Effects of benzene on DNA strand breaks in vivo versus benzene metabolite-induced DNA strand breaks in vitro in mouse bone marrow cells

Lee, Eun Woo; Garner, Charles D.

doi:10.1016/0041-008x(91)90096-w

Cited by 27 publications

(17 citation statements)

References 38 publications

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“…213 However, other results indicated that the presence of oxygen radical scavengers did not reduce HQ-induced phage DNA single strand breaks in vitro, 184 while mouse bone marrow cell DNA breakage was induced by BQ despite its low oxygen radical-generating potential. 214 Finally, in vitro inhibition of DNA and RNA polymerases and of DNA topoisomerases by oxidized HQ metabolites has been reported. 96,97,100,202,205,215 The genotoxicity database for HQ supports a low potential for direct mutagenicity (i.e., induction of frame-shift and point mutations) for this compound.…”

Section: Genotoxicitymentioning

confidence: 99%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

178

128

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Hydroquinone (HQ) is a high-volume commodity chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It is also used in over-the-counter (OTC) drugs as an ingredient in skin lighteners and is a natural ingredient in many plant-derived products, including vegetables, fruits, grains, coffee, tea, beer, and wine. While there are few reports of adverse health effects associated with the production and use of HQ, a great deal of research has been conducted with HQ because it is a metabolite of benzene. Physicochemical differences between HQ and benzene play a significant role in altering the pharmacokinetics of directly administered when compared with benzene-derived HQ. HQ is only weakly positive in in vivo chromosomal assays when expected human exposure routes are used. Chromosomal effects are increased significantly when parenteral or in vitro assays are used. In cancer bioassays, HQ has reproducibly produced renal adenomas in male F344 rats. The mechanism of tumorigenesis is unclear but probably involves a species-, strain-, and sex-specific interaction between renal tubule toxicity and an interaction with the chronic progressive nephropathy that is characteristic of aged male rats. Mouse liver tumors (adenomas) and mononuclear cell leukemia (female F344 rat) have also been reported following HQ exposure, but their significance is uncertain. Various tumor initiation/promotion assays with HQ have shown generally negative results. Epidemiological studies with HQ have demonstrated lower death rates and reduced cancer rates in production workers when compared with both general and employed referent populations. Parenteral administration of HQ is associated with changes in several hematopoietic and immunologic endpoints. This toxicity is more severe when combined with parenteral administration of phenol. It is likely that oxidation of HQ within the bone marrow compartment to the semiquinone or p-benzoquinone (BQ), followed by covalent macromolecular binding, is critical to these effects. Bone marrow and hematologic effects are generally not characteristic of HQ exposures in animal studies employing routes of exposure other than parenteral. Myelotoxicity is also not associated with human exposure to HQ. These differences are likely due to significant route-dependent toxicokinetic factors. Fetotoxicity (growth retardation) accompanies repeated administration of HQ at maternally toxic dose levels in animal studies. HQ exposure has not been associated with other reproductive and developmental effects using current USEPA test guidelines. The skin pigment lightening properties of HQ appear to be due to inhibition of melanocyte tyrosinase. Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. The most serious human health effect related to HQ is p...

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Section: Genotoxicitymentioning

confidence: 99%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

178

128

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“…Despite intensive studies over several decades, mechanisms underlying benzene induced toxicity and leukemogenicity are not yet fully understood. They are complicated by various pathways including those of metabolism (Snyder and Hedli, 1996), growth factor regulation (Niculescu, 1995), oxidative stress (Laskin et al 1996), DNA damage (Lee and Garner, 1991), cell cycle regulation (Yoon et al 2001b) and programmed cell death (Ross et al 1996). To elucidate molecular mechanisms of its toxicity, cDNA microarray analyses have been performed by several workers.…”

