Dose-response metabolomics and pathway sensitivity to map molecular cartography of bisphenol A exposure

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.