API

Stressor: 453

Title

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Other DNA damaging agents

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AOPs Including This Stressor

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Events Including This Stressor

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Chemical Table

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AOP Evidence

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Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer

Breast carcinogenesis from IR and DNA damaging agents has more similarities than differences (Imaoka, Nishimura et al. 2009). Both IR and other DNA damaging agents form adenocarcinomas in rodents with similar pathology and gene expression, although IR also creates a much larger fraction of fibroadenomas than DNA damaging chemicals (Imaoka, Nishimura et al. 2009). Carcinogenicity for IR and chemical mammary carcinogens NMU and DMBA varies with age and exposure to ovarian hormones (Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). Breast carcinogenesis from IR and chemical carcinogens depends strongly on developmental or ongoing exposure to ovarian hormones (Nandi, Guzman et al. 1995; Russo 2015), and estrogen status of tumors increases with ovarian hormone exposure in rats (Nandi, Guzman et al. 1995; Imaoka, Nishimura et al. 2009). The mammary gland is especially susceptible to both IR and mammary carcinogens DMBA and NMU around puberty. This is presumably because puberty is when undifferentiated cells are both large in number and will undergo major subsequent proliferative expansion, although additional factors including metabolism and expression of DNA damage repair genes contribute to variations in the age of maximal susceptibility between agents (Medina 2007; Imaoka, Nishimura et al. 2009; Imaoka, Nishimura et al. 2011; Imaoka, Nishimura et al. 2013). Consistent with general accepted risk assessment assumptions of additivity in carcinogenesis, IR has an additive effect in combination with NMU (Imaoka, Nishimura et al. 2014). Some differences between mammary carcinogens appear around the protective role of breast maturation: pregnancy appears to be more protective in rats exposed to chemical carcinogens than in rats exposed to IR.

The role of DNA damage, mutation, and proliferation outlined in this AOP would presumably apply to other DNA damaging agents while the role of RONS and inflammation is more likely to vary between DNA damaging and other agents based on their ability to induce these key events. DNA damaging agents differ in the degree, type and reparability of the DNA damage they cause. Mammary carcinogens NMU, DMBA, PhIP, and urethane mostly cause adducts with single nucleotide substitutions (Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation 2006; Imaoka, Nishimura et al. 2009; Westcott, Halliwill et al. 2014; Nik-Zainal, Kucab et al. 2015; Sherborne, Davidson et al. 2015). Like ionizing radiation, mammary carcinogen PhIP can cause amplifications and NMU can cause genomic instability (Goepfert, Moreno-Smith et al. 2007; Imaoka, Nishimura et al. 2009). While IR also induces adducts, it characteristically generates complex damage and double-strand breaks leading to deletions and inversions as well as amplification and genomic instability (Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Mukherjee, Coates et al. 2012; Snijders, Marchetti et al. 2012; Yang, Killian et al. 2015; Behjati, Gundem et al. 2016; Mavragani, Nikitaki et al. 2017). The prevalence of complex damage and double strand breaks is likely due to the density of damage delivered by ionizing radiation, but is also attributable to oxidative activity, since IR creates an oxidative state and H2O2 and other oxidizing agents can also cause (less) complex damage, double strand breaks and mutations (Seager, Shah et al. 2012; Sharma, Collins et al. 2016; Cadet, Davies et al. 2017). Radiomimetic compounds (used in chemotherapy) also cause double-strand breaks and simple complex damage. Agents like bleomycin cause double strand breaks through oxidized lesions (Regulus, Duroux et al. 2007), while agents like etoposide and cisplatin cause double strand breaks by interfering with DNA replication forks (Kawashima, Yamaguchi et al. 2017).

Evidence suggests that proliferation and inflammation are also implicated in chemical carcinogenicity. The aforementioned pubertal susceptibility implies a dependence on proliferation, as does the fact that tumorigenesis following NMU depends on proliferation during treatment (Medina 2007).  Like IR, NMU and DMBA promote hyperplasia in terminal end buds and ducts and ductal carcinoma in situ leading to carcinogenesis (Goepfert, Moreno-Smith et al. 2007; Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). In terms of inflammation, some chemical carcinogens appear to share with IR an increase in inflammatory reactions in mammary stroma and a tumor-promoting effect of stroma (Russo and Russo 1996; Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004; Nguyen, Oketch-Rabah et al. 2011) and although bleomycin has not been characterized for its effects on mammary stroma or mammary carcinogenesis it causes lung fibrosis (an anti-inflammatory reaction) so consistently that it is used as a research model for that endpoint (Moeller, Ask et al. 2008).

