ToxSci Advance Access originally published online on August 19, 2009
Toxicological Sciences 2009 112(1):257-272; doi:10.1093/toxsci/kfp200
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Divergent Transcriptomic Responses to Aryl Hydrocarbon Receptor Agonists between Rat and Human Primary Hepatocytes
* General Electric Company, Global Research Center, Environmental Technology Laboratory, One Research Circle, Niskayuna, New York 12309
General Electric Company, Global Research Center, Applied Statistics Laboratory, One Research Circle, Niskayuna, New York 12309
In Vitro Technologies, Inc., Baltimore, Maryland 21227
W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee 38512
1 To whom the correspondence should be addressed at General Electric Company, Global Research Center, Environmental Technology Laboratory, One Research Circle, Niskayuna, NY 12309. Fax: (518) 387-6972. E-mail: silkworth{at}crd.ge.com.
Received June 19, 2009; accepted August 17, 2009
 |
Abstract |
|---|
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.
Key Words: TCDD; PCB; AHR; microarray; toxicogenomics; human; relative potency.