Quantitation of DNA and hemoglobin adducts and apurinic/apyrimidinic sites in tissues of F344 rats exposed to propylene oxide by inhalation.
Propylene oxide (PO) is a relatively weak mutagen that induces nasal tumor formation in rats during long-term inhalation studies at high exposures (> or =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 N:7-(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/micromol 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/micromol 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.
Ríos-Blanco
M N
MN
Curriculum in Toxicology and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Faller
T H
TH
Nakamura
J
J
Kessler
W
W
Kreuzer
P E
PE
Ranasinghe
A
A
Filser
J G
JG
Swenberg
J A
JA
D000818:Animals; D001080:Apurinic Acid / Q000378:metabolism; D002250:Carbon Radioisotopes; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis* / Q000096:biosynthesis; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis* / Q000096:biosynthesis; D006454:Hemoglobins / Q000032:analysis / Q000378:metabolism*; D019570:Inhalation Exposure; D008297:Male; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D010761:Phosphorus Radioisotopes; D051381:Rats; D011916:Rats, Inbred F344; D012474:Salmon; D013737:Testis / Q000737:chemistry; D014633:Valine / Q000031:analogs & derivatives* / Q000032:analysis* / Q000096:biosynthesis
C116199:7-(2-hydroxypropyl)guanine; D002250:Carbon Radioisotopes; D018736:DNA Adducts; D004852:Epoxy Compounds; D006454:Hemoglobins; D009153:Mutagens; D010761:Phosphorus Radioisotopes; D001080:Apurinic Acid; D006147:Guanine; D004247:DNA; C057443:2-hydroxypropylvaline; D014633:Valine; C009068:propylene oxide