Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo[a]pyrene-diol-epoxide and dibenzo[a,l]pyrene-diol-epoxide

Lagerqvist, Anne; Håkansson, Daniel; Prochazka, Gabriela; Lundin, Cecilia; Dreij, Kristian; Segerbäck, Dan; Jernström, Bengt; Törnqvist, Margareta; Seidel, Albrecht; Erixon, Klaus; Jenssen, Dag

doi:10.1016/j.dnarep.2008.03.022

Cited by 37 publications

(25 citation statements)

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“…This can be ascribed to differences in DNA-binding efficiency of their ultimate carcinogenic bay-and fjord-region DE intermediates, differences in both structural features of the DNA adducts and their recognition and consequently in the downstream signalling [Dipple et al, 1987;Ralston et al, 1995;Dreij et al, 2005]. Nevertheless, very few studies have been carried out on the repair of DBPDE-induced DNA lesions [Dreij et al, 2005;Lagerqvist et al, 2008;Paajarvi et al, 2008] and no detailed data on the cytogenetic effects of this compound in mammalian cells are available in the liter ature.…”

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confidence: 99%

DNA Repair Mechanisms Involved in the Removal of DBPDE-Induced Lesions Leading to Chromosomal Alterations in CHO Cells

Meschini

Berni

Marotta

et al. 2010

Cytogenet Genome Res

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Polycyclic aromatic hydrocarbons (PAH) such as dibenzo[a,l]pyrene (DBP) are wide-spread environmental pollutants most probably mutagenic and carcinogenic to humans. Detailed data on the cytogenetic effects of anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) in mammalian cells are not available in the literature. The aim of this study is to elucidate the mechanisms involved in the induction of chromosomal aberrations and sister chromatid exchanges (SCEs) by DBPDE in mammalian cells. In order to achieve this a parental (AA8) and different DNA repair-deficient Chinese hamster ovary cell lines such as UV4, UV5, UV61 (nucleotide excision repair, NER), EM9 (base excision repair, BER), irs1SF (homologous recombination repair, HRR) and V3-3 (non-homologous end joining, NHEJ) were used. The most sensitive cell lines for DBPDE-induced chromosome aberrations were EM9 and irs1SF, while EM9 and V3-3 cell lines were the most sensitive in terms of SCEs induction. It can be suggested that the BER pathway plays an important role in the repair of lesions induced by DBPDE, affecting both chromosomal aberrations and SCEs induction. Moreover, the HRR pathway seems to play a role in cellular resistance to DBPDE mainly in terms of chromosomal aberration induction while the NHEJ pathway takes part affecting only the induction of SCEs.

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confidence: 99%

DNA Repair Mechanisms Involved in the Removal of DBPDE-Induced Lesions Leading to Chromosomal Alterations in CHO Cells

Meschini

Berni

Marotta

et al. 2010

Cytogenet Genome Res

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“…DBP requires metabolic activation by species-specific cytochrome P450 enzymes to generate DNA adducts, mutations, chromosome damage, and tumors (Buters et al 2002;Schober et al 2006;Kushman et al 2007;Lagerqvist et al 2008;Topinka et al 2008;Meschini et al 2010). From additional analyses done on stomach-tissue samples in the ED 001 study, Bailey et al (2009) concluded that there was "clear evidence from stomach tumors that DBP-driven mutations in the Ki-ras oncogene were present even at low dose."…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Models Fit to Ed₀₀₁ Data on >40,000 Trout Exposed to Dibenzo[A,L]Pyrene Indicate Mutations Do Not Drive Increased Tumor Risk

Bogen

2014

Dose-Response

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ᮀ ED 001 -study data on increased liver and stomach tumor risks in >40,000 trout fed dibenzo [a,l]pyrene (DBP), one of the most potently mutagenic chemical carcinogens known, provide the greatest low-dose dose-response resolution of any experimentally induced tumor data set to date. Although multistage somatic mutation/clonal-expansion cancer theory predicts that genotoxic carcinogens increase tumor risk in linear no-threshold proportion to dose at low doses, ED 001 tumor data curiously exhibit substantial low-dose nonlinearity. To explore the role that nongenotoxic mechanisms may have played to yield such nonlinearity, the liver and stomach tumor data sets were each fit by two models that each assume a genotoxic and a nongenotoxic pathway to increased tumor risk: the stochastic 2-stage (MVK) cancer model, and a model implementing the more recent dysregulated adaptive hyperplasia (DAH) theory of tumorigenesis. MVK and DAH fits to the data sets were each excellent, but unexpectedly each MVK fit implies that DBP acts to increase tumor risk by entirely non-mutagenic mechanisms. Given that DBP is such a potent mutagen, the MVK-model fits obtained appear to be biologically implausible, whereas the DAH-model fits reflect that model's assumption that chemical-induced tumorigenesis typically is driven by elevated repair-cell populations rather than mutations per se.

