Exposure, bioactivation and metabolic toxicity of bisphenol a diglycidyl ether

• Main Author: Liu, Min
• Other Authors: Fang Mingliang
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Engineering::Environmental engineering
• Online Access: https://hdl.handle.net/10356/143805
• Institution: Nanyang Technological University

As an emerging organic contaminant (EOC), bisphenol A diglycidy ether (BADGE) is known as an endocrine-disrupting chemical (EDC) with unique epoxide and highly reactive structures. BADGE and its derivatives (BADGEs), manufactured from Bisphenol A (BPA), are widely used as epoxy resins and emerging plasticizers in food packages and material coating. Unlike bisphenol A (BPA) that has been intensely investigated, little information is available on BADGE occurrence, biotransformation and metabolic toxicity. The first part of this thesis focuses on investigating BADGE and other bisphenol occurrences in paired dust and urine samples as well as its association with oxidative stress. First, a novel water-free method was developed to analyze BADGEs in dust to address the challenges of their highly reactive properties and measurable laboratory background. Next, the concentrations of these compounds were quantified in 33 paired samples. A significantly positive correlation of BPA levels in paired dust and urine samples was observed but not for BADGE. This study further found that the oxo-2’-deoxyguanosine (8-OHdG) level as an oxidative biomarker was positively correlated with urinary BPA level, suggesting that elevated oxidative stress might be associated with BPA exposure. In the second part, the focus was to investigate the in vitro biotransformation of BADGE, which mediated the toxicity. First, an effective discovery platform involving empirical prediction and high-resolution mass spectrometry (HRMS) data deconvolution was developed to predict and identify possible metabolites. Next, the reaction, kinetics and fragmentation behavior were investigated for the reaction between BADGE and 17 amino acids to acquire ‘empirical knowledge’ to facilitate further identification. Several novel metabolites such as BADGE’s glucuronide, sulfate and glutathione conjugates as well as the pathways were for the first time identified. Overall, the results showed that complementing HRMS data deconvolution with both in silico and knowledge-based prediction can greatly enhance the discovery potentials of reactive chemicals. In the third part, the focus was to compare the metabolic toxicity between BADGE and BPA upon breast cancer cell (MCF-7) using global metabolomics. This study characterized the affected biochemical pathways to understand the toxicity of these chemicals at system-biological levels. The results showed that both chemicals shared many dysregulated pathways such as the energy/sugar metabolism. Overall, BPA triggered higher cellular perturbations such as arginine and proline metabolism which could be explained by its stronger estrogenic activity. Instead, BADGE has higher potentials to disrupt lipid metabolism, warranting further investigation. In the fourth part, the focus was to investigate the potential cellular perturbations caused by the exposure of human-relevant level chemical mixture including BADGEs and quantify their relative contribution. Omics approaches (e.g. metabolomics and transcriptomic) were employed to characterize the biological effect triggered by the mixture upon MCF-7 and further develop an effective “counting-out” method to evaluate the relative contribution of each chemical in the mixture effect. Both omics results revealed that the cellular activity disturbed by mixture was associated with cell proliferation and increased oxidative stress. In addition, we found that many chemicals have different effects on metabolic pathway perturbations. Overall, dihydroxy benzophenone (DHB) and BPA have comparably higher contributions while the effects of BADGEs are minor.