title: Gene interaction network analysis suggests differences between high and low doses of acetaminophen.
abstract: Bayesian networks for quantifying linkages between genes were applied to detect differences in gene expression interaction networks between multiple doses of acetaminophen at multiple time points. Seventeen (17) genes were selected from the gene expression profiles from livers of rats orally exposed to 50, 150 and 1500 mg/kg acetaminophen (APAP) at 6, 24 and 48 h after exposure using a variety of statistical and bioinformatics approaches. The selected genes are related to three biological categories: apoptosis, oxidative stress and other. Gene interaction networks between all 17 genes were identified for the nine dose-time observation points by the TAO-Gen algorithm. Using k-means clustering analysis, the estimated nine networks could be clustered into two consensus networks, the first consisting of the low and middle dose groups, and the second consisting of the high dose. The analysis suggests that the networks could be segregated by doses and were consistent in structure over time of observation within grouped doses. The consensus networks were quantified to calculate the probability distribution for the strength of the linkage between genes connected in the networks. The quantifying analysis showed that, at lower doses, the genes related to the oxidative stress signaling pathway did not interact with the apoptosis-related genes. In contrast, the high-dose network demonstrated significant interactions between the oxidative stress genes and the apoptosis genes and also demonstrated a different network between genes in the oxidative stress pathway. The approaches shown here could provide predictive information to understand high- versus low-dose mechanisms of toxicity.
authors.affiliation: Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. toyoshiba.hiroyoshi@nies.go.jp
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Toyoshiba
authors.forename: Hideko
authors.initials: H
authors.lastname: Sone
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Parham
authors.forename: Richard D
authors.initials: RD
authors.lastname: Irwin
authors.forename: Gary A
authors.initials: GA
authors.lastname: Boorman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Portier
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D001499:Bayes Theorem; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008957:Models, Genetic; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen