Genotoxicity of benzene and its metabolites

Whysner, John; Reddy, M. Vijayaraj; Ross, Peter M.; Mohan, Melissa; Lax, Elizabeth A.

doi:10.1016/s1383-5742(03)00053-x

Cited by 159 publications

(117 citation statements)

References 246 publications

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“…WRN organizes the response to DNA damage and is critical to the repair of DNA double-strand breaks (DSBs). DSBs are highly toxic lesions that, if not repaired or repaired incorrectly, can cause cell death, mutations, and chromosomal translocations that can lead to cancer [19,20].…”

Section: Discussionmentioning

confidence: 99%

Depletion of WRN enhances DNA damage in HeLa cells exposed to the benzene metabolite, hydroquinone

Galvan

Lim

Zmugg

et al. 2008

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Werner syndrome is a progeroid disorder caused by mutations of the WRN gene. The encoded WRN protein belongs to the family of RecQ helicases that plays a role in the maintenance of genomic stability. Single nucleotide polymorphisms in WRN have been associated with an increased risk for some cancers and were recently linked to benzene hematotoxicity. To further address the role of WRN in benzene toxicity, we employed RNA interference (RNAi) to silence endogenous WRN in HeLa cells and examined the susceptibility of these WRN-depleted cells to the toxic effects of the benzene metabolite hydroquinone. HeLa cells were used as the experimental model because RNAi is highly effective in this system producing almost complete depletion of the target protein. Depletion of WRN led to a decrease in cell proliferation and an enhanced susceptibility to hydroquinone cytotoxicity as revealed by an increase in necrosis. WRN-depleted HeLa cells treated with hydroquinone also displayed an increase in the amount of DNA double strand breaks as determined by the Comet assay, and an elevated DNA damage response as indicated by the 7-fold induction of γH2AX and acetyl-p53 (Lys373 and Lys382) over control levels. Together, these results show that WRN plays an important role in the protection of HeLa cells against the toxicity of the benzene metabolite hydroquinone, specifically in mounting a normal DNA damage response following the induction of DNA double-strand breaks. Further studies in bone marrow-derived stem or progenitor cells are required to confirm our findings in HeLa cells and expand our ability to extrapolate the results to benzene toxicity in humans.

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Section: Discussionmentioning

confidence: 99%

Depletion of WRN enhances DNA damage in HeLa cells exposed to the benzene metabolite, hydroquinone

Galvan

Lim

Zmugg

et al. 2008

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…According to the International Agency of Research on Cancer (IARC), gasoline vapour is included in class of human carcinogens 1,2 . Benzene is a volatile aromatic hydrocarbon solvent used extensively in industry in the past.…”

Section: Introductionmentioning

confidence: 99%

Dna damage in gasoline station workers caused by occupational exposure to petrol vapour in turkey

Beceren¹,

Akdemir²,

Omurtag³

et al. 2016

actapharm

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“…However, the precise mechanism by which benzene and its phenolic-and quinone-based metabolites induce leukemias is not fully characterized. Benzene is not a classic chemical carcinogen as there is little evidence for the production of highly electrophilic DNA-binding metabolites in vivo (4). It is mainly metabolized in the liver and bone marrow and it is believed that the induced hematopoietic cancers in humans are mediated through the generation of reactive oxygen species by its principal metabolite, hydroquinone (HQ) (2).…”

Section: Introductionmentioning

confidence: 99%

The benzene metabolite hydroquinone enhances G2-chromosomal radiosensitivity by inducing a less-efficient G2-M-checkpoint in irradiated lymphocytes

Hatzi

Terzoudi²,

Pantelias³

et al. 2007

Int J Oncol

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Abstract. The hypothesis tested is that a 24-h pre-irradiationexposure of peripheral blood lymphocytes (PBL) to the benzene metabolite hydroquinone (HQ), at doses that are nonacutely toxic (5 μM), induces a less efficient G2-M-checkpoint and enhances the G2-chromosomal radiosensitivity in a statistically significant manner (p<0.01). A less efficient G2-Mcheckpoint may allow the transition of damaged cells from G2-to M-phase and experimental data in the present work support this hypothesis. In fact HQ sensitizes lymphocytes obtained from healthy donors, as they exhibit increased G2-chromosomal radiosensitivity which interestingly is similar to that observed in cases of radiosensitive cancer-prone individuals. This finding is important since a deficiency in cell cycle checkpoints and an increase in G2-chromosomal radiosensitivity are linked to chromosomal instability, cancer proneness and the development of leukemia. The observed chromosome radiosensitization may be a consequence either of an effect of HQ on the initial induction of radiation-induced chromosomal aberrations, or on the DNA repair capacity of the cells, or it may be linked to HQ-induced alterations in the cell cycle and feedback control mechanism during the G2-to M-phase transition. In order to elucidate which is the mechanism involved, conventional cytogenetics and premature chromosome condensation (PCC) methodologies were applied. The experimental data obtained support the hypothesis that HQ increases G2-chromosomal radiosensitivity in human peripheral blood lymphocytes by inducing a less efficient G2-M-checkpoint, facilitating thus the transition of damaged cells from G2-to M-phase.

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Genotoxicity of benzene and its metabolites

Cited by 159 publications

References 246 publications

Depletion of WRN enhances DNA damage in HeLa cells exposed to the benzene metabolite, hydroquinone

Depletion of WRN enhances DNA damage in HeLa cells exposed to the benzene metabolite, hydroquinone

Dna damage in gasoline station workers caused by occupational exposure to petrol vapour in turkey

The benzene metabolite hydroquinone enhances G2-chromosomal radiosensitivity by inducing a less-efficient G2-M-checkpoint in irradiated lymphocytes

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