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In This Issue
Environews
Research Roundup
Comparative genomics
offers enormous potential for transferring knowledge of one
organism’s genome to the mysteries of another. The Forum
(p. A930) reports on the recently completed sequencing
of the Brown Norway rat genome, which adds to our ability to
realize the potential of comparative genomics. In other news,
innate immunity gives up its genetic secrets, antimicrobial
activity reveals its shape, and protein assembly takes on a
new dimension.
Of Peaks and Peptides
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.
Systems Biology: Anatomy at Work
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.
Research
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 ![Beta](https://webarchive.library.unt.edu/eot2008/20080923153911im_/http://www.ehponline.org/image/beta8_14.gif) -estradiol
(E 2). 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
![cell](https://webarchive.library.unt.edu/eot2008/20080923153911im_/http://www.ehponline.org/New%20Site/txg/docs/2004/112-16/98501B-cmyk-ITI57.jpg) 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)
TAO-Gen Algorithm and SOS Repair Pathways
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.
Decision Forest for Prediction of Prostate Cancer
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.
Genomics Fingerprints in Response to Uranyl Nitrate
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.
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