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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.

Spassova MA, Miller DJ, Nikolov AS - Oxid Med Cell Longev (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Dose-response of genotoxic events in the kidney of rats exposed to KBrO3. Data on kidney were selected as the kidney is the target organ of KBrO3 carcinogenicity. (a) Data on 8-OH-dG levels in DNA extracted from the kidneys of rats exposed to KBrO3 [9] are plotted versus KBrO3 concentration. Data are fitted with a quadratic model with a zeroed linear term. (b) Deletion mutations in the kidneys of gpt delta rats exposed to KBrO3. Dose-response data from Umemura et al. [21] are plotted. An exponential, low dose linear, model ([22, model 2]) is fit to the data for Spi− mutation frequency as a measure of deletion mutations. A lognormal distribution of the data at each concentration was assumed and a log-scale constant variance model was used.
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fig6: Dose-response of genotoxic events in the kidney of rats exposed to KBrO3. Data on kidney were selected as the kidney is the target organ of KBrO3 carcinogenicity. (a) Data on 8-OH-dG levels in DNA extracted from the kidneys of rats exposed to KBrO3 [9] are plotted versus KBrO3 concentration. Data are fitted with a quadratic model with a zeroed linear term. (b) Deletion mutations in the kidneys of gpt delta rats exposed to KBrO3. Dose-response data from Umemura et al. [21] are plotted. An exponential, low dose linear, model ([22, model 2]) is fit to the data for Spi− mutation frequency as a measure of deletion mutations. A lognormal distribution of the data at each concentration was assumed and a log-scale constant variance model was used.

Mentions: Dose-response analysis was carried out using EPA's benchmark dose software (BMDS). The results were plotted using Origin software (Figure 6). We used a likelihood approach to evaluate the dose-response models' goodness-of-fit.


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.

Spassova MA, Miller DJ, Nikolov AS - Oxid Med Cell Longev (2015)

Dose-response of genotoxic events in the kidney of rats exposed to KBrO3. Data on kidney were selected as the kidney is the target organ of KBrO3 carcinogenicity. (a) Data on 8-OH-dG levels in DNA extracted from the kidneys of rats exposed to KBrO3 [9] are plotted versus KBrO3 concentration. Data are fitted with a quadratic model with a zeroed linear term. (b) Deletion mutations in the kidneys of gpt delta rats exposed to KBrO3. Dose-response data from Umemura et al. [21] are plotted. An exponential, low dose linear, model ([22, model 2]) is fit to the data for Spi− mutation frequency as a measure of deletion mutations. A lognormal distribution of the data at each concentration was assumed and a log-scale constant variance model was used.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581570&req=5

fig6: Dose-response of genotoxic events in the kidney of rats exposed to KBrO3. Data on kidney were selected as the kidney is the target organ of KBrO3 carcinogenicity. (a) Data on 8-OH-dG levels in DNA extracted from the kidneys of rats exposed to KBrO3 [9] are plotted versus KBrO3 concentration. Data are fitted with a quadratic model with a zeroed linear term. (b) Deletion mutations in the kidneys of gpt delta rats exposed to KBrO3. Dose-response data from Umemura et al. [21] are plotted. An exponential, low dose linear, model ([22, model 2]) is fit to the data for Spi− mutation frequency as a measure of deletion mutations. A lognormal distribution of the data at each concentration was assumed and a log-scale constant variance model was used.
Mentions: Dose-response analysis was carried out using EPA's benchmark dose software (BMDS). The results were plotted using Origin software (Figure 6). We used a likelihood approach to evaluate the dose-response models' goodness-of-fit.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA.

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.

No MeSH data available.


Related in: MedlinePlus