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Mechanism of genotoxicity induced by targeted cytoplasmic irradiation.

Hong M, Xu A, Zhou H, Wu L, Randers-Pehrson G, Santella RM, Yu Z, Hei TK - Br. J. Cancer (2010)

Bottom Line: A microbeam that can target the cytoplasm of cells with high precision was used to study mechanisms involved in mediating the genotoxic effects in irradiated human-hamster hybrid (A(L)) cells.Moreover, cytoplasmic irradiation of A(L) cells increased expression of cyclooxygenase-2 (COX-2) and activation of extracellular signal-related kinase (ERK) pathway.We herein proposed a possible signalling pathway involving reactive oxygen/nitrogen species and COX-2 in the cytoplasmic irradiation-induced genotoxicity effect.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.

ABSTRACT

Background: Direct damage to DNA is generally accepted as the main initiator of mutation and cancer induced by environmental carcinogens or ionising radiation. However, there is accumulating evidence suggesting that extracellular/extranuclear targets may also have a key role in mediating the genotoxic effects of ionising radiation. As the possibility of a particle traversal through the cytoplasm is much higher than through the nuclei in environmental radiation exposure, the contribution to genotoxic damage from cytoplasmic irradiation should not be ignored in radiation risk estimation. Although targeted cytoplasmic irradiation has been shown to induce mutations in mammalian cells, the precise mechanism(s) underlying the mutagenic process is largely unknown.

Methods: A microbeam that can target the cytoplasm of cells with high precision was used to study mechanisms involved in mediating the genotoxic effects in irradiated human-hamster hybrid (A(L)) cells.

Results: Targeted cytoplasmic irradiation induces oxidative DNA damages and reactive nitrogen species (RNS) in A(L) cells. Lipid peroxidation, as determined by the induction of 4-hydroxynonenal was enhanced in irradiated cells, which could be suppressed by butylated hydroxyl toluene treatment. Moreover, cytoplasmic irradiation of A(L) cells increased expression of cyclooxygenase-2 (COX-2) and activation of extracellular signal-related kinase (ERK) pathway.

Conclusion: We herein proposed a possible signalling pathway involving reactive oxygen/nitrogen species and COX-2 in the cytoplasmic irradiation-induced genotoxicity effect.

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Related in: MedlinePlus

Lipid peroxidation in cytoplasmic-irradiated AL cells. (A) Relative fluorescence intensity of 4-HNE in AL cells after irradiation with 0 (control) or eight α-particle (8 α). (B) Effect of BHT on the mutagenic potential of cytoplasmic irradiation at the CD59 locus of AL cells. Data were averaged from three independent experiments. Bars indicate ±s.e. of sample means (asterisk indicated P<0.05).
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fig2: Lipid peroxidation in cytoplasmic-irradiated AL cells. (A) Relative fluorescence intensity of 4-HNE in AL cells after irradiation with 0 (control) or eight α-particle (8 α). (B) Effect of BHT on the mutagenic potential of cytoplasmic irradiation at the CD59 locus of AL cells. Data were averaged from three independent experiments. Bars indicate ±s.e. of sample means (asterisk indicated P<0.05).

Mentions: The presence of free radicals and oxidants often results in lipid peroxidation. As the major α, β-unsaturated aldehydes derived from lipid peroxidation, 4-HNE is considered a biomarker of oxidative stress (Poli et al, 1987; Esterbauer et al, 1991) and has been shown to stimulate cellular proliferation (Dianzani et al, 1999), differentiation (Yang et al, 2003), and cytoprotective responses (Dickinson et al, 2002; Zhang et al, 2005) through various signalling pathways. Our next logical step was to analyse the lipid peroxidation level in irradiated cells. As indicated in Figure 2A, cells irradiated with eight α-particles through the cytoplasm showed a significantly higher level of 4-HNE compared with the control, non-irradiated cells (P<0.05). Moreover, pre-treating the cells with BHT, a well known lipid peroxidation chain blocker, suppressed the induction of lipid peroxidation.


