Clues hint how particulates harm lungs.

For more than a decade, epidemiologist have been homing in on the health risks posed by dustlike, inhalable polutants known as airborne particulates can aggravate existing respiratory disease or heart problem--and perhaps even cause cancer--scientist have been at a loss to explain how.

By eavesdropping on the chemical chatter within lung cells growing in test tubes, researchers have now identified a cascade of intracellular commands provoked by these pollutants. In the Oct 15 Cancer Research, they report that the particulates trigger the cells to synthesize new DNA.

This might constitute a first step in preparing the cells damage, notes study leader Cynthia Timblin, a molecular biologist at the University of Vermont in Burlington. For example, they might need to reverse changes caused by oxidants created in reactions with metals on the pariculates' surfaces. However, she adds, "it is interesting to note that the particular cascades initiated by these particulates have,in other cell types of proliferation," including cancer.

For 2 days, the scientist incubated epithelial cells from the interior surface of the lungs with a solution containing tiny particles, having an average diameter just under 40 nanometers. Some were particulates collected by state pollution-sampling stations, others were similarly fine spheres of titanium dioxide. The latter is a nontoxic industrial whitening agent.

Some researchers had speculated that ultrafine particulates might induce lung damage through some interaction fostered by their size, irrespective of their chemical makeup. If so, the titanium dioxide and particulates should induce similar changes in lung cells.

Indeed, both activated a gene called c-jun. Though it normally help cells mature, c-jun can also act as a proto-oncogene, Timblin explains. If expressed at inappropriate times, proto-oncogenes can foster the development of tumor cells and cancer.

To trigger such abnormal cell proliferation, c-jun has to make a protein that serves as a building block of a larger cell-signaling protein, AP-1. By binding to specific portions of DNA, AP-1 turns genes on or off. Though cells incubated showed AP-1 activity, those exposed to the titanium dioxide did not.

Probing further downstream in the cell-signaling cascade launched by c-jun, Timblin's team found that only the pollutant-exposed cells had synthesized new DNA, a necessary step if they were going to proliferate.

"As someone who's worked on c-jun and AP-1 for a long time, I'd be delighted if there were some rational data to link [them] to human cancer," says Michael J. Birrer of the National Cancer Institute in Rockville, Md. However, he told Science News, "I don't think we have the data anywhere, including in this paper."

The problem, he explains, is that cells exposed to almost any stress can increase their c-jun-AP-1 activity. So while the new paper is interesting and suggestive, he says, it fails to demonstrate that the pollutants' activation of c-jun-AP-1 is what caused the DNA synthesis.

Timblin agrees, noting that her team plans to look for such a link. For now, the group is examining whether the increased DNA production triggered by the particulates leads to abnormal cell proliferation. It's also looking to see whether particulates activate cascades of genes leading to other toxic responses, such as inflammation.