152
D. L. Svoboda et al.
Table 8.2 (continued)
Tool
Functionality
Compound compare
Presents a table of two-dimensional images of the molecular
structures of the compounds in the specified list of compounds
Pathway visualization
Enables the user to see the impact of compounds on the genes
in a pathway of interest at various doses and times
GO data query
Allows the user to analyze a specified gene list using Gene
Ontology annotations to find significantly over-represented
terms
Significant gene finder
Extracts the most significant set of genes for a list of
experiments
Drug signature heat-map
Generates a heat-map view of the signature hits for the
experiments
Drug signature histogram
Allows the user to generate a view of SVM signatures
displayed as a histogram for the query experiment and the
control list
Pattern assessment
Assesses the accuracy of the signature derived from the
“Pattern Creator” tool
The data was first normalized using the Affymetrix Expression Console using the
Plier algorithm. The normalized CHP files were uploaded into DrugMatrix using
the DrugMatrix Study Builder. An initial assessment of the data in the Similarity
tab of Expression domain indicated that DE-71 elicited a gene expression pattern
that was most similar to Phenobarbital-like inducers, such as Phenobarbital and
Dypyrone, consistent with previous observations with other brominated diphenyl
ethers (BDEs). A Hypergeometric Analysis (Chemical/drug annotation enrichment
analysis) of the 25 most similar reference experiments in DrugMatrix indicated an
enrichment of aromatase inhibitors suggesting that DE-71 may be interfering with
steroid metabolism, an observation consistent with other studies [5].
A review of the top induced genes presented on the Induced tab indicated induction of Cyp2b1 and Cyp1a1. This is consistent with the PB-like induction properties
of the BDEs and the AhR-activating properties of contaminating brominated dioxins/furans, respectively [6]. In addition, there was a striking induction of the urinary
protein, Rup2, estrogen sulfotransferase and Sult1e1. A review of the top–downregulated genes on the Repressed tab, a down-regulation of Cyp17 which in combination with the effects on Rup2 and Sult1e1 suggests a perturbation of the sex steroid
signaling cascade and the potential for endocrine disruption which is consistent with
the hypogeometric analysis and published findings [5]. Fgf21, a growth factor with
antidiabetic properties was down-regulated. In combination with observed induction
of Lep this observation suggests the potential for metabolic perturbations associated
with DE-71 exposure [7]. Down-regulation of Lrp10 and Abcg8 suggest a potential
alteration in cholesterol homeostasis which is consistent with the clinical chemistry
results observed in this and other studies [8].
D. L. Svoboda et al.
Table 8.2 (continued)
Tool
Functionality
Compound compare
Presents a table of two-dimensional images of the molecular
structures of the compounds in the specified list of compounds
Pathway visualization
Enables the user to see the impact of compounds on the genes
in a pathway of interest at various doses and times
GO data query
Allows the user to analyze a specified gene list using Gene
Ontology annotations to find significantly over-represented
terms
Significant gene finder
Extracts the most significant set of genes for a list of
experiments
Drug signature heat-map
Generates a heat-map view of the signature hits for the
experiments
Drug signature histogram
Allows the user to generate a view of SVM signatures
displayed as a histogram for the query experiment and the
control list
Pattern assessment
Assesses the accuracy of the signature derived from the
“Pattern Creator” tool
The data was first normalized using the Affymetrix Expression Console using the
Plier algorithm. The normalized CHP files were uploaded into DrugMatrix using
the DrugMatrix Study Builder. An initial assessment of the data in the Similarity
tab of Expression domain indicated that DE-71 elicited a gene expression pattern
that was most similar to Phenobarbital-like inducers, such as Phenobarbital and
Dypyrone, consistent with previous observations with other brominated diphenyl
ethers (BDEs). A Hypergeometric Analysis (Chemical/drug annotation enrichment
analysis) of the 25 most similar reference experiments in DrugMatrix indicated an
enrichment of aromatase inhibitors suggesting that DE-71 may be interfering with
steroid metabolism, an observation consistent with other studies [5].
A review of the top induced genes presented on the Induced tab indicated induction of Cyp2b1 and Cyp1a1. This is consistent with the PB-like induction properties
of the BDEs and the AhR-activating properties of contaminating brominated dioxins/furans, respectively [6]. In addition, there was a striking induction of the urinary
protein, Rup2, estrogen sulfotransferase and Sult1e1. A review of the top–downregulated genes on the Repressed tab, a down-regulation of Cyp17 which in combination with the effects on Rup2 and Sult1e1 suggests a perturbation of the sex steroid
signaling cascade and the potential for endocrine disruption which is consistent with
the hypogeometric analysis and published findings [5]. Fgf21, a growth factor with
antidiabetic properties was down-regulated. In combination with observed induction
of Lep this observation suggests the potential for metabolic perturbations associated
with DE-71 exposure [7]. Down-regulation of Lrp10 and Abcg8 suggest a potential
alteration in cholesterol homeostasis which is consistent with the clinical chemistry
results observed in this and other studies [8].