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Benzene's adverse effects: microarrays reveal breadth of toxicity.

Benzene is both widely used and widely studied. Yet, although the chemical is strongly associated with leukemia in humans, questions remain regarding its mechanism of action. Hoping to better understand the genetic mechanisms behind benzene's hematotoxicity and leukemogenicity, a group of researchers from Japan and Korea used cDNA microarrays to analyze mouse bone marrow tissue both during and after a two-week exposure to the compound by inhalation [EHP 111:1411-1420]. The researchers found, among other discoveries, that benzene may perturb cell cycling that is mediated by the gene for the protein p53, triggering a host of fatal problems at the cellular level and thus causing blood cell malignancies epigenetically (that is, without encoding the information in the genetic code).

Benzene is used in fuels, as an industrial solvent, and in other manufacturing applications, and is also found in cigarette smoke. Human populations generally are exposed through polluted ambient air or contaminated water. Benzene is known to cause hematotoxicity and blood tumors in humans and mice. Studies so far have focused on benzene's carcinogenic and genotoxic metabolites, which cause various types of tumors in a number of mouse organ systems. Hepatic enzymes convert inhaled benzene into genotoxic metabolites. Then, to add insult to injury, a number of these benzene metabolites (primarily phenol, hydroquinone, catechol, and trans-trans muconic acid) actually intensify the chemical's toxic effect on an organ.

Past studies have suggested that benzene's toxic effects on bone marrow tissue--its major target organ--may be enacted through multiple pathways, including growth factor regulation, oxidative stress reduction, DNA damage repair, cell cycle regulation, and apoptosis. Also, genetic variations may upset the cellular-environmental homeostasis that protects bone marrow cells from toxic effects such as those caused by benzene, resulting in altered gene expression. Therefore, the authors suggest, studying just a few specific genes may not be enough to thoroughly explain the complex molecular mechanisms of benzene-induced hematotoxicity and leukemogenicity.

With this in mind, the research team conducted broad cDNA microarray analyses using multiple gene expression profiling technologies. The team analyzed mouse bone marrow tissue during and after exposure to 300 parts per million benzene over a 2-week period for 6 hours a day, 5 days a week. Two types of C57BL/6 mice were used--standard wild-type mice possessing the gene for p53 and p53-knockout mice. The mice were randomly grouped into control and benzene-exposed groups.

Twice during the exposure period and then 3 days after the full 2-week exposure, the researchers collected bone marrow from both femurs of each mouse in each group. RNA was extracted from this tissue and used to synthesize cDNA, which was then hybridized onto a microarray chip. The resulting array of gene fragments was scanned as a digital image and analyzed using software that searched for clustering genes specifically expressed and/or suppressed in each group.

The researchers found that benzene caused DNA damage in cells during all phases of the cell cycle. In the benzene-exposed wild-type mice, DNA repair genes were activated, but they were suppressed in the p53-knockout mice. Mice in the latter group were therefore susceptible to benzene's direct genotoxic leukemogenicity, whereas those in the former still experienced epigenetic leukemogenicity via cell-cycle perturbations despite DNA repair.

Besides the p53-mediated pathway, the investigators identified other specific genes that may be involved in G1 cell cycle arrest and apoptosis following benzene exposure, and confirmed that certain repair genes--including the tuberous sclerosis gene and the metallothionein 1 gene--are also triggered by such exposure. They also found that, during benzene exposure, the production of blood cells was arrested due to alterations in the expression of cell cycle checkpoint genes in the wild-type mice. However, production continued in the p53-knockout mice, an important difference that the researchers say could point to mechanisms of benzene's hematotoxicity.

The researchers' cDNA microarray analyses supported the theory that the gene for p53 mediates the effect of benzene on bone marrow tissue by regulating specific genes instrumental in cell cycle arrest, apoptosis, and DNA repair. Because careful simultaneous screening of different expression patterns of many interrelated genes between the two groups is necessary, the researchers write, toxicogenomics should prove extremely useful for future investigations into the toxicity and leukemogenicity mechanisms of benzene.
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Title Annotation:Science Selections
Author:Medlin, Jennifer
Publication:Environmental Health Perspectives
Date:Aug 15, 2003
Previous Article:Pharmacogenomics: the promise of personalized medicine.
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