Molecular dosimetry of N7-(2-hydroxypropyl)guanine in tissues of F344 rats after inhalation exposure to propylene oxide.
Propylene oxide (PO) is a high-volume chemical intermediate that causes a low incidence of nasal tumors in rodents exposed to high concentrations (> or =300 p.p.m.). PO reacts with DNA forming mainly N7-(2-hydroxypropyl)guanine (7-HPG). The exposure-dependent accumulation of 7-HPG in nasal respiratory epithelium (NRE), lung and liver was determined in male F344 rats exposed to PO (0, 5, 25, 50, 300 or 500 p.p.m.) by the inhalation route for 3 or 20 days (6 h/day; 5 days/week). These exposures ranged from low concentrations, such as those potentially occurring in the workplace, to high concentrations that proved to be carcinogenic in rodents. Analysis of 7-HPG in DNA by gas chromatography-high-resolution mass spectrometry (GC-HRMS) showed a linear response in 7-HPG for all three tissues after 3 days of exposure, and for NRE and lung after 20 days of exposure. A slightly sublinear response in 7-HPG was observed in liver after 20 days of exposure. For both exposure periods, the NRE had the highest concentration of 7-HPG, followed by lung and liver. The amount of 7-HPG in NRE was seven and 17 times higher than in lung and liver, respectively, for the 3 day exposures. For the 20 day exposures, the concentration of 7-HPG in NRE was six and 13 times higher than that in lung and liver, respectively, over the concentration range studied. These results demonstrate a much higher extent of DNA alkylation in the target tissue for carcinogenesis, than in non-target tissues. As PO-induced tumor formation was highly sublinear, occurring only at high vapor concentrations, whereas 7-HPG adducts were shown to be linearly dependent on airborne concentration, these results suggest that 7-HPG is not sufficient for PO nasal carcinogenesis and that other factors such as increased cell proliferation may be important in determining the tumor exposure response.
Ríos-Blanco
Melva N
MN
Curriculum in Toxicology, Campus Box 7431, Rosenau Hall 253c, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ranasinghe
Asoka
A
Lee
Moung S
MS
Faller
Thomas
T
Filser
Johannes G
JG
Swenberg
James A
JA
D000478:Alkylation / Q000187:drug effects; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis; D004852:Epoxy Compounds / Q000008:administration & dosage*; D008401:Gas Chromatography-Mass Spectrometry; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D015994:Incidence; D019570:Inhalation Exposure; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors
C116199:7-(2-hydroxypropyl)guanine; D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; D006147:Guanine; D004247:DNA; C009068:propylene oxide