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Defining a No Observable Transcriptional Effect Level (NOTEL) for low dose N-OH-PhIP exposures in human BEAS-2B bronchioepithelial cells

ABSTRACT: The estimation of acceptable exposure levels for genotoxicants is accomplished by defining thresholds from apical endpoints, or by modeling points of departure from data that are acquired from high dose experiments, followed by linear extrapolation of the response through zero. We recently proposed that low dose exposure-induced transcriptional changes that can be linked to mechanisms of pathogenesis could provide a more sensitive alternative for defining thresholds for biological responses. In the present study, we used gene expression profiling data to determine an empirical transcriptional dose response threshold for the food and tobacco smoke borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5]pyridine (PhIP) in human BEAS-2B bronchial epithelial cells exposed to concentrations of N-hydroxylated PhIP ranging from 1 x 10-6 to 5 x 10-10 M.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34635 | GEO | 2011/12/22

SECONDARY ACCESSION(S): PRJNA151269

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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Defining a No Observable Transcriptional Effect Level (NOTEL) for low dose N-OH-PhIP exposures in human BEAS-2B bronchioepithelial cells

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