Journal Article

Quantitation of DNA and hemoglobin adducts and apurinic/apyrimidinic sites in tissues of F344 rats exposed to propylene oxide by inhalation

Melva N. Ríos-Blanco, Thomas H. Faller, Jun Nakamura, Winfried Kessler, Paul E. Kreuzer, Asoka Ranasinghe, Johannes G. Filser and James A. Swenberg

in Carcinogenesis

Volume 21, issue 11, pages 2011-2018
Published in print November 2000 | ISSN: 0143-3334
Published online November 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.11.2011
Quantitation of DNA and hemoglobin adducts and apurinic/apyrimidinic sites in tissues of F344 rats exposed to propylene oxide by inhalation

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Propylene oxide (PO) is a relatively weak mutagen that induces nasal tumor formation in rats during long-term inhalation studies at high exposures (≥300 p.p.m.), concentrations that also cause cytotoxicity and increases in cell proliferation. Direct alkylation of DNA by PO leads mainly to the formation of N7-(2-hydroxypropyl)guanine (7-HPG). In this study, the accumulation of 7-HPG in tissues of male F344 rats exposed to 500 p.p.m. PO (6 h/day, 5 days/week for 4 weeks) by the inhalation route was measured by gas chromatography–high resolution mass spectrometry (GC-HRMS). In animals killed up to 7 h following the end of the last exposure the levels of 7-HPG (pmol/μmol guanine) in nasal respiratory tissue, nasal olfactory tissue, lung, spleen, liver and testis DNA were 606.2 ± 53.0, 297.5 ± 56.5, 69.8 ± 3.8, 43.0 ± 3.8, 27.5 ± 2.4 and 14.2 ± 0.7, respectively. The amounts of 7-HPG in the same tissues of animals killed 3 days after cessation of exposure were 393.3 ± 57.0, 222.7 ± 29.5, 51.5 ± 1.2, 26.7 ± 1.0, 18.0 ± 2.6 and 10.4 ± 0.1. A comparable rate of disappearance of 7-HPG was found among all tissues. DNA from lymphocytes pooled from four rats killed at the end of the last exposure was found to have 39.6 pmol adduct/μmol guanine. Quantitation of DNA apurinic/apyrimidinic sites, potentially formed after adduct loss by chemical depurination or DNA repair, showed no difference between tissues from control and exposed rats. The level of N-(2-hydroxypropyl)valine in hemoglobin of exposed rats was also determined using a modified Edman degradation method followed by GC-HRMS analysis. The value obtained was 90.2 ± 10.3 pmol/mg globin. These data demonstrate that nasal respiratory tissue, which is the target tissue for carcinogenesis, has a much greater level of alkylation of DNA than non-target tissues.

Keywords: AP, apurinic/apyrimidinic; ARP, aldehyde-reactive probe; ddH2O, doubly distilled water; EO, ethylene oxide; GC-HRMS, gas chromatography–high resolution mass spectrometry; Hb, hemoglobin; MMS, methylmethanesulfonate; 7-HEG, N7-(hydroxyethyl)guanine; N6-HPdAdo, N6-(2-hydroxypropyl)deoxyadenosine; 1-HPdAdo, N1-(2-hydroxypropyl)deoxyadenosine; 3-HPdCyd, N3-(2-hydroxypropyl)deoxycytidine; 3-HPdUrd, N3-(2-hydroxypropyl)deoxyuridine; 7-HPG, N7-(2-hydroxypropyl)guanine; 7-MG, N7-methylguanine; N-dl-HPVal-Leu-anilide, N-dl-2-hydroxypropyl-Val-Leu-anilide; N-HPVal, N-(2-hydroxypropyl)valine; PBS, phosphatebuffered saline; PO, propylene oxide.

Journal Article.  8688 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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