Barcellos-Hoff, M. H. and S. A. Ravani (2000). "Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells." Cancer Res 60(5): 1254-1260.

Behjati, S., G. Gundem, et al. (2016). "Mutational signatures of ionizing radiation in second malignancies." Nat Commun 7: 12605.

Cadet, J., K. J. A. Davies, et al. (2017). "Formation and repair of oxidatively generated damage in cellular DNA." Free radical biology & medicine 107: 13-34.

Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation (2006). Health risks from exposure to low levels of ionizing radiation : BEIR VII, Phase 2, National Research Council of the National Academies.

Datta, K., S. Suman, et al. (2012). "Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine." PLoS One 7(8): e42224.

Goepfert, T. M., M. Moreno-Smith, et al. (2007). "Loss of chromosomal integrity drives rat mammary tumorigenesis." Int J Cancer 120(5): 985-994.

Imaoka, T., M. Nishimura, et al. (2013). "Influence of age on the relative biological effectiveness of carbon ion radiation for induction of rat mammary carcinoma." International journal of radiation oncology, biology, physics 85(4): 1134-1140.

Imaoka, T., M. Nishimura, et al. (2014). "Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis." Int J Cancer 134(7): 1529-1538.

Imaoka, T., M. Nishimura, et al. (2009). "Radiation-induced mammary carcinogenesis in rodent models: what's different from chemical carcinogenesis?" J Radiat Res 50(4): 281-293.

Imaoka, T., M. Nishimura, et al. (2011). "Pre- and postpubertal irradiation induces mammary cancers with distinct expression of hormone receptors, ErbB ligands, and developmental genes in rats." Mol Carcinog 50(7): 539-552.

Kawashima, Y., N. Yamaguchi, et al. (2017). "Detection of DNA double-strand breaks by pulsed-field gel electrophoresis." Genes to cells : devoted to molecular & cellular mechanisms 22(1): 84-93.

Maffini, M. V., A. M. Soto, et al. (2004). "The stroma as a crucial target in rat mammary gland carcinogenesis." J Cell Sci 117(Pt 8): 1495-1502.

Mavragani, I. V., Z. Nikitaki, et al. (2017). "Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis." Cancers (Basel) 9(7).

Medina, D. (2007). "Chemical carcinogenesis of rat and mouse mammary glands." Breast Dis 28: 63-68.

Moeller, A., K. Ask, et al. (2008). "The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?" Int J Biochem Cell Biol 40(3): 362-382.

Mukherjee, D., P. J. Coates, et al. (2012). "The in vivo expression of radiation-induced chromosomal instability has an inflammatory mechanism." Radiation research 177(1): 18-24.

Nandi, S., R. C. Guzman, et al. (1995). "Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis." Proceedings of the National Academy of Sciences of the United States of America 92(9): 3650-3657.

Nguyen, D. H., H. A. Oketch-Rabah, et al. (2011). "Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type." Cancer Cell 19(5): 640-651.

Nik-Zainal, S., J. E. Kucab, et al. (2015). "The genome as a record of environmental exposure." Mutagenesis 30(6): 763-770.

Pazhanisamy, S. K., H. Li, et al. (2011). "NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability." Mutagenesis 26(3): 431-435.

Regulus, P., B. Duroux, et al. (2007). "Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion." Proceedings of the National Academy of Sciences of the United States of America 104(35): 14032-14037.

Russo, I. H. and J. Russo (1996). "Mammary gland neoplasia in long-term rodent studies." Environmental health perspectives 104(9): 938-967.

Russo, J. (2015). "Significance of rat mammary tumors for human risk assessment." Toxicologic pathology 43(2): 145-170.

Seager, A. L., U. K. Shah, et al. (2012). "Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance." Toxicological sciences : an official journal of the Society of Toxicology 128(2): 387-397.

Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.

Sherborne, A. L., P. R. Davidson, et al. (2015). "Mutational Analysis of Ionizing Radiation Induced Neoplasms." Cell Rep 12(11): 1915-1926.

Snijders, A. M., F. Marchetti, et al. (2012). "Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility." PLoS One 7(10): e45394.

Westcott, P. M. K., K. D. Halliwill, et al. (2014). "The mutational landscapes of genetic and chemical models of Kras-driven lung cancer." Nature 517: 489.

