Volz David C, Hinton David E, Law J McHugh, Kullman Seth W
Integrated Toxicology Program and Nicholas School of the Environment and Earth Sciences, Duke University, Durham, North Carolina 27708, USA.
Toxicol Sci. 2006 Feb;89(2):524-34. doi: 10.1093/toxsci/kfj033. Epub 2005 Nov 2.
A major challenge for environmental genomics is linking gene expression to cellular toxicity and morphological alteration. Herein, we address complexities related to hepatic gene expression responses after a single injection of the aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and illustrate an initial stress response followed by cytologic and adaptive changes in the teleost fish medaka. Using a custom 175-gene array, we find that overall hepatic gene expression and histological changes are strongly dependent on dose and time. The most pronounced dioxin-induced gene expression changes occurred early and preceded morphologic alteration in the liver. Following a systematic search for putative Ah response elements (AHREs) (5'-CACGCA-3') within 2000 bp upstream of the predicted transcriptional start site, the majority (87%) of genes screened in this study did not contain an AHRE, suggesting that gene expression was not solely dependent on AHRE-mediated transcription. Moreover, in the highest dosage, we observed gene expression changes associated with adaptation that persisted for almost two weeks, including induction of a gene putatively identified as ependymin that may function in hepatic injury repair. These data suggest that the cellular response to dioxin involves both AHRE- and non-AHRE-mediated transcription, and that coupling gene expression profiling with analysis of morphologic pathogenesis is essential for establishing temporal relationships between transcriptional changes, toxicity, and adaptation to hepatic injury.
环境基因组学面临的一个主要挑战是将基因表达与细胞毒性和形态改变联系起来。在此，我们探讨了单次注射芳烃受体（AHR）激动剂2,3,7,8-四氯二苯并对二恶英（二恶英）后与肝脏基因表达反应相关的复杂性，并阐述了硬骨鱼青鳉中最初的应激反应，随后是细胞学和适应性变化。使用定制的175基因阵列，我们发现肝脏整体基因表达和组织学变化强烈依赖于剂量和时间。二恶英诱导的最显著基因表达变化发生在早期，且先于肝脏形态学改变。在对预测转录起始位点上游2000 bp范围内的假定Ah反应元件（AHREs）（5'-CACGCA-3'）进行系统搜索后，本研究中筛选的大多数（87%）基因不包含AHRE，这表明基因表达并非仅依赖于AHRE介导的转录。此外，在最高剂量下，我们观察到与适应相关的基因表达变化持续了近两周，包括诱导一个可能在肝损伤修复中起作用的假定为ependymin的基因。这些数据表明，细胞对二恶英的反应涉及AHRE介导和非AHRE介导的转录，并且将基因表达谱分析与形态发病机制分析相结合对于建立转录变化、毒性和肝损伤适应性之间的时间关系至关重要。
