Divergent Transcriptomic Responses to Aryl Hydrocarbon Receptor Agonists between Rat and Human Primary Hepatocytes
Divergent Transcriptomic Responses to Aryl Hydrocarbon Receptor Agonists between Rat and Human Primary Hepatocytes
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DOI：
10.1093/toxsci/kfp200
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发表时间：
2009-11-01
影响因子：
3.8
通讯作者：
Silkworth, Jay B.
中科院分区：
文献类型：
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作者：
Carlson, Erik A.;McCulloch, Colin;Silkworth, Jay B.
毒理基因组学在提高我们对环境化学毒性的理解方面具有巨大的潜力，有望导致更好地了解人类健康风险评估。本研究采用毒理基因组学技术揭示了两种典型的芳烃受体（AHR）激动剂2，3，7，8-四氯二苯并-p-二恶英和多氯联苯（PCB）同系物PCB 126的物种差异。使用共享超过4000个基因直系同源物的物种特异性微阵列确定大鼠和人肝细胞原代培养物的剂量反应。47个人类和79个大鼠基因满足两种化学品的剂量反应标准，并进行了进一步的分析，包括计算PCB 126对每个基因的50%有效浓度和相对效价（REP）。两个物种之间只有5个响应性正向同源基因是共享的，然而，所有大鼠和人类模型响应性基因的REP的几何平均值为0.06（95%置信区间[CI]; 0.03-0.1）和0.002（95% CI; 0.001-0.005），表明在AHR激活后但在毒性前的初始事件中存在广泛的种属差异。这表明，在响应的特定基因以及这些基因的激动剂效力和REP两者中存在物种差异。这种观察到的人类细胞对PCB 126的不敏感性与AHR激活的更传统的测量（即，细胞色素P450 1A 1酶活性），并表明PCB 126敏感性的物种差异可能是由于AHR功能的某些方面。在这个扩展的AHR调节基因库中也存在物种差异是一个新的发现，应该有助于将动物数据外推到人类。
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.