ISSN:0893-6692    

DOI:10.1002/em.2850260302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe US Environmental Protection Agency (EPA) developed a genetic risk assessment model for exposures to ethylene oxide utilizing data on the induction of reciprocal translocations in male germ cells [Rhomberg et al. 1990]. This particular approach served as a reasonable initial attempt, albeit somewhat limited with regard to endpoint and only partially attentive to the mechanisms of induction of genetic alterations and the behavior of chromosomes during meiosis. The present paper discusses the scientific basis for a reassessment of the EPA model, providing data and hypotheses related to effective dose to the target cells and shape of the dose‐response relationship at low doses, and dose rates. While the present genetic risk assessment approach is discussed in terms of ethylene oxide, it would be applicable to most mutagenic chemicals. The outcome of the discussion is that the genetic risk for exposed males from reciprocal translocation induction will be negligible at low doses since the dose‐response curve is likely to be a function of the square of the dose. In addition, the proportion of genetically unbalanced live born offspring in humans arising from reciprocal translocation carriers is less than 10% of the frequency formed through meiotic segregation and fertilization for such carriers. Simply from a consideration of mechanism—namely, the very high probability of DNA repair prior to the next S‐phase for a resting oocyte—it would be predicted that there would be a very low to negligible frequency of translocations in female germ cells from ethylene oxide exposure. It is further stressed that additional components of a genetic risk model require a consideration of all germ cell stages in the male, and the inclusion of calculations for point and deletion mutations. Some indications of likely response are presented with these points in mind. © 1995 Wiley

ISSN:0893-6692    

DOI:10.1002/em.2850260303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractTo assess the potential effect of maternal environments on human embryonic/fetal somatic mutation, we measured the frequencies of hypoxanthine‐guanine phosphoribosyltransferase (HPRT,hprtgene), mutant T lymphocytes (Mf), and glycophorin A (GPA) variant erythrocytes (Vf) of both allele‐loss (ø/N) and allele‐loss‐and‐duplication (N/N) phenotypes in umbilical cord blood. The meanhprtMf(1.40 ± 1.11 × 10−6, N = 66) and GPA Vf(ø/N 4.0 ± 2.2 × 10−6, N = 114; N/N 2.7 ± 2.0 × 10−6, N = 91) were significantly lower than those previously reported for adult populations. In addition, thehprtMfwas significantly higher than that of a published study of newborn cord blood samples from a geographically distant population (0.64 ± 0.41 × 10−6, N = 45,P<0.01; t test,P<0.01, Mann‐Whitney U test). An examination of the demographic data from these two populations led to the sampling of 10 additional newborns specifically matched to the published study for maternal socioeconomic status. ThehprtMf(0.70 ± 0.49 × 10−6) of this selected population was consistent with the published report and significantly lower than that of our initial population (P<0.03, t test;P<0.01, Mann‐Whitney U test). These results indicate that there is an environmental effect related to maternal socioeconomic status on the frequency of embryonic/fetal somatic mutations. Molecular analyses ofhprtmutants from this cohort with elevated Mfrevealed a significant decrease in the relative contribution of gross structural mutations to the overall Mf(25 of 38, 66% vs. 34 of 41, 83%,P= 0.024, x2test), suggesting that the higher Mfresulted from an elevated level of “point” mutations. No individual maternal demographic or environmental factor was identified as contributing more significantly than other any factor to the observed variability in

ISSN:0893-6692    

DOI:10.1002/em.2850260304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe mutagenic impact of various environmental and therapeutic agents can now be directly assayed in humans by the T‐lymphocyte cloning assay. We have previously reported that following radioimmu‐noglobulin therapy, cancer patients exhibited increased mutant frequency at thehprtlocus and an increased yield of large intergenic deletions compared to unexposed controls. Here we report the results of the analysis of 26 independenthprtmutations in nine cancer patients who underwent radioimmunoglobulin therapy. The majority of mutations (52%) had lost exon sequences from the mRNA. The remaining mutations were 20% small deletions and frameshifts and 28% base substitutions. The type of mutations observed were similar to those seen in unexposed controls. The site distribution of the mutations, however, indicates that some sequence contexts may be more sensitive to radiation mutagenesis than others. © 1995 Wiley‐Lis

ISSN:0893-6692    

DOI:10.1002/em.2850260305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractTo study the mechanisms of mutagenesis in vivo, we analyzed mutations at the hypoxanthine phosphoribosyl transferase (hprt) locus using cDNA from cynomolgus monkey T‐lymphocytes. In the present study, the spectrum of spontaneoushprtmutations arising in vivo in wild‐caught cynomolgus monkey peripheral T‐lymphocytes is described. Cells were isolated from peripheral blood, and mutant clones were selected in 6‐thioguanine, propagated, and stored frozen. cDNA was copied fromhprtmRNA from a lysate of 7,000 to 20,000 cells. A 780‐base‐pairs (bp) region including the coding region was amplified by polymerase chain reaction and directly sequenced. We sequenced 40 spontaneous mutants from 11 monkeys. Of these 40 clones, 23 (57%) had base‐pair substitutions, 11 (28%) had small (20 bp) deletions and/or insertions. Of the 23 base substitutions, 13 were transitions (11 G:C → A:T, 1 A:T → G:C, and 1 tandem TT → CC) and 10 were transversions (3 G:C → T:A, 3 G:C → C:G, 2 A:T → T:A, 2 A:T → C:G). Bases 209 and 617 were apparent substitution hotspots, which have also been observed as hotspots in humanhprt. In 2 clones with large insertions, the inserted bases were of intronic origin. One of these lost 272 bp from exons 2–3 and contained a 93‐bp insertion from the middle of intron 3. Two clones with small deletions and 5 clones with large deletions or insertions (7/40 or 17.5%) could be splice

