Metabolomics study of dose-response and time-resolved effect of bisphenol a exposure in vitro

• Main Author: Zhao, Haoduo
• Other Authors: Fei Xunchang
• Format: Thesis-Master by Research
• Language: English
• Published: Nanyang Technological University 2022
• Subjects: Science::Biological sciences::Biochemistry; Science::Chemistry::Analytical chemistry; Engineering::Environmental engineering::Hazardous substances
• Online Access: https://hdl.handle.net/10356/163019
• Institution: Nanyang Technological University

The biochemical consequences induced by xenobiotics exposure are featured with dose-response and time-resolved landscapes. Metabolomics, a systematic study of intercellular chemical fingerprints, exhibits its advantages in toxicological mechanisms identification and dynamic physiology characterization. Yet, most metabolome studies were adopted in single dosing point with static snapshot, while little is known about the continuous dysregulation behavior under environmental stress, regardless of the metabolite/ pathway sensitivity extrapolation. In this thesis, bisphenol A (BPA), a well acknowledged endocrine disrupting chemical with multiple toxicological endpoints, was chosen as the model compound to systematically investigate the biological dysfunctions in terms of dynamic dose-response and time-resolved change. For the former part, metabolites’ dose-response relationships were established based on the dysregulation manner at four consecutive doses, which were further extrapolated into full range cartography prediction and sensitive biomarkers discovery. For the latter part, time-resolved metabolic adaptions were observed from eleven time points to characterize temporal cellular change at different stages. Pathway enrichments suggested the enhancing metabolic requirements for elevated energy homeostasis, oxidative stress response and ER-α mediated cell proliferation. In sum, the dose-response and time-resolved metabolomics studies provided an insightful characterization into xenobiotics’ metabolic disruption effect with significant dosage and temporal patterns, which may play essential roles in dynamic hazard identification and chemical risk assessment.