In the toxicological regime, the toxicological endpoint and its dose-response relationship are two of the most prominent characters in conducting a risk assessment for chemical exposure. Systems biological methods have been used to comprehensively characterize the impact of toxicants on the biochemical pathways. However, the majority of the current studies are only based on single-dose, and limited information can be extrapolated to other doses from these experiments, regardless of the sensitivity of each endpoint. This study aims to understand the dose-response metabolite dysregulation pattern and metabolite sensitivity at the system-biological level. Here, we applied bisphenol A (BPA), an endocrine-disrupting chemical (EDC), as the model chemical. We first employed the global metabolomics method to characterize the metabolome of breast cancer cells (MCF-7) upon exposure to different doses (0, 20, 50, and 100 µM) of BPA. The dysregulated features with a clear dose-response relationship were also effectively picked up with an R-package named TOXcms. Overall, most metabolites were dysregulated by showing a significant dose-dependent behaviour. The results suggested that BPA exposure greatly perturbed purine metabolism and pyrimidine metabolism. Interestingly, most metabolites within the purine metabolism were described as a biphasic dose-response relationship. With the established dose-response relationship, we were able to fully map the metabolite cartography of BPA exposure within a wide range of concentrations and observe some unique patterns. Furthermore, an effective concentration of certain fold changes (e.g., EC₊₁₀ means the dose at which metabolite is 10% upregulated) and metabolite sensitivity were defined and introduced to this dose-response omics information. The result showed that the purine metabolism pathway is the most venerable target of BPA, which can be a potential endogenous biomarker for its exposure. Overall, this study applied the dose-response metabolomics method to fully understand the biochemical pathway disruption of BPA treatment at different doses. Both dose-response omics strategy and metabolite sensitivity analysis can be further considered and emphasized in future chemical risk assessments.

在毒理学体系中，毒理学终点及其剂量-反应关系是进行化学品暴露风险评估的两个最突出的特征。系统生物学方法已被用于全面表征毒物对生化途径的影响。然而，目前的大多数研究仅基于单剂量，无论每个终点的敏感性如何，都可以从这些实验中将有限的信息外推到其他剂量。本研究旨在了解系统生物学水平的剂量反应代谢物失调模式和代谢物敏感性。在这里，我们应用了双酚 A (BPA)，一种内分泌干扰化学品 (EDC)，作为模型化学品。我们首先采用全局代谢组学方法来表征乳腺癌细胞 (MCF-7) 在暴露于不同剂量（0、20、50 和 100 µM）的 BPA 后的代谢组。具有明显剂量反应关系的失调特征也可以通过名为 TOXcms 的 R 包有效提取。总体而言，大多数代谢物通过显示出显着的剂量依赖性行为而失调。结果表明，BPA 暴露极大地扰乱了嘌呤代谢和嘧啶代谢。有趣的是，嘌呤代谢中的大多数代谢物被描述为双相剂量反应关系。借助已建立的剂量反应关系，我们能够完全绘制出各种浓度范围内 BPA 暴露的代谢物图，并观察到一些独特的模式。此外，₊₁₀表示代谢物上调 10% 的剂量）和代谢物敏感性已被定义并引入此剂量反应组学信息。结果表明，嘌呤代谢途径是 BPA 最古老的靶点，可能是其暴露的潜在内源性生物标志物。总体而言，本研究应用剂量反应代谢组学方法全面了解不同剂量 BPA 治疗的生化途径破坏。在未来的化学风险评估中，可以进一步考虑和强调剂量反应组学策略和代谢物敏感性分析。