ISSN:0893-6692    

DOI:10.1002/em.2850260306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractIt has been reported that exogenous alkylated purines, such as O6‐methylguanine (O6meG), induce aneuploidy in mammalian cells. It is shown here that the aneugenic effect of O6meG, evidenced by its ability to induce micronuclei in rodent cells, is dependent on its conversion to O6‐methyl‐guano‐sine‐5′‐monophosphate (O6me‐5′‐GMP) by hypo‐xanthine‐guanine phosphoribosyl transferase (HPRT). This conclusion, in contrast with previous in vitro data showing that O6meG does not seem to be a substrate for HPRT, was based on the following observations: 1) O6meG did not induce micronuclei in HPRT‐deficient Chinese hamster cells, but did induce micronuclei in HPRT‐proficient cells, and in mouse cells partially or totally deficient in adenine phosphoribosyl transferase; 2) O6meG was not metabolized in HPRT‐deficient cells, while in wild‐type cells a number of metabolites were detected by high performance liquid chromatography (HPLC) analysis of cold acid extracts, one of them coeluting with O6me‐5′‐GMP used as a marker; 3) when de novo synthesis of purine nucleotides was inhibited by aminopterin, O6meG sustained the growth of HPRT‐proficient, but not of HPRT‐deficient, cells; and 4) when HPRT‐deficient cells were treated with lipo‐somes charged with O6me‐5′‐GMP, induction of micronuclei was shown. The finding that methylated guanine exerts its aneugenic action through methylated nucleotide(s) provides an important, though indirect, support to the hypothesis that alkylating agents may induce aneuploidy via

ISSN:0893-6692    

DOI:10.1002/em.2850260307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractAflatoxin BI, 2‐aminoanthracene, and 7,12‐dimethylbenz[a]anthracene have been implicated in the etiology of human cancers. In this study, we demonstrate that these three chemicals can be activated by rat liver homogenate S9 coupled with NADPH coenzymes to produce a dose‐dependent increase in the frequency ofAPRTreversion in the APRT‐deficient human cell line HTD114. HTD114 contains single nucleotide insertions at different positions in eachAPRTallele and the spontaneous reversion frequency is<10−8. However, the highest reversion frequency induced by these chemicals is 1.2–2.0 × 10−5, at least a 103‐fold increase over the frequency of spontaneous reversion. Reversion of either mutant allele was observed to be a consequence of a frame‐restoring loss of a single nucleotide, which indicates that these three chemicals can function as frameshift mutagens in human cells. © 1

ISSN:0893-6692    

DOI:10.1002/em.2850260308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractA rapid and simple procedure for the micronucleus test (MNT) in vitro using Chinese hamster ovary (CHO) cells was established in our laboratory. The assay is intended to quickly screen chromosomal aberrations in vitro within the framework of industrial genotoxicity studies. To test the sensitivity of the assay in the experiments described here, four substances, classified as noncarcinogens but reported as weak inducers of micronuclei (MN) in bone‐marrow cells of mice, were evaluated in the MNT in vitro. Of the four compounds, ascorbic acid, phenol, and 2,6‐diaminotoluene proved to be genotoxic in the MNT in vitro. Titanium dioxide, which could not be dissolved in the culture medium, did not induce MN. The MNT in vitro proved to be quick and relatively simple and to yield highly reproducible results when testing the four chemicals. © 1995 Wiley‐Lis

ISSN:0893-6692    

DOI:10.1002/em.2850260309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractNaturally occurring antimutagenic compounds are extensively analyzed for their capacity to protect cells from induced damage. We selected two agents, taurine and ellagic acid, treated in the literature as antioxidants, but whose activity is insufficiently known. This paper reports on the ability of these agents to act against damage induced by mitomycin‐C and hydrogen peroxide in Chinese hamster ovary cells cultivated in vitro. Cytogenetic and cytofluorimetric analyses were performed. Ellagic acid proved to have more than one mechanism of action, probably as a scavenger of oxygen species produced by H2O2treatment, and as a protector of the DNA double helix from alkylating agent injury. In our experimental conditions, taurine seems able to scavenge oxygen species. © 1995 Wiley‐Liss,

ISSN:0893-6692    

DOI:10.1002/em.2850260310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractStructural analyses of azadirachtin, a promising biopesticide recently introduced into the United States, indicates that this natural product has the potential for acting as a “genotoxic” carcinogen. In view of the fact that genotoxic carcinogens are regarded as presenting a potential carcinogenic risk to humans, the present finding suggests that the possible metabolism of azadirachtin to DNA‐reactive products be evaluated experimentally. © 1995 Wiley‐L

ISSN:0893-6692    

DOI:10.1002/em.2850260311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY