Frequent mutations of the Trp53, Hras1 and β-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice

Zhuang, Shi‐Mei; Wiseman, Roger W.; Söderkvist, Peter

doi:10.1038/sj.onc.1205649

Cited by 16 publications

(13 citation statements)

References 32 publications

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“…G:C3 C:G transversions were previously found as activating mutations in codon 13 of the K-ras gene of neoplasms of the forestomach, Harderian gland, liver, lung, and lymphocytes [Goodrow et al, 1990[Goodrow et al, , 1994Hong et al, 1997;Zhuang et al, 1997;Sills et al, 1999Sills et al, , 2001 and in codon 13 of the H-ras gene of mammary gland tumors of BD-exposed mice [Zhuang et al, 2002], while A:T3 T:A transversions were observed as activating lesions in codon 61 of the H-ras and/or K-ras genes of the same types of neoplasms except mammary gland tumors of BD-exposed mice (Table IX). A:T3 G:C transitions were also found as activating mutations in H-ras codon 61 of forestomach and Harderian gland tumors from BD-exposed mice, but not at higher frequencies than background in corresponding neoplasms from control animals [Sills et al, 1999[Sills et al, , 2001].…”

Section: Discussionmentioning

confidence: 96%

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Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Meng

Walker

Scott

et al. 2004

Environ and Mol Mutagen

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A multiplex PCR procedure for analysis of genomic DNA mutations in the mouse hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene was developed and then used with other established methods for the coincident identification of large- and small-scale genetic alterations in the Hprt gene of mutant T-cell isolates propagated from sham- and 1,3-butadiene (BD)-exposed mice and rats. The spectra data for RT-PCR/cDNA analysis and multiplex PCR of genomic DNA from Hprt mutants were combined, and statistical analyses of the mutant fractions for the classes of mutations identified in control versus exposed animals were conducted. Under the assumption that the mutant fractions are distributed as Poisson variates, BD exposure of mice significantly increased the frequencies of (1) nearly all types of base substitutions; (2) single-base deletions and insertions; and (3) all subcategories of deletions. Significantly elevated fractions of G:C-->C:G and A:T-->T:A transversions in the Hprt gene of BD-exposed mice were consistent with the occurrence of these substitutions as the predominant ras gene mutations in multiple tumor types increased in incidence in carcinogenicity studies of BD in mice. BD exposure of rats produced significant increases in (1) base substitutions only at A:T base pairs; (2) single-base insertions; (3) complex mutations; and (4) deletions (mainly 5' partial and complete gene deletions). Future coincident analyses of large- and small-scale mutations in rodents exposed to specific BD metabolites should help identify species differences in the sources of deletion mutations and other types of mutations induced by BD exposures in mice versus rats.

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Section: Discussionmentioning

confidence: 96%

“…e Data for lymphocytes from Goodrow et al [1990] and Zhuang et al [1997]. f Data for mammary gland from Zhuang et al [2002].…”

Section: Class Of Mutationmentioning

confidence: 96%

Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Meng

Walker

Scott

et al. 2004

Environ and Mol Mutagen

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“…These effects on cell cycle progression were accompanied by increases in the nuclear levels of p53 and p21 cip1 . These findings indicate that in addition to the reported effects of BDO 2 on biomarkers of genetic damage Skopek, 1994a, 1994b;Hayes et al, 1996Hayes et al, , 2000Hayes et al, , 2001Kligerman et al, 1999;Jackson et al, 2000;Zhuang et al, 2002], acute BDO 2 exposure also results in substantial perturbation of cell cycle progression.…”

Section: Discussionmentioning

confidence: 78%

Acute exposure of human lung cells to 1,3-butadiene diepoxide results in G1 and G2 cell cycle arrest

Schmiederer

Knutson

Muganda³

et al. 2005

Environ. Mol. Mutagen.

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1,3-Butadiene (BD) causes genetic damage, including adduct formation, sister chomatid exchange, and point mutations. Previous studies have focused on the types of genetic damage and tumors found after long-term exposure of rodents to butadiene. This study examined the effect of the most active BD metabolite, butadiene diepoxide (BDO2), on cell cycle entry and progression in human lung fibroblasts (LU cells) with a normal diploid karyotype. Serum-arrested (G0) LU cells were exposed to BDO2 for 1 hr and stimulated to divide with medium containing 10% fetal bovine serum. The BDO2-treated LU cells were evaluated for cell cycle progression, nuclear localization of arrest mediators, mitotic index, and cellular proliferation. The BDO2-treated cells demonstrated a substantial inhibition of cell proliferation when treated with 100 microM BDO2 for 1 hr. No appreciable levels of apoptosis or mitotic figures were observed in the BDO2-treated cells through 96 hr posttreatment. Flow cytometric analysis revealed that the lack of proliferation in BDO2-treated LU cells was related to G1 arrest in about half of the cells and a delayed progression through S and G2 arrest in nearly all of the remaining cells. Both G1 and G2 arrest were prolonged and only a very small percentage of BDO2-treated cells were eventually able to replicate. Increased nuclear localization of both p53 and p21(cip1) was observed in BDO2-treated cells, suggesting that the cell cycle arrest was p21(cip1)-mediated. These results demonstrate that BDO2 induces cell cycle perturbation and arrest even with short-term exposure that does not produce other pathologic cellular effects.

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“…In addition, the genetic alterations are similar to the major molecular pathways observed in human brain tumors and suggest a possible role of environmental exposure in human neurocarcinogenesis. The predominant G → A transition in the p53 gene in these mouse brain tumors suggests that treatment of 1,3-butadiene may have caused DNA damage as has been shown for other 1,3-butadiene induced tumors, although the mutation profiles are different in several tumors (Wiseman et al, 1994;Zhuang et al, 1997;Hong et al, 2000;Sills et al, 2001;Zhuang et al, 2002). The G → A transition appeared to be consistent with the mutational specificity of alkylating agents, including 1,3-butadiene, that frequently cause G:C → AT transition mutations, suggesting that they may arise from the predicted miscoding of guanine-N7-adducts or from cross linking of DNA strands (Trukhanova et al, 1998;Melnick, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…However, the development of malignant gliomas and neuroblastomas in B6C3F1 mice exposed to 1,3-butadiene provided the first opportunity to compare genetic alterations in chemically induced mouse brain tumors with those of humans (NTP, 1984(NTP, , 1993. Exposure TOXICOLOGIC PATHOLOGY of mice with 1,3-butadiene also caused increased incidences of tumors in multiple organ systems and mutations in tumor suppressor genes and oncogenes were often detected (Hong et al, 2000;Walker and Meng, 2000;Zhuang et al, 2000;Sills et al, 2001;Zhuang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Genetic Alterations in Brain Tumors Following 1,3-Butadiene Exposure in B6C3F1 Mice

Kim

Hong

Lachat³

et al. 2005

Toxicol Pathol

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The nervous system of the B6C3F1 mouse has rarely been a target for chemical carcinogenesis in the National Toxicology Program (NTP) bioassays. However, 6 malignant gliomas and 2 neuroblastomas were observed in B6C3F1 mice exposed to 625 ppm 1,3-butadiene (NTP technical reports 288 and 434). These mouse brain tumors were evaluated with regard to the profile of genetic alterations that are observed in human brain tumors. Alterations in the p53 tumor suppressor gene were common. Missense mutations were observed in 3/6 malignant gliomas and 2/2 neuroblastomas and were associated with loss of heterozygosity. Most of the mutations occurred in exons 5-8 of the p53 gene and were G → A transitions, and did not involve CpG sites. Loss of heterozygosity at the Ink4a/Arf gene locus was observed in 5/5 malignant gliomas and 1/1 neuroblastoma, while the PTEN (phosphatase and tensin homologue) gene locus was unaffected by deletions. One of 2 neuroblastomas had a mutation in codon 61 of H-ras, while H-ras mutations were not observed in the malignant gliomas examined. Only 1 brain tumor has been reported from control mice of over 500 NTP studies. This malignant glioma showed no evidence of alterations in the p53 gene or K -and H-ras mutations. It is likely that the specific genetic alterations observed were induced or selected for by 1,3-butadiene treatment that contributed to the development of mouse brain tumors. The observed findings are similar in part to the genetic alterations reported in human brain tumors.

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Frequent mutations of the Trp53, Hras1 and β-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice

Cited by 16 publications

References 32 publications

Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Acute exposure of human lung cells to 1,3-butadiene diepoxide results in G1 and G2 cell cycle arrest

Genetic Alterations in Brain Tumors Following 1,3-Butadiene Exposure in B6C3F1 Mice

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