Safety of multiple administrations of spermicidal LL-37 antimicrobial peptide into the mouse female reproductive tract

被引:1
作者
Lee, Seung Gee [1 ]
Kiattiburut, Wongsakorn [1 ]
Burke Schinkel, Stephanie C. [1 ]
Angel, Jonathan [1 ,2 ,3 ]
Tanphaichitr, Nongnuj [1 ,4 ,5 ]
机构
[1] Ottawa Hosp Res Inst, Chron Dis Program, Ottawa, ON, Canada
[2] Univ Ottawa, Fac Med, Dept Biochem, Microbiol,Immunol, Ottawa, ON, Canada
[3] Ottawa Hosp, Dept Med, Div Infect Dis, Ottawa, ON, Canada
[4] Univ Ottawa, Fac Med, Dept Obstet Gynecol, Ottawa, ON, Canada
[5] Ottawa Hosp Res Inst, Chron Dis Program, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada
基金
加拿大健康研究院;
关键词
LL-37; antimicrobial peptide; spermicide; vaginal microbicide; multipurpose prevention technology; nonoxynol-9; female reproductive tract; vaginal epithelium; fecundity; cytokines; chemokines; MULTIPURPOSE PREVENTION TECHNOLOGIES; IMMUNODEFICIENCY-VIRUS; VAGINAL MICROBICIDES; GENITAL HERPES; HIV-INFECTION; NONOXYNOL-9; TRANSMISSION; INFLAMMATION; CELLS; MODEL;
D O I
10.1093/molehr/gaad023
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 & mu;M-10x 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 h after the last injection, while the second set were artificially inseminated with sperm from fertile males 1 week 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.
引用
收藏
页数:10
相关论文
共 34 条
  • [1] Serine protease inhibitor disrupts sperm motility leading to reduced fertility in female mice
    Barton, Brooke E.
    Rock, Jenna K.
    Willie, Anna M.
    Harris, Emily A.
    Finnerty, Ryan M.
    Herrera, Gerardo G.
    Anamthathmakula, Prashanth
    Winuthayanon, Wipawee
    [J]. BIOLOGY OF REPRODUCTION, 2020, 103 (02) : 400 - 410
  • [2] Mouse Estrous Cycle Identification Tool and Images
    Byers, Shannon L.
    Wiles, Michael V.
    Dunn, Sadie L.
    Taft, Robert A.
    [J]. PLOS ONE, 2012, 7 (04):
  • [3] Vaginal microbicides:: detecting toxicities in vivo that paradoxically increase pathogen transmission
    Cone, Richard A.
    Hoen, Timothy
    Wong, XiXi
    Abusuwwa, Raed
    Anderson, Deborah J.
    Moench, Thomas R.
    [J]. BMC INFECTIOUS DISEASES, 2006, 6 (1)
  • [4] Disruption of the upper female reproductive tract epithelium by nonoxynol-9
    Dayal, MB
    Wheeler, J
    Williams, CJ
    Barnhart, KT
    [J]. CONTRACEPTION, 2003, 68 (04) : 273 - 279
  • [5] Exploiting common targets in human fertilization and HIV infection: development of novel contraceptive microbicides
    Doncel, GF
    [J]. HUMAN REPRODUCTION UPDATE, 2006, 12 (02) : 103 - 117
  • [6] The molecular basis of nonoxynol-9-induced vaginal inflammation and its possible relevance to human immunodeficiency virus type 1 transmission
    Fichorova, RN
    Tucker, LD
    Anderson, DJ
    [J]. JOURNAL OF INFECTIOUS DISEASES, 2001, 184 (04) : 418 - 428
  • [7] New Candidate Biomarkers in the Female Genital Tract to Evaluate Microbicide Toxicity
    Fields, Scott
    Song, Benben
    Rasoul, Bareza
    Fong, Julie
    Works, Melissa G.
    Shew, Kenneth
    Yiu, Ying
    Mirsalis, Jon
    D'Andrea, Annalisa
    [J]. PLOS ONE, 2014, 9 (10):
  • [8] Low concentrations of LL-37 alter IL-8 production by keratinocytes and bronchial epithelial cells in response to proinflammatory stimuli
    Filewod, Niall C. J.
    Pistolic, Jelena
    Hancock, Robert E. W.
    [J]. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY, 2009, 56 (03): : 233 - 240
  • [9] A comprehensive murine model to evaluate topical vaginal microbicides: Mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety
    Galen, Benjamin T.
    Martin, Andrea P.
    Hazrati, Ehsan
    Garin, Alexandre
    Guzman, Esmeralda
    Wilson, Sarah S.
    Porter, David D.
    Lira, Sergio A.
    Keller, Marla J.
    Herold, Betsy C.
    [J]. JOURNAL OF INFECTIOUS DISEASES, 2007, 195 (09) : 1332 - 1339
  • [10] Towards a roadmap to advance non-hormonal contraceptive multipurpose prevention technologies: strategic insights from key stakeholders
    Hemmerling, Anke
    Christopher, Emily
    Holt, Bethany Young
    [J]. BIOLOGY OF REPRODUCTION, 2020, 103 (02) : 289 - 298