Yang, X. R., J. K. Killian, et al. (2015). "Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH) arrays." PLoS One 10(3): e0116078



Increased DNA damage leading to increased risk of breast cancer

Breast carcinogenesis from IR and DNA damaging agents has more similarities than differences (Imaoka, Nishimura et al. 2009). Both IR and other DNA damaging agents form adenocarcinomas in rodents with similar pathology and gene expression, although IR also creates a much larger fraction of fibroadenomas than DNA damaging chemicals (Imaoka, Nishimura et al. 2009). Carcinogenicity for IR and chemical mammary carcinogens NMU and DMBA varies with age and exposure to ovarian hormones (Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). Breast carcinogenesis from IR and chemical carcinogens depends strongly on developmental or ongoing exposure to ovarian hormones (Nandi, Guzman et al. 1995; Russo 2015), and estrogen status of tumors increases with ovarian hormone exposure in rats (Nandi, Guzman et al. 1995; Imaoka, Nishimura et al. 2009). The mammary gland is especially susceptible to both IR and mammary carcinogens DMBA and NMU around puberty. This is presumably because puberty is when undifferentiated cells are both large in number and will undergo major subsequent proliferative expansion, although additional factors including metabolism and expression of DNA damage repair genes contribute to variations in the age of maximal susceptibility between agents (Medina 2007; Imaoka, Nishimura et al. 2009; Imaoka, Nishimura et al. 2011; Imaoka, Nishimura et al. 2013). Consistent with general accepted risk assessment assumptions of additivity in carcinogenesis, IR has an additive effect in combination with NMU (Imaoka, Nishimura et al. 2014). Some differences between mammary carcinogens appear around the protective role of breast maturation: pregnancy appears to be more protective in rats exposed to chemical carcinogens than in rats exposed to IR.

The role of DNA damage, mutation, and proliferation outlined in this AOP would presumably apply to other DNA damaging agents while the role of RONS and inflammation is more likely to vary between DNA damaging and other agents based on their ability to induce these key events. DNA damaging agents differ in the degree, type and reparability of the DNA damage they cause. Mammary carcinogens NMU, DMBA, PhIP, and urethane mostly cause adducts with single nucleotide substitutions (Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation 2006; Imaoka, Nishimura et al. 2009; Westcott, Halliwill et al. 2014; Nik-Zainal, Kucab et al. 2015; Sherborne, Davidson et al. 2015). Like ionizing radiation, mammary carcinogen PhIP can cause amplifications and NMU can cause genomic instability (Goepfert, Moreno-Smith et al. 2007; Imaoka, Nishimura et al. 2009). While IR also induces adducts, it characteristically generates complex damage and double-strand breaks leading to deletions and inversions as well as amplification and genomic instability (Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Mukherjee, Coates et al. 2012; Snijders, Marchetti et al. 2012; Yang, Killian et al. 2015; Behjati, Gundem et al. 2016; Mavragani, Nikitaki et al. 2017). The prevalence of complex damage and double strand breaks is likely due to the density of damage delivered by ionizing radiation, but is also attributable to oxidative activity, since IR creates an oxidative state and H2O2 and other oxidizing agents can also cause (less) complex damage, double strand breaks and mutations (Seager, Shah et al. 2012; Sharma, Collins et al. 2016; Cadet, Davies et al. 2017). Radiomimetic compounds (used in chemotherapy) also cause double-strand breaks and simple complex damage. Agents like bleomycin cause double strand breaks through oxidized lesions (Regulus, Duroux et al. 2007), while agents like etoposide and cisplatin cause double strand breaks by interfering with DNA replication forks (Kawashima, Yamaguchi et al. 2017).

Evidence suggests that proliferation and inflammation are also implicated in chemical carcinogenicity. The aforementioned pubertal susceptibility implies a dependence on proliferation, as does the fact that tumorigenesis following NMU depends on proliferation during treatment (Medina 2007).  Like IR, NMU and DMBA promote hyperplasia in terminal end buds and ducts and ductal carcinoma in situ leading to carcinogenesis (Goepfert, Moreno-Smith et al. 2007; Medina 2007; Imaoka, Nishimura et al. 2009; Russo 2015). In terms of inflammation, some chemical carcinogens appear to share with IR an increase in inflammatory reactions in mammary stroma and a tumor-promoting effect of stroma (Russo and Russo 1996; Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004; Nguyen, Oketch-Rabah et al. 2011) and although bleomycin has not been characterized for its effects on mammary stroma or mammary carcinogenesis it causes lung fibrosis (an anti-inflammatory reaction) so consistently that it is used as a research model for that endpoint (Moeller, Ask et al. 2008).

