Did evolution really anticipate dioxin?

Most, if not all, mammalian cells possess a clump of proteins that will bind to dioxin, polychlorinated biphenyls (PCBs), and many other toxic pollutants. Once this pairing occurs, the complex travels as a unit to the cell's nucleus, where it can wreak havoc with DNA's normal, genetically prescribed activities.

For more than a decade, toxicologists have wrestled with the question of why animals evolved a receptor for pollutants emitted largely since World War II.

A study now appears to confirm what these scientists had come to suspect: The "dioxin receptor" harbors a split personality. While toxicologists probed the dark side of this aryl hydrocarbon (Ah) receptor -- its ability to unleash dioxin's toxicity -- a benign alter ego has quietly hidden away. And while the precise nature of its beneficial persona still remains concealed, the new data suggest that this receptor performs several indispensable functions.

To probe the receptor's role, Frank J. Gonzalez of the National Cancer Institute in Bethesda, Md., and his colleagues developed a line of mice in which they genetically knocked out, or eliminated, the Ah receptor. In the May 5 Science, they note that these mice exhibit several potentially lethal defects.

For instance, they begin life with only 10 to 20 percent as many infection-fighting T and B cells circulating in their blood as mice who carry the Ah receptor. Not surprisingly, roughly half these receptor-free newborns die within 2 weeks of birth. In survivors, numbers of these immune cells eventually build to near normal levels -- only to plummet permanently following puberty.

The knockout mice also develop liver fibrosis -- pockets of dead tissue, Gonzalez notes. The affected area covers 10 percent of the newborns' livers and grows with time. Such damage usually signals toxic chemical exposures.

Gonzalez concludes that the receptor appears to offer protection from still-unidentified toxicants. During fetal development, mom's receptors may take over for those her offspring lack. Certainly, he says, this scenario would explain why the animals' vitality declines immediately after birth.

The new knockout data "confirm that this [receptor] has an important role in development," says dioxin toxicologist Linda Birnbaum of the Environmental Protection Agency in Research Triangle Park, N.C. She says this study also goes a long way toward establishing that some "natural partner" of the Ah receptor exists in the body -- one that either becomes dislodged or blocked by dioxin and its toxic cronies.

Chris Bradfield of Northwestern University Medical School in Chicago is also working on an Ah receptor knockout. One justification for developing these mice has been to test the receptor's role in any toxic effects linked to dioxin and PCBs. But that won't be possible in such sick mice. So before such studies can begin, Bradfield says, researchers may have to "tweak this model a little more" to "rescue these mice" -- perhaps by reinserting the receptor back into certain tissues.