Laboratory of Systems Pharmacology and Department of Systems Biology, Harvard Medical School, Boston, MA, USA
Laboratory of Systems Pharmacology and Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Mol Syst Biol. 2019 Feb 19;15(2):e8636. doi: 10.15252/msb.20188636.
The liver and kidney in mammals play central roles in protecting the organism from xenobiotics and are at high risk of xenobiotic-induced injury. Xenobiotic-induced tissue injury has been extensively studied from both classical histopathological and biochemical perspectives. Here, we introduce a machine-learning approach to analyze toxicological response. Unsupervised characterization of physiological and histological changes in a large toxicogenomic dataset revealed nine discrete toxin-induced disease states, some of which correspond to known pathology, but others were novel. Analysis of dynamics revealed transitions between disease states at constant toxin exposure, mostly toward decreased pathology, implying induction of tolerance. Tolerance correlated with induction of known xenobiotic defense genes and decrease of novel ferroptosis sensitivity biomarkers, suggesting ferroptosis as a druggable driver of tissue pathophysiology. Lastly, mechanism of body weight decrease, a known primary marker for xenobiotic toxicity, was investigated. Combined analysis of food consumption, body weight, and molecular biomarkers indicated that organ injury promotes cachexia by whole-body signaling through Gdf15 and Igf1, suggesting strategies for therapeutic intervention that may be broadly relevant to human disease.
哺乳动物的肝脏和肾脏在保护机体免受外源性物质侵害方面发挥着核心作用，并且容易受到外源性物质诱导的损伤。从经典的组织病理学和生化角度来看，外源性物质诱导的组织损伤已经得到了广泛的研究。在这里，我们介绍了一种用于分析毒理学反应的机器学习方法。在一个大型毒理学基因组数据集上，对生理和组织学变化进行无监督特征描述，揭示了九个离散的毒素诱导疾病状态，其中一些与已知的病理学相对应，但也有一些是新的。分析动力学表明，在恒定毒素暴露下疾病状态之间的转变，主要是向病理减轻的方向转变，这意味着诱导了耐受。耐受与已知的外源性物质防御基因的诱导以及新的铁死亡敏感性生物标志物的减少相关，这表明铁死亡是一种可治疗的组织病理生理学驱动因素。最后，我们研究了体重下降这一已知的外源性物质毒性的主要标志物的机制。通过对食物消耗、体重和分子生物标志物的综合分析表明，器官损伤通过 Gdf15 和 Igf1 进行全身信号传递，导致恶病质，这提示了可能对人类疾病具有广泛相关性的治疗干预策略。
