007435-200210000-00006","article-title":"Entry of inflammatory cells into 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