Population-Based Discovery of Toxicogenomics Biomarkers for Hepatotoxicity Using a Laboratory Strain Diversity Panel
Population-Based Discovery of Toxicogenomics Biomarkers for Hepatotoxicity Using a Laboratory Strain Diversity Panel
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DOI：
10.1093/toxsci/kfp096
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发表时间：
2009-07-01
影响因子：
3.8
通讯作者：
Rusyn, Ivan
中科院分区：
文献类型：
--
作者：
Harrill, Alison H.;Ross, Pamela K.;Rusyn, Ivan
毒物基因组学研究越来越多地用于发现不良健康事件的潜在生物标志物，丰富化学品风险评估，并促进对易受毒性影响的人的适当识别和治疗。目前通过基因表达谱发现生物标志物的方法通常利用单一或少数啮齿动物品系，限制了检测生物标志物的能力，这些生物标志物可能代表在遗传异质人群中通常观察到的广泛毒性反应。为了提高动物模型的效用，以检测遗传多样性群体的反应生物标志物，我们使用了实验室小鼠品系多样性面板。具体地说，用对乙酰氨基酚（300 mg/kg, ig）模型肝毒性剂治疗36只来自小家鼠、麻鼠和家养小家鼠的近交系小鼠。给药后24小时采集肝组织进行基因表达谱分析。我们确定了26个群体范围内对乙酰氨基酚肝毒性反应的生物标志物，其中基因表达的变化在治疗和肝坏死评分中是显著的，但在单个小鼠品系中不显著。重要的是，大多数这些生物标记基因都是参与肝细胞死亡的细胞内信号传导的一部分，包括先前与对乙酰氨基酚诱导的肝毒性相关的基因，如细胞周期蛋白依赖性激酶抑制剂1A （p21）和白细胞介素6信号传感器（Il6st），以及先前与对乙酰氨基酚无关的基因，如抑癌素M受体（Osmr）和MLX相互作用蛋白样（Mlxipl）。我们的数据表明，多菌株方法可以为理解基因型无关的毒性反应提供实用工具，并有助于确定治疗干预的新靶点。
Toxicogenomic studies are increasingly used to uncover potential biomarkers of adverse health events, enrich chemical risk assessment, and to facilitate proper identification and treatment of persons susceptible to toxicity. Current approaches to biomarker discovery through gene expression profiling usually utilize a single or few strains of rodents, limiting the ability to detect biomarkers that may represent the wide range of toxicity responses typically observed in genetically heterogeneous human populations. To enhance the utility of animal models to detect response biomarkers for genetically diverse populations, we used a laboratory mouse strain diversity panel. Specifically, mice from 36 inbred strains derived from Mus mus musculus, Mus mus castaneous, and Mus mus domesticus origins were treated with a model hepatotoxic agent, acetaminophen (300 mg/kg, ig). Gene expression profiling was performed on liver tissue collected at 24 h after dosing. We identified 26 population-wide biomarkers of response to acetaminophen hepatotoxicity in which the changes in gene expression were significant across treatment and liver necrosis score but not significant for individual mouse strains. Importantly, most of these biomarker genes are part of the intracellular signaling involved in hepatocyte death and include genes previously associated with acetaminophen-induced hepatotoxicity, such as cyclin-dependent kinase inhibitor 1A (p21) and interleukin 6 signal transducer (Il6st), and genes not previously associated with acetaminophen, such as oncostatin M receptor (Osmr) and MLX interacting protein like (Mlxipl). Our data demonstrate that a multistrain approach may provide utility for understanding genotype-independent toxicity responses and facilitate identification of novel targets of therapeutic intervention.