Mechanism of genotoxicity induced by targeted cytoplasmic irradiation.

Hong M, Xu A, Zhou H, Wu L, Randers-Pehrson G, Santella RM, Yu Z, Hei TK - Br. J. Cancer (2010)

Lipid peroxidation in cytoplasmic-irradiated AL cells. (A) Relative fluorescence intensity of 4-HNE in AL cells after irradiation with 0 (control) or eight α-particle (8 α). (B) Effect of BHT on the mutagenic potential of cytoplasmic irradiation at the CD59 locus of AL cells. Data were averaged from three independent experiments. Bars indicate ±s.e. of sample means (asterisk indicated P<0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2967061&req=5

fig2: Lipid peroxidation in cytoplasmic-irradiated AL cells. (A) Relative fluorescence intensity of 4-HNE in AL cells after irradiation with 0 (control) or eight α-particle (8 α). (B) Effect of BHT on the mutagenic potential of cytoplasmic irradiation at the CD59 locus of AL cells. Data were averaged from three independent experiments. Bars indicate ±s.e. of sample means (asterisk indicated P<0.05).
Mentions: The presence of free radicals and oxidants often results in lipid peroxidation. As the major α, β-unsaturated aldehydes derived from lipid peroxidation, 4-HNE is considered a biomarker of oxidative stress (Poli et al, 1987; Esterbauer et al, 1991) and has been shown to stimulate cellular proliferation (Dianzani et al, 1999), differentiation (Yang et al, 2003), and cytoprotective responses (Dickinson et al, 2002; Zhang et al, 2005) through various signalling pathways. Our next logical step was to analyse the lipid peroxidation level in irradiated cells. As indicated in Figure 2A, cells irradiated with eight α-particles through the cytoplasm showed a significantly higher level of 4-HNE compared with the control, non-irradiated cells (P<0.05). Moreover, pre-treating the cells with BHT, a well known lipid peroxidation chain blocker, suppressed the induction of lipid peroxidation.

Bottom Line: A microbeam that can target the cytoplasm of cells with high precision was used to study mechanisms involved in mediating the genotoxic effects in irradiated human-hamster hybrid (A(L)) cells.Moreover, cytoplasmic irradiation of A(L) cells increased expression of cyclooxygenase-2 (COX-2) and activation of extracellular signal-related kinase (ERK) pathway.We herein proposed a possible signalling pathway involving reactive oxygen/nitrogen species and COX-2 in the cytoplasmic irradiation-induced genotoxicity effect.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.

ABSTRACT

Background: Direct damage to DNA is generally accepted as the main initiator of mutation and cancer induced by environmental carcinogens or ionising radiation. However, there is accumulating evidence suggesting that extracellular/extranuclear targets may also have a key role in mediating the genotoxic effects of ionising radiation. As the possibility of a particle traversal through the cytoplasm is much higher than through the nuclei in environmental radiation exposure, the contribution to genotoxic damage from cytoplasmic irradiation should not be ignored in radiation risk estimation. Although targeted cytoplasmic irradiation has been shown to induce mutations in mammalian cells, the precise mechanism(s) underlying the mutagenic process is largely unknown.

Methods: A microbeam that can target the cytoplasm of cells with high precision was used to study mechanisms involved in mediating the genotoxic effects in irradiated human-hamster hybrid (A(L)) cells.

Results: Targeted cytoplasmic irradiation induces oxidative DNA damages and reactive nitrogen species (RNS) in A(L) cells. Lipid peroxidation, as determined by the induction of 4-hydroxynonenal was enhanced in irradiated cells, which could be suppressed by butylated hydroxyl toluene treatment. Moreover, cytoplasmic irradiation of A(L) cells increased expression of cyclooxygenase-2 (COX-2) and activation of extracellular signal-related kinase (ERK) pathway.

Conclusion: We herein proposed a possible signalling pathway involving reactive oxygen/nitrogen species and COX-2 in the cytoplasmic irradiation-induced genotoxicity effect.

Show MeSH
Related in: MedlinePlus