16 October 2002 15:30 EST

by Tabitha M. Powledge

Even at miniscule levels, environmental toxins like mercury and caffeine can be critical in altering the progression and prognosis of a disease, experts said yesterday at meeting on the biology of sex differences in environmental health. But at least one of the methods researchers employ to identify these "co-conspirators" proved unexpectedly controversial.

To determine the disease-promoting effects of toxins in the environment, researchers must first identify variants of genes that augment the toxins' effects, said Kent Hunter, a geneticist at the US National Cancer Institute.

Hunter uses transgenic mice to examine what causes breast cancer to metastasize. Employing hard-to-do quantitative trait loci (QTL) methods, he and his colleagues have identified several polymorphisms in the tumor-suppressor gene Atm as possible suspects in the movement of mouse mammary tumors to the lungs.

But caffeine, an Atm inhibitor, may prevent that movement, the researchers have found. "The interaction of what might be subtle variants of genes with common environmental exposures may have critical effects on cancer survival as well as incidence," Hunter said. He was speaking at the meeting, held yesterday at the National Institute of Environmental Health Sciences in North Carolina.

Genetic variants that determine disease severity can often be sex-specific. The female-male ratio ranges from 2:1 in multiple sclerosis, for example, and up to 50:1 in other autoimmune disorders. But those lopsided figures may reflect sex differences in the severity of autoimmune diseases, rather than their actual incidence, says Ellen Silbergeld, professor of environmental health sciences at Johns Hopkins University.

Silbergeld and her colleagues are investigating mercury as "a co-conspirator" in autoimmune disorders, postulating that it interacts with sex-linked genetic or endocrine factors and leads to worse outcomes for women.

In mouse models of lupus-like disease, the researchers found that mercury seems to potentiate the disorder, even at levels 50-100 times lower than those used in mercury toxicity studies. Silbergeld reports similar findings in a mouse model of induced autoimmune myocarditis. "We have not determined the lowest level of interaction yet," she said. "We're getting toward the amount present in a can of tuna."

Mercury by itself cannot cause autoimmune disease in nonsuceptible animal models, Silbergeld says, adding that may also be true in humans. But in the presence of a thus-far unidentified stimulatory event, mercury alters interactions and can cause lethal autoimmune disease, she argues. To get at those mechanisms, rather than applying conventional epidemiology, researchers should study people with the disease and assess their exposure to mercury, she suggests.

For screening potential toxins and investigating previously unknown metabolic pathways, microarrays could replace the bioassay as a major tool, reported Mary Jane Cunningham, a researcher at the Massachusetts-based Molecular Mining Corporation. Automated microarray screening methods for toxicology will be available in much less than 20 years, she predicted.

Describing microarray studies of how liver toxins affect gene expression in rat liver cells, Cunningham reported that benzopyrene, one of the pollutants in tobacco smoke, either up- or down-regulated 275 out of 7,400 genes on the arrays.

There were some differences between the sexes: Genes involved in steroid metabolism were more often upregulated in female cells, for example. But the big surprise was that a quarter of the affected genes had never been annotated, so their functions were unknown, Cunningham said.

But Cunningham's report was assailed because it rests on a proprietary gene database at Incyte, her former employer. It is "very disturbing" that this sort of information is being accumulated in private databases, said Sherry Marts, scientific program director at the Society for Women's Health Research, the meeting's sponsor.

Marts argued that the data are unusable, and that the technology cannot realize its potential without far more openess. "We don't know anything about these animals," she pointed out. "We have to take your word for it that this stained-glass toxicology means anything."

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