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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

Simulations with an additional SSB repair (SSBR) mechanism. (a) An additional SSB repair mechanism was included in the model. (b) SSB repair rate constant was set to be slower than BER. In this case the dose-response of 8-OH-dG was highly sublinear, while the SSB dose-response had linear behavior as in our base model. (c) SSB repair rate constant was set to be similar to the BER rate constant. Dose-response dependence of 8-OH-dG and that of SSB (inset) both had some level of sublinearity.
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fig5: Simulations with an additional SSB repair (SSBR) mechanism. (a) An additional SSB repair mechanism was included in the model. (b) SSB repair rate constant was set to be slower than BER. In this case the dose-response of 8-OH-dG was highly sublinear, while the SSB dose-response had linear behavior as in our base model. (c) SSB repair rate constant was set to be similar to the BER rate constant. Dose-response dependence of 8-OH-dG and that of SSB (inset) both had some level of sublinearity.

Mentions: Finally, we considered the possibility that SSB formed by a failed BER attempt is later detected and repaired by other SSB repair pathways. SSB repair (SSBR) most often includes several steps [25]: (1) SSB detection; (2) DNA end processing; (3) DNA gap filling; and (4) DNA ligation. There is a possibility of failure at any of these steps. Failure at different stages of these processes can have different outcomes, including single point mutations and deletions. For simplicity, we did not include all of these possible failure processes in our model and included only efficient SSB repair. First, we considered the case when the rate of SSB repair is low compared to the rate of SSB generation by failed BER. In this case, with sustained exposure to bromate, the 8-OH-dG adducts were efficiently repaired at low concentrations of bromate exposure and resulted in highly sublinear, threshold-like dose-response dependence as in our base model. However, when the rate of SSBR is slower, the SSB accumulate and the dose-response dependence of SSB remains linear (Figure 5(b)), again similar to our base model. Under another scenario, we considered similar rates of SSB formation and repair. In this case both dose-response curves had some sublinearity (Figure 5(c)). Overall, the shape of the SSB dose-response was defined by the relative rate of the SSBR compared to the BER. Highly efficient SSB repair can increase the sublinearity of the SSB dose-response to a threshold-like behavior.


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)

Simulations with an additional SSB repair (SSBR) mechanism. (a) An additional SSB repair mechanism was included in the model. (b) SSB repair rate constant was set to be slower than BER. In this case the dose-response of 8-OH-dG was highly sublinear, while the SSB dose-response had linear behavior as in our base model. (c) SSB repair rate constant was set to be similar to the BER rate constant. Dose-response dependence of 8-OH-dG and that of SSB (inset) both had some level of sublinearity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig5: Simulations with an additional SSB repair (SSBR) mechanism. (a) An additional SSB repair mechanism was included in the model. (b) SSB repair rate constant was set to be slower than BER. In this case the dose-response of 8-OH-dG was highly sublinear, while the SSB dose-response had linear behavior as in our base model. (c) SSB repair rate constant was set to be similar to the BER rate constant. Dose-response dependence of 8-OH-dG and that of SSB (inset) both had some level of sublinearity.
Mentions: Finally, we considered the possibility that SSB formed by a failed BER attempt is later detected and repaired by other SSB repair pathways. SSB repair (SSBR) most often includes several steps [25]: (1) SSB detection; (2) DNA end processing; (3) DNA gap filling; and (4) DNA ligation. There is a possibility of failure at any of these steps. Failure at different stages of these processes can have different outcomes, including single point mutations and deletions. For simplicity, we did not include all of these possible failure processes in our model and included only efficient SSB repair. First, we considered the case when the rate of SSB repair is low compared to the rate of SSB generation by failed BER. In this case, with sustained exposure to bromate, the 8-OH-dG adducts were efficiently repaired at low concentrations of bromate exposure and resulted in highly sublinear, threshold-like dose-response dependence as in our base model. However, when the rate of SSBR is slower, the SSB accumulate and the dose-response dependence of SSB remains linear (Figure 5(b)), again similar to our base model. Under another scenario, we considered similar rates of SSB formation and repair. In this case both dose-response curves had some sublinearity (Figure 5(c)). Overall, the shape of the SSB dose-response was defined by the relative rate of the SSBR compared to the BER. Highly efficient SSB repair can increase the sublinearity of the SSB dose-response to a threshold-like behavior.

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