Metals leave their mark: fingerprints of low-dose exposure. (Science Selections).

As the emerging field of toxicogenomics continues to progress, the search for biologically relevant biomarkers of exposure, effect, and susceptibility is in full swing. Much of the current work focuses on the genomic effects of potentially toxic metals. In this issue, Angeline Andrew and her colleagues at Dartmouth College report the results of their study of four metals--arsenic, cadmium, chromium, and nickel--that have been associated with a variety of adverse health effects [EHP 111:825-837]. They identified "fingerprints" of early changes in gene and protein expression in response to each metal that may someday serve as biomarkers of exposure to these toxicants.

The team used cDNA microarrays to compare the effects of each metal on the expression of 1,200 human genes in human bronchial BEAS-2B cells. These cells were chosen because inhalation is a common route of exposure for the metals currently under study.

In order to ensure that the effects seen were not nonspecific responses to toxic high doses, the cells were exposed to low, relatively nontoxic doses of the metal compounds sodium arsenite, cadmium chloride, sodium dichromate, and nickel subsulfide for 4 hours. They also administered a much higher, cytotoxic dose of sodium arsenite to explore the effects of dose.

Although the results showed that each of the exposures modified expression of only a small subset of the 1,200 genes, the data suggest that each metal modifies expression of a largely unique set of genes that may be characteristic of each substance. This supports the potential for the development of metal-specific biomarkers.

There was some overlap in which genes were modified, but none were affected by all five chemical treatments, and only one, heat shock protein 90A, was modified by four of the five. Conversely, the authors found it remarkable that the genes that were altered by more than one treatment were all modified in the same direction, with either increased or decreased expression. They say this lends support to the idea that these represent biologically relevant responses to these treatments.

Comparison of the effects of the low and high doses of arsenic also yielded some unexpected insights. Of a total of 158 genes modified, only 16 were altered at both doses, and substantially more genes were modified by the lower dose than by the higher one.

The lower dose modified expression of a wide variety of genes representing a diverse range of protein classes, such as transcription factors, inflammatory cytokines, kinases, and DNA repair proteins. The higher dose showed what the authors call a "striking shift" in the profile, modifying a variety of heat shock proteins and other genes involved in stress response pathways.

The researchers suggest that this dramatic contrast in gene expression profiles represents a switch from a survival-based biological response at the lower dose to a cell death-inducing apoptotic response at the higher dose. Whereas the high dose of arsenic clearly induced a stress response, it was a more universal, less toxicant-specific response; the lower doses of the four metals produced "a more subtle modification of cell signaling pathways," implying a unique, identifiable signature in the gene expression profile generated by each chemical.

The authors conclude that these metal response patterns may shed new light on the mechanisms of human diseases caused by toxic metal exposures, and may also be useful for developing molecular biomarkers of exposure and effect in future mechanistic, epidemiologic, and risk assessment studies.