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UC Berkeley Researchers Use SELDI to Find Proteins for Potential Benzene-Exposure Test

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Researchers at the University of California, Berkeley, have used SELDI and mass spectrometry to identify proteins that could potentially serve as markers for a benzene-exposure test.

The study is significant because benzene has been linked to leukemia and bone marrow damage, and US regulatory agencies have said they would investigate the effects of benzene exposure, said Martyn Smith, the leader of the study.

A previous study by Smith and his co-workers, published in Science last year, showed that workers in a shoe factory in China who were exposed to low levels of benzene transmitted from shoe glue that contained the chemical had significantly lower levels of white blood cells when compared to controls.

"What we're interested in is an effective test [for benzene exposure]," said Smith of the new research, which appears in the Nov. 22 Proceedings of the National Academy of Sciences. "These markers can serve as warning tests."

While white blood cell counts are currently used to test for benzene exposure, a protein-based test that could be used in the field would be easier, said Smith.

"With blood counts, you have to collect blood in a certain way, send it off to a lab, and use an expensive machine to determine the counts," said Smith. "It's not a fingerprick in the field, if you know what I mean. If you had a blood spot, and you could just look at proteins in the blood, or maybe a chip that you could use in the field, that would be considerably easier."


"What we're interested in
is an effective test [for benzene exposure]. These markers can serve as warning tests."


People are also exposed to benzene through fire, said Smith. Any time there is combustion, benzene is produced as a by-product. Also, benzene is found in paints and in certain types of glue, and it makes up about one percent of gasoline.

To find proteins that changed with benzene exposure, Smith and his colleagues first used Ciphergen's SELDI chips to examine the proteomes of 10 Chinese shoe factory workers who had been exposed to an overall mean benzene air level of greater than 30 parts per million, and 10 controls who worked in a clothing manufacturing plant in the same geographical area.

The researchers found three proteins that were consistently down regulated in people who had been exposed to benzene. All three proteins were highly inversely correlated with individual estimates of benzene exposure.

The researchers then purified the proteins and attempted to identify them using tandem mass spectrometry. Two of the proteins were successfully identified as platelet factor 4 and connective tissue activating peptide III.

The researchers then validated the discovery on a different set of 10 workers exposed to benzene and 10 matched controls. A Protein Chip array was obtained from Ciphergen to specifically capture PF4 and CTAPIII proteins in human blood samples. Using the chips, it was determined that expression of both PF4 and CTAPIII were significantly lowered in benzene-exposed workers, compared to matched controls. The difference in expression was significant even when the researchers statistically adjusted for the lowered platelet count in benzene-exposed workers.

"This is a proof-of-principle study — you discover proteins in the first set, and then you validate in the second set," said Smith. "It's the same sort of approach that is taken with cancer diagnostics. What we've done is apply that same idea to looking for markers related to chemical exposures."

Smith said that he and his research teams plan to apply the same approach to find markers for arsenic exposure and dioxin exposure. In addition, they are looking at fractions of serum that they did not look at in their first proteomic benzene study to try to find more markers for benzene exposure.

Smith and his colleagues also did a microarray study to find altered gene expression patterns in benzene-exposed workers. In that study, they found that one of the genes that was lowered in expression was PF4 — findings that matched with the proteomics studies, said Smith.

In response to Smith's Science article last year, blood counts of workers in the Chinese shoe factory are now routinely monitored, Smith said. If a worker's blood counts drop, he or she is removed to a different job and given financial compensation.

In the United States, regulatory agencies have said that they would investigate the effects of benzene exposure. However, no specific policy has been put in place.

"You'd hope that if [benzene-exposed workers'] blood counts went down, they would be removed from any exposure to benzene and allowed to recover, and that they would be monitored until their blood counts came back to normal," said Smith. "Whether that happens or not is another thing."

— Tien Shun Lee ([email protected])

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