Example of Adverse Outcome Pathway (AOP) Concept Enabling Genome-to-Phenome Discovery in Toxicology.
Example of Adverse Outcome Pathway (AOP) Concept Enabling Genome-to-Phenome Discovery in Toxicology.
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不良结果途径 (AOP) 概念在毒理学中实现基因组到表型组发现的示例。
DOI：
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发表时间：
2020
影响因子：
2.6
通讯作者：
Xiao Luo
中科院分区：
文献类型：
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作者：
K. Gust;Qing Ji;Xiao Luo
下面的论文代表了由不良结果途径（AOP）概念指导的基因组到现象组发现的密集十年进展的迷你回顾。这个例子是作为一种手段来刺激这个毒理学概念的交叉，以加强更广泛的生物科学界的基因组-表型发现。案例研究展示了AOP方法在跨生物组织的多个层次建立因果联系的好处，最终将分子起始（通常在基因组尺度上）与感兴趣的生物体水平表型联系起来。该案例研究总结了美国军方为确定暴露于硝基芳香弹药（如2,4,6-三硝基甲苯（TNT））后嗜睡和体重减轻的潜在毒理学表型机制所做的努力。最初的关键发现包括毒性基因组学结果，即硝基甲苯暴露抑制过氧化物酶体增殖物激活受体α (PPARα)途径的表达。我们引入AOP概念来验证一种假设，即硝基甲苯暴露中PPARα信号的抑制会影响脂质代谢过程，从而影响全身能量收支，最终导致体重减轻。一系列转录组学、蛋白质组学、脂质组学、体外PPARα核信号传导和PPARα敲除研究的结果最终支持了这一假设的各个方面。鉴于这些结果，我们下一步继续开发一个正规化的AOP描述PPARα拮抗剂导致体重减轻。这个AOP经过深入的文献回顾和多轮同行评议而得到改进，最终被国际社会接受为经济合作与发展组织（OECD）批准的AOP。简要地说，AOP将PPARα拮抗剂结合确定为分子启动事件（MIE），导致一系列关键事件（KEs），包括抑制控制脂质代谢和生酮基因的核转激活，抑制脂肪酸β氧化和生酮动力学，负能量预算，最终导致体重减轻的不良结果（AO）。鉴于PPARα拮抗剂MIE是该途径中AO进展的可靠指标，我们进行了系统发育分析，结果表明PPARα氨基酸亲缘关系通常跟踪物种亲缘关系。此外，使用SeqAPASS的PPARα氨基酸相关性分析预测了脊椎动物对MIE的易感性，为跨物种的AOP外推提供了背景。总的来说，我们希望这个关于AOP概念如何使毒理学受益的说明性示例在更广泛的生物科学界播下一颗种子，以重新定义这个概念，以促进生物学中增强的基因组到现象组的发现。
The following paper represents a mini-review of an intensive ten year progression of genome-to-phenome discovery guided by the adverse outcome pathway (AOP) concept. This example is presented as a means to stimulate crossover of this toxicological concept to enhance genome-to-phenome discovery within the broader biological sciences community. The case study demonstrates the benefits of the AOP approach for establishing causal linkages across multiple levels of biological organization ultimately linking molecular initiation (often at the genomic scale) to organism-level phenotypes of interest. The case study summarizes a US military effort to identify the mechanism(s) underlying toxicological phenotypes of lethargy and weight loss in response to nitroaromatic munitions exposures, such as 2,4,6-trinitrotolune (TNT). Initial key discoveries are described including the toxicogenomic results that nitrotoluene exposures inhibited expression within the peroxisome proliferator activated receptor α (PPARα) pathway. We channeled the AOP concept to test the hypothesis that inhibition of PPARα signaling in nitrotoluene exposures impacted lipid metabolic processes, thus affecting systemic energy budgets, ultimately resulting in body weight loss. Results from a series of transcriptomic, proteomic, lipidomic, in vitro PPARα nuclear signaling, and PPARα knock-out investigations ultimately supported various facets of this hypothesis. Given these results, we next proceeded to develop a formalized AOP description of PPARα antagonism leading to body weight loss. This AOP was refined through intensive literature review and polished through multiple rounds of peer-review leading to final international acceptance as an Organisation for Economic Cooperation and Development (OECD)-approved AOP. Briefly, that AOP identifies PPARα antagonist binding as the molecular initiating event (MIE) leading to a series of key events (KEs) including inhibition of nuclear transactivation for genes controlling lipid metabolism and ketogenesis, inhibition of fatty acid beta-oxidation and ketogenesis dynamics, negative energy budget, and ultimately the adverse outcome (AO) of body-weight loss. Given that the PPARα antagonism MIE represented a reliable indicator of AO progression within the pathway, a phylogenetic analysis was conducted which indicated that PPARα amino acid relatedness generally tracked species relatedness. Additionally, PPARα amino acid relatedness analysis using SeqAPASS predicted susceptibility to the MIE across vertebrates providing context for AOP extrapolation across species. Overall, we hope this illustrative example of how the AOP concept has benefited toxicology sows a seed within the broader biological sciences community to repurpose the concept to facilitate enhanced genome-to-phenome discovery in biology.
影响因子：
4.6
作者：
Rawat, Arun;Gust, Kurt A.;Perkins, Edward J.
通讯作者：
Perkins, Edward J.
影响因子：
29
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria