Molecular dosimetry of endogenous and ethylene oxide-induced N7-(2-hydroxyethyl) guanine formation in tissues of rodents.
The formation of N7-(2-hydroxyethyl)guanine (7-HEG) in DNA was investigated previously in target and non-target tissues of F-344 rats and B6C3F1 mice exposed to >/=ISOdia>/=10 p.p.m. concentrations of ethylene oxide (EO) using fluorescence-linked high-performance liquid chromatography [V.E. Walker et al. (1992) Cancer Res., 52, 4238-4334]. In order to study the dose-responses for 7-HEG at lower exposures, a highly sensitive and specific gas chromatography coupled with high-resolution mass spectrometry (GC-HRMS) assay was developed. DNA was extracted from liver, brain, lung and spleen of B6C3F1 mice and F-344 rats exposed to 0, 3, 10, 33 or 100 p.p.m. EO for 4 weeks (6 h/day, 5 days/week). Analysis of DNA from control rodents showed that endogenous 7-HEG varied from 0.2 +/- 0.1 to 0.3 +/- 0.2 pmol/micromol guanine in tissues of rats and mice. 7-HEG exhibited tissue- and species-specific dose-response relationships in EO-exposed animals. Linear dose-response relationships were evident in mouse liver, brain and spleen at exposures between 3 and 100 p.p.m. Mouse lung exhibited a slightly sublinear response between 33 and 100 p.p.m. EO. The relationships were linear in liver and spleen of rats between 3 and 100 p.p.m. EO, but were slightly sublinear in brain and lung between 33 and 100 p.p.m. EO. The number of 7-HEG adducts present in rats exposed to 3 p.p.m. EO was 5.3-12.5 times higher than endogenous 7-HEG in unexposed controls. In contrast, mice exposed to 3 p.p.m. EO only had 1.3- to 2.5-fold greater numbers of 7-HEG adducts. The factors driving the exposure-response relationships are also likely to affect carcinogenic and mutagenic responses of rodents to EO. Likewise, a better understanding of the relationships between 7-HEG derived from low exposures to EO and endogenously formed 7-HEG may be important for the accurate extrapolation of risk to humans.
Wu
K Y
KY
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA.
Ranasinghe
A
A
Upton
P B
PB
Walker
V E
VE
Swenberg
J A
JA
D000818:Animals; D001923:Brain Chemistry; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D005027:Ethylene Oxide / Q000008:administration & dosage / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D008297:Male; D051379:Mice; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000737:chemistry
D002273:Carcinogens; D018736:DNA Adducts; C035018:N(7)-hydroxyethylguanine; D006147:Guanine; D004247:DNA; D005027:Ethylene Oxide