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首页> 美国卫生研究院文献>Toxicological Sciences >Population-Based Discovery of Toxicogenomics Biomarkers for Hepatotoxicity Using a Laboratory Strain Diversity Panel
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Population-Based Discovery of Toxicogenomics Biomarkers for Hepatotoxicity Using a Laboratory Strain Diversity Panel

机译：基于人群的肝毒性毒物基因组学生物标志物的发现使用实验室菌株多样性小组

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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.
机译：毒性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，丰富化学风险评估并促进对易受毒性影响的人的正确识别和治疗。通过基因表达谱分析发现生物标志物的当前方法通常利用单个或少量啮齿动物菌株，限制了检测生物标志物的能力，这些生物标志物代表了通常在遗传异质人群中观察到的广泛的毒性反应。为了增强动物模型的效用，以检测遗传多样性人群的反应生物标志物，我们使用了实验室小鼠品系多样性小组。具体而言，用模型肝毒剂对乙酰氨基酚（300 mg / kg，ig）处理来自小家鼠，家鼠和家蝇的36个自交系的小鼠。在给药后24小时对收集的肝组织进行基因表达谱分析。我们确定了对乙酰氨基酚肝毒性反应的26种人群生物标志物，其中基因表达的变化在整个治疗和肝坏死评分中均显着，但对单个小鼠品系却不显着。重要的是，这些生物标志物基因中的大多数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，例如细胞周期蛋白依赖性激酶抑制剂1A（p21）和白介素6信号转导子（Il6st），以及基因以前与对乙酰氨基酚不相关，例如制瘤素M受体（Osmr）和MLX相互作用蛋白（Mlxipl）。我们的数据表明，多菌株方法可为理解基因型非依赖性毒性反应提供实用性，并有助于确定治疗干预的新靶标。

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