title: Formation of DNA adducts in rat lung following chronic inhalation of diesel emissions, carbon black and titanium dioxide particles.
abstract: Exposure of rats to diesel emissions results in the development of lung tumors. The objective of this study was to determine whether the polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs or other polycyclic organic matter adsorbed to diesel particles induces the formation of DNA adducts in the lung when compared to particles with little or no adsorbed organic matter. Rats were exposed to diesel emissions containing particles with over 30% solvent-extractable adsorbed organic matter and to particles with < 0.1% adsorbed organic matter (carbon black particles and TiO2). Wistar rats were exposed to diesel emissions (7.5 mg/m3) for 2 months, 6 months and 2 years and for 2 years to carbon black (11.3 mg/m3) and TiO2 particles (10.4 mg/m3) to compare tumorigenic response and DNA adduct formation in the lung. Two versions of the 32P-postlabeling assay for the detection of DNA adducts were used to tentatively identify nitrated-amine or arylamine adducts formed relative to other nitro PAH based on the demonstrated sensitivity of these adducts to nuclease P1 treatment. Total adduct levels were determined for peripheral lung tissue DNA as detected in a diagonal radioactive zone. One major adduct which migrated outside this region (adduct 1) and a nuclease P1-sensitive adduct (adduct 2) were quantitated separately. Adduct 1 increased significantly over time in the filtered air exposed animals but decreased markedly at the 2 year time points regardless of particle type, presumably as a result of adduct dilution through de novo cell synthesis or cell proliferation invoked in response to particle loading and/or effect on the endogenous synthesis or degradation of DNA reactive moieties. The nuclease sensitive adduct (adduct 2), possibly resulting from exposure to nitro-PAHs, was detected in diesel-exposed rats but was not detected in the rats exposed to TiO2 and carbon black. No significant elevation in PAH-derived adducts, relative to the filtered air controls, was observed in the rodents exposed to diesel emission. Our data suggest that long-term contact with these particles may result in a cell proliferative response, enhanced degradation of I-compounds not related to cell proliferation, and/or synthesis of I-compounds, irrespective of the differences in organic content associated with the three particle types. This response may be an important factor in explaining the reported similarity in tumorigenic response in rodents exposed to diesel emissions, carbon black and TiO2 particles.
authors.affiliation: Health Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711.
authors.forename: J
authors.initials: J
authors.lastname: Gallagher
authors.forename: U
authors.initials: U
authors.lastname: Heinrich
authors.forename: M
authors.initials: M
authors.lastname: George
authors.forename: L
authors.initials: L
authors.lastname: Hendee
authors.forename: D H
authors.initials: DH
authors.lastname: Phillips
authors.forename: J
authors.initials: J
authors.lastname: Lewtas
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002244:Carbon / Q000633:toxicity*; D004247:DNA / Q000378:metabolism*; D005260:Female; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D014025:Titanium / Q000633:toxicity*; D001335:Vehicle Emissions / Q000009:adverse effects*
chemical_list: D001335:Vehicle Emissions; C009495:titanium dioxide; D002244:Carbon; D004247:DNA; D014025:Titanium