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Radiation effects on lung carcinogenesis in neonatal, juvenile, and adult Wistar rats after thoracic X-ray irradiation

ABSTRACT: Studies of radiation exposed populations have shown that children are at greater overall risk of radiation-induced cancer, although there is considerable debate relating to heterogeneity of the effect in different tissues. Given public concern around increasing radiation doses received by children from advanced diagnostic imaging, and the use of radiotherapy to treat childhood cancers, understanding the relationship between age-at-exposure and radiation-induced cancer risk is a priority of radiation protection research. Although tobacco smoking accounts for up to 90% of lung cancers in some countries, epidemiological studies and animal experiments show that exposure to ionizing radiation is also a risk factor for developing cancers of the lung. Female Wistar rats are susceptible to lung cancer upon thoracic X-ray irradiation, developing adenocarcinomas (AC) and squamous cell carcinomas (SCC) similar to those seen in humans, and have been used previously to evaluate the interaction of radiation and a chemical carcinogen in neonatal, juvenile and young adult rats. In the present study, the induction of lung tumors was analyzed in female Wistar rats exposed to increasing doses of thoracic X-rays as neonates, juveniles or adults, to allow the effect of age-at-exposure to be observed in the absence of interaction with smoking. Histology was used to compare tumor subtypes between groups, and genomic DNA copy number alterations in a number of tumors arising after exposure to radiation at different ages were examined.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE78869 | GEO | 2017/03/03

SECONDARY ACCESSION(S): PRJNA314232

REPOSITORIES: GEO

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Project description:Although various mechanisms have been inferred for combinatorial actions of multiple carcinogens, these mechanisms have not been well demonstrated in experimental carcinogenesis models. We evaluated mammary carcinogenesis initiated by combined exposure to various doses of radiation and chemical carcinogens. Female rats at 7 weeks of age were M-NM-3-irradiated (0.2M-bM-^@M-^S2 Gy) and/or exposed to 1-methyl-1-nitrosourea (20 or 40 mg/kg, single intraperitoneal injection) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (40 mg/kg/day by gavage for 10 days) and were observed until 50 weeks of age. The incidence of mammary carcinoma increased steadily as a function of radiation dose in the absence of chemicals; mathematical analysis supported an additive increase when radiation was combined with a chemical carcinogen, irrespective of the chemical species and its dose. Hras mutations were characteristic of carcinomas that developed after chemical carcinogen treatments and were overrepresented in carcinomas induced by the combination of radiation and MNU (but not PhIP), indicating an interaction of radiation and MNU at the level of initiation. The expression profiles of seven classifier genes, previously shown to distinguish two classes of rat mammary carcinomas, categorized almost all examined carcinomas that developed after individual or combined treatments with radiation (1 Gy) and chemicals as belonging to a single class; more comprehensive screening using microarrays and a separate test sample set failed to identify differences in gene expression profiles among these carcinomas. These results suggest that a complex, multilevel interaction underlies the combinatorial action of radiation and chemical carcinogens in the experimental model. Mammary cancers were from untreated rats (n = 3) and rats treated with radiation (1 Gy; n = 4), MNU (40 mg/kg; H-rasM-bM-^@M-^Smutated cancers, n = 5; H-rasM-bM-^@M-^Snonmutated cancers, n = 4), PhIP (H-rasM-bM-^@M-^Smutated, n = 1; H-rasM-bM-^@M-^Snonmutated, n = 3), radiation 1 Gy plus MNU (40 mg/kg; H-rasM-bM-^@M-^Smutated, n = 5; H-rasM-bM-^@M-^Snonmutated, n = 4) and radiation 1 Gy plus PhIP (H-rasM-bM-^@M-^Snonmutated , n = 4). Normal mammary tissues were from untreated rats (n = 3).

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Radiation effects on lung carcinogenesis in neonatal, juvenile, and adult Wistar rats after thoracic X-ray irradiation

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