The NCT Update (p. A936) describes the work of the Mass Spectrometry Group, which uses the titular technology, as well as other methods, to characterize proteins and learn how proteomes change in response to environmental exposures.

Genes, proteins, metabolites--all are critical to the workings of any given organism, but the organism comprises far more than the sum of its parts. The Focus (p. A938) looks at the field of systems biology, which pulls in several different “omics” disciplines to create a big-picture perspective of how an organism works. Genomics, proteomics, and metabolomics all offer up pieces of the biological puzzle, while bioinformatics processes the data to yield working models of whole systems.

Uterotrophic Transcriptional Program

A major challenge in toxicogenomics is to define the relationships between changes in gene expression and alterations in conventional toxicologic parameters. Using the rodent uterotrophic assay as a model system, Moggs et al. (p. 1589) examined gene expression levels, uterine weights, and histologic parameters after exposure to 17-estradiol (E₂). Uterine growth and maturation is preceded and accompanied by a complex multistage molecular program. The program begins with the induction of genes involved in transcriptional regulation and signal transduction and is followed, sequentially, by the regulation of genes involved in protein biosynthesis, cell proliferation, and epithelial cell differentiation. Comparison of temporal changes in gene expression and conventional toxicological end points can facilitate the phenotypic anchoring of toxicogenomic data. (Also see Science Selections, p. A944)

Toxicant-Specific Signatures in Breast Cell Lines

The environmental stress response to a range of toxicants commonly includes repression of protein synthesis and cell-cycle regulated genes and induction of DNA damage and oxidative stress responsive genes. Troester et al. (p. 1607) characterized the general stress response of breast cell lines following treatment with either doxorubicin (DOX), 5-fluorouracil (5FU) or etoposide, a compound that is mechanistically similar to DOX. Cross-validation analyses identified genes with high predictive accuracy in classifying samples into two treatment classes. The predictive accuracy was 100% for classifying the etoposide samples as more similar in expression to DOX- than 5FU-treated samples. The toxicant-specific stress response gene expression patterns also varied according to cell type. (Also see Science Selections, p. A944)

Several methods have been proposed for identifying gene regulatory networks using multiple pairwise comparisons to identify the network structure. Yamanaka et al. (p. 1614) have developed a method for analyzing gene expression data to determine a regulatory structure consistent with an observed set of expression profiles by using likelihood-based statistical methods to obtain the network that is most consistent with the complete data set. The method is used to evaluate interactions between genes in the SOS-signaling pathway in Escherichia coli with each gene in the network overexpressed using plasmids inserts.

Class prediction plays an increasing role in toxicogenomics, diagnosis/prognosis, and risk assessment; however, the data are usually noisy and represented by relatively few samples and a very large number of predictor variables. Tong et al. (p. 1622) present a classification method, Decision Forest (DF), that combines the results of multiple heterogeneous but comparable Decision Tree models to produce a consensus prediction. For the high confidence prediction, the model achieved 99.2% sensitivity and 98.2% specificity. Comparison of model prediction with imposed random correlation demonstrated biologic relevance of the model and the reduction of overfitting in DF.

Nephrotoxicity of uranium is well established, but little is known about effects of long-term uranium exposure. Taulan et al. (p. 1628) used conventional biochemical studies and serial analysis of gene expression to examine the renal responses to chronic uranyl nitrate (UN) exposure. UN induced dramatic alterations in expression levels of more than 200 genes related to oxidative response, cellular metabolism, ribosomal protein, signal transduction, and solute transporters. Significantly increased peroxide levels support the implication of oxidative stress in UN toxicant response.

 

Gene Expression Analysis of Dioxin and Related Compounds.

Vezina et al. (p. 1636) employed DNA microarray to identify unique hepatic gene expression patterns associated with subchronic exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and other halogenated aromatic hydrocarbons in female rats exposed to toxicologically equivalent doses of TCDD, 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,3,4,4´,5-pentachlorobiphenyl (PCB126), or 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB153). The aryl hydrocarbon receptor (AhR) ligands TCDD, PeCDF, and PCB126 produced very similar global gene expression profiles that were unique from the non-AhR ligand, PCB153, underscoring the extensive impact of AhR activation and/or the resulting hepatic injury on global gene expression in female rat liver.