TXG at SOT. (Meeting Report).

Since the first seminal paper on genomics appeared in the 20 October 1995 issue of Science, coverage has grown rapidly to some 3,000-4,000 reports yearly, many on gene-environment interactions, according to NIEHS deputy director Samuel Wilson. The influx of new data is revealing many surprises, many described at the 42nd annual meeting of the Society of Toxicology, held 9-13 March 2003 in Salt Lake City, Utah.

Just 15 years ago, researchers could study how toxicants alter only individual genes, and they spent years dissecting single genes. This approach was grossly inadequate, because "genes do not act in isolation, but by talking to other genes," says Kenneth Ramos, chairman of the Department of Biochemistry and Molecular Biology at Kentucky's University of Louisville School of Medicine and toxicogenomics editor of EHP. Today, DNA microarrays capture the expression of thousands of genes in response to environmental stressors.

Ramos and colleagues study molecular and genetic impacts of environmental contaminants--including the polycyclic hydrocarbon benzo[a]pyrene (BaP)--on heart disease and cancer. In a study of mouse vascular cells exposed to BaP, 1,383 of 9,000 genes were altered. Many affected genes regulate cell growth and differentiation; the big surprise, says Ramos, was that BaP also affects genes involved in immune modulation, such as those of the class I histocompatibility complex. "Our findings link immune cell activation as a key molecular event in the BaP-induced atherogenic response," he says. This fits well with in vivo observations that immune cells infiltrate the arterial wall in the early stages of atherosclerosis.

Leona Samson, a professor of toxicology at the Massachusetts Institute of Technology in Cambridge, described her work with Saccharomyces cerevisiae. She used S. cerevisiae mutants, each missing one gene, to identify genes that help cells recover from damage by the alkylating agent methylmethane sulfonate (MMS). Of the 6,000 yeast genes, about 400 are sensitive to MMS, including genes related to cell death and DNA repair. But most of the recovery genes Samson identified are involved with functions such as cytoskeleton remodeling, protein degradation, RNA synthesis, and lipid metabolism. The new data suggest that to recover from DNA damage and avoid cell death, "cells have a lot of other things to repair," says Samson. She and her colleagues are examining recovery pathways for other alkylating agents and ultraviolet light, and each shows a unique pattern. She says the goal is to ! "predict whether a cell, organism, or even person will recover from damage."

Yet another surprise came from research at the NIEHS National Center for Toxicogenomics (NCT), where the gene Dss1--previously associated only with a developmental abnormality of the hands and feet--was found to play a role in skin cancer. In mouse skin cells treated with phorbol ester tumor promoters, Dss1 was expressed during early stages of tumor formation. "There is no previously recognized basis for predicting a role of Dss1 in skin tumorigenesis," says NCT director Raymond Tennant.

Scientists are uncovering many new genes and pathways never before imagined to be associated with gene-environment responses. A key next step is "phenotypic anchoring," connecting specific gene changes to markers of toxicity [see NCT Update, p. A338 this issue]. In a proof-of-concept experiment on phenotypic anchoring, researchers in Richard Paules's NCT lab monitored liver toxicity in rats induced by the drug methapyrilene. They verified that the expression of a group of genes corresponds to histological changes such as liver necrosis and periportal inflammation.

In addition to the data presented at the annual meeting, another source of information was unveiled--EHP's new Toxicogenomics Section. This section will appear quarterly and will present news, research, and perspectives in toxicogenomics and related disciplines.