Zebrafish is a popular animal model used for high-throughput screening of chemical hazards, however, investigations of transcriptomic mechanisms of toxicity are still needed. Here, our goal was to identify genes and biological pathways that Aryl Hydrocarbon Receptor 2 (AHR2) Activators and flame retardant chemicals (FRCs) alter in developing zebrafish. Taking advantage of a compendium of phenotypically-anchored RNA sequencing data collected from 48-h post fertilization (hpf) zebrafish, we inferred a co-expression network that grouped genes based on their transcriptional response. Genes responding to the FRCs and AHR2 Activators localized to distinct regions of the network, with FRCs inducing a broader response related to neurobehavior. AHR2 Activators centered in one region related to chemical stress responses. We also discovered several highly co-expressed genes in this module, including cyp1a, and we subsequently show that these genes are definitively within the AHR2 signaling pathway. Systematic removal of the two chemical types from the data, and analysis of network changes identified neurogenesis associated with FRCs, and regulation of vascular development associated with both chemical classes. We also identified highly connected genes responding specifically to each class that are potential biomarkers of exposure. Overall, we created the first zebrafish chemical-specific gene co-expression network illuminating how chemicals alter the transcriptome relative to each other. In addition to our conclusions regarding FRCs and AHR2 Activators, our network can be leveraged by other studies investigating chemical mechanisms of toxicity.

中文翻译：

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斑马鱼中的基因共表达网络分析揭示了化学类别特定的模块

斑马鱼是一种流行的动物模型，用于化学危害的高通量筛选，但是，仍然需要研究毒性的转录组学机制。在这里，我们的目标是确定芳基烃受体 2 (AHR2) 激活剂和阻燃化学品 (FRC) 在斑马鱼发育过程中改变的基因和生物途径。利用从受精后 (hpf) 斑马鱼 48 小时收集的表型锚定 RNA 测序数据纲要，我们推断出一个共表达网络，该网络根据基因的转录反应对基因进行分组。响应 FRC 和 AHR2 激活子的基因定位于网络的不同区域，FRC 引起与神经行为相关的更广泛的反应。AHR2 激活剂集中在一个与化学应激反应相关的区域。我们还在该模块中发现了几个高度共表达的基因，包括 cyp1a，我们随后证明这些基因明确存在于 AHR2 信号通路中。从数据中系统地去除两种化学类型，并对网络变化进行分析，确定了与 FRC 相关的神经发生，以及与这两种化学类型相关的血管发育的调节。我们还确定了高度相关的基因，这些基因对每一类都有特异性反应，这些基因是暴露的潜在生物标志物。总体而言，我们创建了第一个斑马鱼化学特异性基因共表达网络，阐明了化学物质如何相对于彼此改变转录组。除了我们关于 FRC 和 AHR2 激活剂的结论之外，我们的网络还可以被其他研究毒性化学机制的研究所利用。