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“…[e.g. Venkitaraman (2003), Lagerqvist (2008), Friedenson (2007)]. Cancers that depend on gene translocations may occur because double strand breaks are repaired by combining inappropriate pieces of broken chromosomes.…”

Section: Introductionmentioning

confidence: 99%

“…The incidence of mantle cell lymphoma increased 70 fold when the BRCA1/2 pathway molecule ATM was inactivated [Friedenson, 2007]. At least in some cases, losses of whole chromosomes or fragments damage such fundamental and essential systems that alternative mechanisms are unable to compensate without allowing dangerous mutations [Lagerqvist et al (2008)]. …”

Section: Introductionmentioning

confidence: 99%

Preventing hereditary cancers caused by opportunistic carcinogens

Friedenson¹

2011

Nat Prec

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ObjectivesPrevious studies reported inherited BRCA1/2 deficits can cause cancer by impairing normal protective responses. Opportunistic carcinogens can exploit these deficits by causing chronic inflammation, constant cell death and replacement in a mutagenic environment, DNA crosslinking or double strand breaks. Some of the resulting cancers may be prevented if opportunistic carcinogens are identified. MethodsThe literature was systematically searched for carcinogens capable of exploiting deficits in BRCA1/2 pathways. Search criteria were common exposure, available information, required BRCA1/2 pathway repairs, increased risks for any cancer, and effects on stem cells. ResultsFormaldehyde and acetaldehyde are closely related carcinogens and common pollutants that seem everywhere. Alcohol metabolism also produces acetaldehyde. High levels of either carcinogen overwhelm normal detoxification systems, cause inflammation, inhibit DNA repair and produce DNA cross links as critical carcinogenic lesions. Searching model system studies revealed both carcinogens activate stem cells, BRCA1/2 pathways and connected BRCA1/2 pathways to myeloid leukemia. For example, the BRCA1-BARD1 complex is required for proper nucleophosmin functions. Nucleophosmin prevents a major subset of acute myeloid leukemia (AML). Next, these concepts were independently tested against risks for myeloid leukemia. Epidemiologic results showed that BRCA2 gene defects inherited on both chromosomes increased risks so dramatically that AML occurs in most children. Using data from 14 studies, known/potential heterozygous BRCA1/BRCA2 mutations increased risks for myeloid leukemias by at least 3 fold in 7 studies and by at least 50% in 12.Acetaldehyde occurs in breast milk. In model studies, excessive acetaldehyde/alcohol exposure affects estrogen metabolism and stimulates alternate alcohol detoxification pathways. These pathways can also cause DNA cross linking by releasing oxygen species and activating procarcinogens. Acetaldehyde in rats' drinking water increased incidence of leukemias, lymphomas, pancreatic tumors and fibroadenomas. Six human epidemiologic studies support an association between alcohol related genotype or alcohol consumption and early onset breast cancers, including those in BRCA1/2 mutation carriers. ConclusionsAlthough it is difficult to prove direct causation, BRCA1/2 mutation carriers may reduce cancer risks by avoiding excessive formaldehyde and acetaldehyde. Broader genetic testing and pharmacologic/nutritional detoxification are possible.

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Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo[a]pyrene-diol-epoxide and dibenzo[a,l]pyrene-diol-epoxide

Cited by 37 publications

References 47 publications

DNA Repair Mechanisms Involved in the Removal of DBPDE-Induced Lesions Leading to Chromosomal Alterations in CHO Cells

DNA Repair Mechanisms Involved in the Removal of DBPDE-Induced Lesions Leading to Chromosomal Alterations in CHO Cells

Mechanistic Models Fit to Ed₀₀₁ Data on >40,000 Trout Exposed to Dibenzo[A,L]Pyrene Indicate Mutations Do Not Drive Increased Tumor Risk

Preventing hereditary cancers caused by opportunistic carcinogens

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Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo[a]pyrene-diol-epoxide and dibenzo[a,l]pyrene-diol-epoxide

Cited by 37 publications

References 47 publications

DNA Repair Mechanisms Involved in the Removal of DBPDE-Induced Lesions Leading to Chromosomal Alterations in CHO Cells

DNA Repair Mechanisms Involved in the Removal of DBPDE-Induced Lesions Leading to Chromosomal Alterations in CHO Cells

Mechanistic Models Fit to Ed001 Data on >40,000 Trout Exposed to Dibenzo[A,L]Pyrene Indicate Mutations Do Not Drive Increased Tumor Risk

Preventing hereditary cancers caused by opportunistic carcinogens

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Mechanistic Models Fit to Ed₀₀₁ Data on >40,000 Trout Exposed to Dibenzo[A,L]Pyrene Indicate Mutations Do Not Drive Increased Tumor Risk