TY - JOUR
T1 - Propylene oxide
T2 - Mutagenesis, carcinogenesis and molecular dose
AU - Ríos-Blanco, Melva N.
AU - Plna, Kamila
AU - Faller, Thomas
AU - Kessler, Winfried
AU - Håkansson, Krystyna
AU - Kreuzer, Paul E.
AU - Ranasinghe, Asoka
AU - Filser, Johannes G.
AU - Segerbäck, Dan
AU - Swenberg, James A.
N1 - Funding Information:
We are grateful to K.T. Morgan and E.A. Gross at CIIT for demonstrating the technique for the dissection of the nasal mucosa, to C. Pütz and A. Keller for excellent technical assistance and to Dr. Pott for animal health care. This work was supported by the Chemical Manufacturers Association.
PY - 1997/10/31
Y1 - 1997/10/31
N2 - The results from mutagenic and carcinogenic studies of propylene oxide (PO) and the current efforts to develop molecular dosimetry methods for PO-DNA adducts are reviewed. PO has been shown to be active in several bacterial and mammalian mutagenicity tests and induces site of contact tumors in rodents after long-term administration. Quantitation of N7-(2 hydroxypropyl)guanine (7-HPG) in nasal and hepatic tissues of male F344 rats exposed to 500 ppm PO (6 h/day; 5 days/week for 4 weeks) by inhalation was performed to evaluate the potential of high concentrations of PO to produce adducts in the DNA of rodent tissues and to obtain information necessary for the design of molecular dosimetry studies. The persistence of 7-HPG in nasal and hepatic tissues was studied in rats killed three days after cessation of a 4-week exposure period. DNA samples from exposed and untreated animals were analyzed for 7-HPG by two different methods. The first method consisted of separation of the adduct from DNA by neutral thermal hydrolysis, followed by electrophoretic derivatization of the adduct and gas chromatography-high resolution mass spectrometry (GC-HRMS) analysis. The second method utilized 32P-postlabeling to quantitate the amount of this adduct in rat tissues. Adducts present in tissues from rats killed immediately after cessation of exposure were 835.4 ± 80.1 (respiratory), 396.8 ± 53.1 (olfactory) and 34.6 ± 3.0 (liver) pmol adduct/μmol guanine using GC-HRMS. Lower values, 592.7 ± 53.3, 296.5 ± 32.6 and 23.2 ± 0.6 pmol adduct/μmol guanine were found in respiratory, olfactory and hepatic tissues of rats killed after three days of recovery. Analysis of the tissues by 32P-postlabeling yielded the following values; 445.7 ± 8.0 (respiratory), 301.6 ± 49.2 (olfactory) and 20.6 ± 1.8 (liver) pmol adduct/μmol guanine in DNA of rats killed immediately after exposure cessation and 327.1 ± 21.7 (respiratory), 185.3 ± 29.2 (olfactory) and 15.7 ± 0.9 (liver) pmol adduct/μmol guanine after recovery. Current methods of quantitation did not provide evidence for the endogenous formation of this adduct in control animals. These studies demonstrated that the target tissue for carcinogenesis has much greater alkylation of DNA than liver, a tissue that did not exhibit a carcinogenic response.
AB - The results from mutagenic and carcinogenic studies of propylene oxide (PO) and the current efforts to develop molecular dosimetry methods for PO-DNA adducts are reviewed. PO has been shown to be active in several bacterial and mammalian mutagenicity tests and induces site of contact tumors in rodents after long-term administration. Quantitation of N7-(2 hydroxypropyl)guanine (7-HPG) in nasal and hepatic tissues of male F344 rats exposed to 500 ppm PO (6 h/day; 5 days/week for 4 weeks) by inhalation was performed to evaluate the potential of high concentrations of PO to produce adducts in the DNA of rodent tissues and to obtain information necessary for the design of molecular dosimetry studies. The persistence of 7-HPG in nasal and hepatic tissues was studied in rats killed three days after cessation of a 4-week exposure period. DNA samples from exposed and untreated animals were analyzed for 7-HPG by two different methods. The first method consisted of separation of the adduct from DNA by neutral thermal hydrolysis, followed by electrophoretic derivatization of the adduct and gas chromatography-high resolution mass spectrometry (GC-HRMS) analysis. The second method utilized 32P-postlabeling to quantitate the amount of this adduct in rat tissues. Adducts present in tissues from rats killed immediately after cessation of exposure were 835.4 ± 80.1 (respiratory), 396.8 ± 53.1 (olfactory) and 34.6 ± 3.0 (liver) pmol adduct/μmol guanine using GC-HRMS. Lower values, 592.7 ± 53.3, 296.5 ± 32.6 and 23.2 ± 0.6 pmol adduct/μmol guanine were found in respiratory, olfactory and hepatic tissues of rats killed after three days of recovery. Analysis of the tissues by 32P-postlabeling yielded the following values; 445.7 ± 8.0 (respiratory), 301.6 ± 49.2 (olfactory) and 20.6 ± 1.8 (liver) pmol adduct/μmol guanine in DNA of rats killed immediately after exposure cessation and 327.1 ± 21.7 (respiratory), 185.3 ± 29.2 (olfactory) and 15.7 ± 0.9 (liver) pmol adduct/μmol guanine after recovery. Current methods of quantitation did not provide evidence for the endogenous formation of this adduct in control animals. These studies demonstrated that the target tissue for carcinogenesis has much greater alkylation of DNA than liver, a tissue that did not exhibit a carcinogenic response.
UR - http://www.scopus.com/inward/record.url?scp=19244383235&partnerID=8YFLogxK
U2 - 10.1016/S0027-5107(97)00135-8
DO - 10.1016/S0027-5107(97)00135-8
M3 - Article
C2 - 9385398
AN - SCOPUS:19244383235
SN - 0027-5107
VL - 380
SP - 179
EP - 197
JO - Mutation Research Regular Papers
JF - Mutation Research Regular Papers
IS - 1-2
ER -