 

Barcellos-Hoff, M. H. and S. A. Ravani (2000). "Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells." Cancer Res 60(5): 1254-1260.

Behjati, S., G. Gundem, et al. (2016). "Mutational signatures of ionizing radiation in second malignancies." Nat Commun 7: 12605.

Cadet, J., K. J. A. Davies, et al. (2017). "Formation and repair of oxidatively generated damage in cellular DNA." Free radical biology & medicine 107: 13-34.

Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation (2006). Health risks from exposure to low levels of ionizing radiation : BEIR VII, Phase 2, National Research Council of the National Academies.

Datta, K., S. Suman, et al. (2012). "Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine." PLoS One 7(8): e42224.

Goepfert, T. M., M. Moreno-Smith, et al. (2007). "Loss of chromosomal integrity drives rat mammary tumorigenesis." Int J Cancer 120(5): 985-994.

Imaoka, T., M. Nishimura, et al. (2013). "Influence of age on the relative biological effectiveness of carbon ion radiation for induction of rat mammary carcinoma." International journal of radiation oncology, biology, physics 85(4): 1134-1140.

Imaoka, T., M. Nishimura, et al. (2014). "Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis." Int J Cancer 134(7): 1529-1538.

Imaoka, T., M. Nishimura, et al. (2009). "Radiation-induced mammary carcinogenesis in rodent models: what's different from chemical carcinogenesis?" J Radiat Res 50(4): 281-293.

Imaoka, T., M. Nishimura, et al. (2011). "Pre- and postpubertal irradiation induces mammary cancers with distinct expression of hormone receptors, ErbB ligands, and developmental genes in rats." Mol Carcinog 50(7): 539-552.

Kawashima, Y., N. Yamaguchi, et al. (2017). "Detection of DNA double-strand breaks by pulsed-field gel electrophoresis." Genes to cells : devoted to molecular & cellular mechanisms 22(1): 84-93.

Maffini, M. V., A. M. Soto, et al. (2004). "The stroma as a crucial target in rat mammary gland carcinogenesis." J Cell Sci 117(Pt 8): 1495-1502.

Mavragani, I. V., Z. Nikitaki, et al. (2017). "Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis." Cancers (Basel) 9(7).

Medina, D. (2007). "Chemical carcinogenesis of rat and mouse mammary glands." Breast Dis 28: 63-68.

Moeller, A., K. Ask, et al. (2008). "The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?" Int J Biochem Cell Biol 40(3): 362-382.

Mukherjee, D., P. J. Coates, et al. (2012). "The in vivo expression of radiation-induced chromosomal instability has an inflammatory mechanism." Radiation research 177(1): 18-24.

Nandi, S., R. C. Guzman, et al. (1995). "Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis." Proceedings of the National Academy of Sciences of the United States of America 92(9): 3650-3657.

Nguyen, D. H., H. A. Oketch-Rabah, et al. (2011). "Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type." Cancer Cell 19(5): 640-651.

Nik-Zainal, S., J. E. Kucab, et al. (2015). "The genome as a record of environmental exposure." Mutagenesis 30(6): 763-770.

Pazhanisamy, S. K., H. Li, et al. (2011). "NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability." Mutagenesis 26(3): 431-435.

Regulus, P., B. Duroux, et al. (2007). "Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion." Proceedings of the National Academy of Sciences of the United States of America 104(35): 14032-14037.

Russo, I. H. and J. Russo (1996). "Mammary gland neoplasia in long-term rodent studies." Environmental health perspectives 104(9): 938-967.

Russo, J. (2015). "Significance of rat mammary tumors for human risk assessment." Toxicologic pathology 43(2): 145-170.

Seager, A. L., U. K. Shah, et al. (2012). "Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance." Toxicological sciences : an official journal of the Society of Toxicology 128(2): 387-397.

Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.

Sherborne, A. L., P. R. Davidson, et al. (2015). "Mutational Analysis of Ionizing Radiation Induced Neoplasms." Cell Rep 12(11): 1915-1926.

Snijders, A. M., F. Marchetti, et al. (2012). "Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility." PLoS One 7(10): e45394.

Westcott, P. M. K., K. D. Halliwill, et al. (2014). "The mutational landscapes of genetic and chemical models of Kras-driven lung cancer." Nature 517: 489.

Yang, X. R., J. K. Killian, et al. (2015). "Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH) arrays." PLoS One 10(3): e0116078.




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