Nucleic acid microarray technology for toxicology: promise and practicalities

Much ongoing research in toxicology focuses on a hypothesis-driven mechanism of action approach aimed at understanding the molecular events mediating the actions of the chemicals of interest. Using this approach, investigators develop hypotheses based on observations, which may be derived from a host of resources but most frequently have been made within their own laboratories, or uncovered by others and reported in the scientific literature. Although the bulk of current understanding ofbiochemical toxicology emerged using studies based on observations derived in this way, this process, which is essentially based on existing information, may often limit the expansion knowledge. More simply expressed, one only finds that which one seeks. Without a clear understanding of the processes targeted by a specific toxin the problem of making observations that globally and accurately reflect the events mediating pathology which have been induced by the toxic agent is challenging. Recently, the development of high-throughput technologies for biochemical analysis of gene expression has led to innovative approaches in addressing the problem of making broad-based observations that more accurately reflect the entire spectrum of molecular lesions induced by specific toxins. These strategies include the use of new techniques in analysis of gene expression to convey information on alterations in mRNA levels, one of the earliest cellular signs initiated in response to a potential toxin. Prior to this time studies on toxicant-induced altered gene expression were limited to single, or small numbers of identified genes chosen by an investigator who reasoned, based on an existing observations, that levels of the proteins encoded by these genes were likely to be altered during toxic injury. Now, using cDNA or oligonucleotide genome-wide arrays, toxin-induced alterations in gene expression of thousands of genes can be examined simultaneously. Using these tools, molecular toxicologists can for the first time employ reasoned strategies to make observations, and then formulate hypotheses based on these observations.