Mouse model of cervicovaginal toxicity and inflammation for preclinical evaluation of topical vaginal microbicides.
Clinical trials evaluating the efficacy of nonoxynol-9 (N-9) as a topical microbicide concluded that N-9 offers no in vivo protection against human immunodeficiency virus type 1 (HIV-1) infection, despite demonstrated in vitro inactivation of HIV-1 by N-9. These trials emphasize the need for better model systems to determine candidate microbicide effectiveness and safety in a preclinical setting. To that end, time-dependent in vitro cytotoxicity, as well as in vivo toxicity and inflammation, associated with N-9 exposure were characterized with the goal of validating a mouse model of microbicide toxicity. In vitro studies using submerged cell cultures indicated that human cervical epithelial cells were inherently more sensitive to N-9-mediated damage than human vaginal epithelial cells. These results correlated with in vivo findings obtained by using Swiss Webster mice in which intravaginal inoculation of 1% N-9 or Conceptrol gel (containing 4% N-9) resulted in selective and acute disruption of the cervical columnar epithelial cells 2 h postapplication accompanied by intense inflammatory infiltrates within the lamina propria. Although damage to the cervical epithelium was apparent out to 8 h postapplication, these tissues resembled control tissue by 24 h postapplication. In contrast, minimal damage and infiltration were associated with both short- and long-term exposure of the vaginal mucosa to either N-9 or Conceptrol. These analyses were extended to examine the relative toxicity of polyethylene hexamethylene biguanide (PEHMB), a polybiguanide compound under evaluation as a candidate topical microbicide. In similar studies, in vivo exposure to 1% PEHMB caused minimal damage and inflammation of the genital mucosa, a finding consistent with the demonstration that PEHMB was >350-fold less cytotoxic than N-9 in vitro. Collectively, these studies highlight the murine model of toxicity as a valuable tool for the preclinical assessment of toxicity and inflammation associated with exposure to candidate topical microbicides.
Catalone
Bradley J
BJ
Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Kish-Catalone
Tina M
TM
Budgeon
Lynn R
LR
Neely
Elizabeth B
EB
Ferguson
Maelee
M
Krebs
Fred C
FC
Howett
Mary K
MK
Labib
Mohamed
M
Rando
Robert
R
Wigdahl
Brian
B
D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000633:toxicity*; D002460:Cell Line; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000187:drug effects / Q000473:pathology*; D005260:Female; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D017137:Nonoxynol / Q000008:administration & dosage / Q000009:adverse effects; D014621:Vagina / Q000187:drug effects / Q000473:pathology*; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000633:toxicity; D014627:Vaginitis / Q000139:chemically induced* / Q000473:pathology
D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local; D014622:Vaginal Creams, Foams, and Jellies; D017137:Nonoxynol