title: Prolonged exposure to the candidate microbicide C31G differentially reduces cellular sensitivity to agent re-exposure.
abstract: Comparative assays of in vitro cytotoxicity using nonoxynol-9 (N-9) and the candidate microbicides C31G and sodium dodecyl sulfate (SDS) demonstrated that these agents, which are, respectively, characterized as nonionic, amphoteric, and anionic surfactants, differed in their concentration-dependent effects on cell viability, especially after prolonged exposure. We hypothesized that differences in cellular sensitivity may have been due, in part, to cellular changes induced by long-term exposure to each agent. To examine this possibility, HeLa cells were exposed to N-9, C31G, or SDS for extended periods of time and subsequently reassessed for sensitivity to each of these agents. Following 10 continuous days of C31G exposure, HeLa cells were less sensitive to a subsequent C31G exposure compared to cells that had not undergone long-term C31G treatment. Interestingly, long-term C31G exposure also changed subsequent sensitivity to N-9 but not SDS. In contrast, prolonged exposure to either N-9 or SDS did not reduce sensitivity to re-exposure. The effect of long-term C31G exposure was both concentration-dependent and transient, as treated cells reverted to pre-exposure sensitivity in a time-dependent manner following the cessation of C31G exposure. Lipid analyses of cells exposed to C31G for extended durations revealed altered phospholipid profiles relative to C31G-naïve cells. Experiments examining the individual components of C31G demonstrated the involvement of the amine oxide moiety in reductions in cellular sensitivity. These studies, which provide new information concerning the cytotoxicity of surfactant microbicides, suggest that cervicovaginal epithelial cells may have greater in vivo tolerance for products containing C31G through unique interactions between C31G and components of the cellular membranes.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Catalone
authors.forename: Mary Lee
authors.initials: ML
authors.lastname: Ferguson
authors.forename: Shendra R
authors.initials: SR
authors.lastname: Miller
authors.forename: Dan
authors.initials: D
authors.lastname: Malamud
authors.forename: Tina
authors.initials: T
authors.lastname: Kish-Catalone
authors.forename: Nina J
authors.initials: NJ
authors.lastname: Thakkar
authors.forename: Fred C
authors.initials: FC
authors.lastname: Krebs
authors.forename: Mary K
authors.initials: MK
authors.lastname: Howett
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D001622:Betaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D017137:Nonoxynol / Q000494:pharmacology; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000588:Amines; D000890:Anti-Infective Agents; D005231:Fatty Acids, Unsaturated; D008563:Membrane Lipids; D017137:Nonoxynol; D012967:Sodium Dodecyl Sulfate; D001622:Betaine; C081627:hexadecylbetaine; C038360:C 31G