title: Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO₃-Induced DNA Damage.
abstract: We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemical KBrO3 which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibits KBrO3-caused oxidative damage. Our modeling revealed that sustained exposure to KBrO3 can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical's toxicity dose dependence based on the dose-response of early genotoxic events.
authors.affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Spassova
authors.affiliation: Division of Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, MD 20892, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
authors.affiliation: Langley High School, McLean, VA 22101, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Nikolov
mesh_terms: D001959:Bromates / Q000737:chemistry*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D009152:Mutagenicity Tests; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D001959:Bromates; D017382:Reactive Oxygen Species; C019536:potassium bromate