Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes.
Toxicogenomics has great potential for enhancing our understanding of environmental chemical toxicity, hopefully leading to better informed human health risk assessments. This study employed toxicogenomic technology to reveal species differences in response to two prototypical aryl hydrocarbon receptor (AHR) agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin and the polychlorinated biphenyl (PCB) congener PCB 126. Dose-responses of primary cultures of rat and human hepatocytes were determined using species-specific microarrays sharing over 4000 gene orthologs. Forty-seven human and 79 rat genes satisfied dose-response criteria for both chemicals and were subjected to further analysis including the calculation of the 50% effective concentration and the relative potency (REP) of PCB 126 for each gene. Only five responsive orthologous genes were shared between the two species; yet, the geometric mean of the REPs for all rat and human modeled responsive genes were 0.06 (95% confidence interval [CI]; 0.03-0.1) and 0.002 (95% CI; 0.001-0.005), respectively, suggesting broad species differences in the initial events that follow AHR activation but precede toxicity. This indicates that there are species differences in both the specific genes that responded and the agonist potency and REP for those genes. This observed insensitivity of human cells to PCB 126 is consistent with more traditional measurements of AHR activation (i.e., cytochrome P450 1A1 enzyme activity) and suggests that the species difference in PCB 126 sensitivity is likely due to certain aspects of AHR function. That a species divergence also exists in this expanded AHR-regulated gene repertoire is a novel finding and should help when extrapolating animal data to humans.
Carlson
Erik A
EA
General Electric Company, Global Research Center, Environmental Technology Laboratory, One Research Circle, Niskayuna, New York 12309, USA.
McCulloch
Colin
C
Koganti
Aruna
A
Goodwin
Shirlean B
SB
Sutter
Thomas R
TR
Silkworth
Jay B
JB
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*
D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl