Discernment of possible mechanisms of hepatotoxicity via biological processes over-represented by co-expressed genes.
BACKGROUND
Hepatotoxicity is a form of liver injury caused by exposure to stressors. Genomic-based approaches have been used to detect changes in transcription in response to hepatotoxicants. However, there are no straightforward ways of using co-expressed genes anchored to a phenotype or constrained by the experimental design for discerning mechanisms of a biological response.


RESULTS
Through the analysis of a gene expression dataset containing 318 liver samples from rats exposed to hepatotoxicants and leveraging alanine aminotransferase (ALT), a serum enzyme indicative of liver injury as the phenotypic marker, we identified biological processes and molecular pathways that may be associated with mechanisms of hepatotoxicity. Our analysis used an approach called Coherent Co-expression Biclustering (cc-Biclustering) for clustering a subset of genes through a coherent (consistency) measure within each group of samples representing a subset of experimental conditions. Supervised biclustering identified 87 genes co-expressed and correlated with ALT in all the samples exposed to the chemicals. None of the over-represented pathways related to liver injury. However, biclusters with subsets of samples exposed to one of the 7 hepatotoxicants, but not to a non-toxic isomer, contained co-expressed genes that represented pathways related to a stress response. Unsupervised biclustering of the data resulted in 1) four to five times more genes within the bicluster containing all the samples exposed to the chemicals, 2) biclusters with co-expression of genes that discerned 1,4 dichlorobenzene (a non-toxic isomer at low and mid doses) from the other chemicals, pathways and biological processes that underlie liver injury and 3) a bicluster with genes up-regulated in an early response to toxic exposure.


CONCLUSIONS
We obtained clusters of co-expressed genes that over-represented biological processes and molecular pathways related to hepatotoxicity in the rat. The mechanisms involved in the response of the liver to the exposure to 1,4-dichlorobenzene suggest non-genotoxicity whereas the exposure to the hepatotoxicants could be DNA damaging leading to overall genomic instability and activation of cell cycle check point signaling. In addition, key pathways and biological processes representative of an inflammatory response, energy production and apoptosis were impacted by the hepatotoxicant exposures that manifested liver injury in the rat.
Chou
Jeff W
JW
Biostatistics Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA. jchou@wfubmc.edu
Bushel
Pierre R
PR
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002722:Chlorobenzenes / Q000633:toxicity*; D016000:Cluster Analysis; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D015415:Biomarkers; D002722:Chlorobenzenes; C018511:4-dichlorobenzene; D000410:Alanine Transaminase