Expression profiling of interindividual variability following xenobiotic exposures in primary human hepatocyte cultures.
To examine the magnitude of human variability across the entire transcriptome after chemical challenge, we profiled gene expression responses to three different prototypic chemical inducers in primary human hepatocyte cultures from ten independent donors. Correlation between basal expression in any two hepatocyte donors ranged from r(2) values of 0.967 to 0.857, and chemical treatment tended to negatively impact correlation between donors. Including anticipated target genes, 10,812, 8373, and 7847 genes were changed in at least one donor by Aroclor 1254 (A1254), di(2-ethylhexyl) phthalate (DEHP), and phenobarbital (PB), respectively. A subset of these gene targets (n=41) were altered with a high level of reproducibility in at least 9 donors, gene responses that correlated well with literature-reported mechanism of action. Filtering responses to the level of gene subsets clarified the biological impact associated with the respective chemical effectors, in lieu of substantial interindividual variation among donor responses. In these respects, the use of hierarchical clustering methods successfully grouped seven of the ten donors into chemical-specific rather than donor-specific clusters. However, at the whole-genome level, the magnitude of conserved gene expression changes among donors was surprisingly small, with fewer than 50% of the gene responses altered by a single chemical conserved in more than one donor. The use of higher level descriptors, such as those defined by the PANTHER classification system, may enable more consistent categorization of gene expression changes across individuals, as increased reproducibility was identified using this method.
Goyak
Katy M O
KM
Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, USA.
Johnson
Mary C
MC
Strom
Stephen C
SC
Omiecinski
Curtis J
CJ
D002478:Cells, Cultured; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects*; D015894:Genome, Human; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D010634:Phenobarbital / Q000494:pharmacology; D015203:Reproducibility of Results; D015262:Xenobiotics / Q000494:pharmacology*
D015262:Xenobiotics; D020111:Chlorodiphenyl (54% Chlorine); D004051:Diethylhexyl Phthalate; D010634:Phenobarbital