Section: Introductionmentioning

confidence: 99%

Time Dependent Gene Expression Changes in the Liver of Mice Treated with Benzene

Park

Yoon

et al. 2008

Biomark�Insights

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Benzene is used as a general purpose solvent. Benzene metabolism starts from phenol and ends with p-benzoquinone and o-benzoquinone. Liver injury inducted by benzene still remains a toxicologic problem. Tumor related genes and immune responsive genes have been studied in patients suffering from benzene exposure. However, gene expression profiles and pathways related to its hepatotoxicity are not known. This study reports the results obtained in the liver of BALB/C mice (SLC, Inc., Japan) administered 0.05 ml/100 g body weight of 2% benzene for six days. Serum, ALT, AST and ALP were determined using automated analyzer (Fuji., Japan). Histopathological observations were made to support gene expression data. c-DNA microarray analyses were performed using Affymetrix Gene-chip system. After six days of benzene exposure, twenty five genes were down regulated whereas nineteen genes were up-regulated. These gene expression changes were found to be related to pathways of biotransformation, detoxification, apoptosis, oxidative stress and cell cycle. It has been shown for the first time that genes corresponding to circadian rhythms are affected by benzene. Results suggest that gene expression profile might serve as potential biomarkers of hepatotoxicity during benzene exposure.

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“…Mechanisms of Benzene-Induced Hematotoxicity and Leukemogenicity: cDNA Microarray Analyses Using Mouse Bone Marrow Tissue production of oxidative stress (Laskin et al 1996;Subrahmanyam et al 1991), DNA damage and repair (Lee and Garner 1991), cell cycle regulation (Yoon et al 2001b), and apoptosis Ross et al 1996). These studies indicate that investigation of the roles of a few specific genes may not be sufficient to explain the complete molecular mechanism of benzene-induced hematotoxicity and leukemogenicity.…”

mentioning

confidence: 99%

“…Benzene metabolites subsequently undergo secondary activation by myeloperoxidase (MPO) that is present at high levels in the bone marrow tissue. This results in the production of genotoxic quinones and reactive oxygen species, thereby inducing not only hemopoietic cellular damage (Farris et al 1997;Kolachana et al 1993; Lee and Garner 1991;Smith et al 1989) but also the dysfunction of bone marrow stromal cells (Niculescu et al 1995).…”

mentioning

confidence: 99%

Mechanisms of benzene-induced hematotoxicity and leukemogenicity: cDNA microarray analyses using mouse bone marrow tissue.

Yoon

Kitada

et al. 2003

Environ Health Perspect

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Although the mechanisms underlying benzene-induced toxicity and leukemogenicity are not yet fully understood, they are likely to be complicated by various pathways, including those of metabolism, growth factor regulation, oxidative stress, DNA damage, cell cycle regulation, and programmed cell death. With this as a background, we performed cDNA microarray analyses on mouse bone marrow tissue during and after a 2-week benzene exposure by inhalation. Our goal was to clarify the mechanisms underlying the hematotoxicity and leukemogenicity induced by benzene at the level of altered multigene expression. Because a few researchers have postulated that the cell cycle regulation mediated by p53 is a critical event for benzene-induced hematotoxicity, the present study was carried out using p53-knockout (KO) mice and C57BL/6 mice. On the basis of the results of large-scale gene expression studies, we conclude the following: a) Benzene induces DNA damage in cells at any phase of the cell cycle through myeloperoxidase and in the redox cycle, resulting in p53 expression through Raf-1 and cyclin D-interacting myb-like protein 1. b) For G1/S cell cycle arrest, the p53-mediated pathway through p21 is involved, as well as the pRb gene-mediated pathway. c) Alteration of cyclin G1 and Wee-1 kinase genes may be related to the G2/M arrest induced by benzene exposure. d) DNA repair genes such as Rad50 and Rad51 are markedly downregulated in p53-KO mice. e) p53-mediated caspase 11 activation, aside from p53-mediated Bax gene induction, may be an important pathway for cellular apoptosis after benzene exposure. Our results strongly suggest that the dysfunction of the p53 gene, possibly caused by strong and repeated genetic and epigenetic effects of benzene on candidate leukemia cells, may induce fatal problems such as those of cell cycle checkpoint, apoptosis, and the DNA repair system, finally resulting in hemopoietic malignancies. Our cDNA microarray data provide valuable information for future investigations of the mechanisms underlying the toxicity and leukemogenicity of benzene.

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Effects of benzene on DNA strand breaks in vivo versus benzene metabolite-induced DNA strand breaks in vitro in mouse bone marrow cells

Cited by 27 publications

References 38 publications

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

Time Dependent Gene Expression Changes in the Liver of Mice Treated with Benzene

Mechanisms of benzene-induced hematotoxicity and leukemogenicity: cDNA microarray analyses using mouse bone marrow tissue.

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