The Study Of Risk Associated With Bisphenol A And Replacement Bisphenol S Exposure Based On Metabolomics And Stable Isotope Tracing

The structure of Bisphenol S(Bisphenol S,BPS)is similar to that of BPA(Bisphenol A,BPA).BPS has become one of the major substitutes for the production of “BPA-free” products,and is widely used as a chemical building block in the manufacture of polycarbonate plastics and epoxy resins for consumer products.Due to its associated health effects based on endocrine-disruption activity,restrictions have been placed on the use of BPA.The relationship between BPA exposure and increased risk of obesity and diabetes has been noted,although the potential influence of BPS exposure is not fully understood.The safety of alternatives to BPA is a controversial issue at present.In this study,to study the comprehensive metabolome rewiring induced by BPA/BPS associated with differentiation of the 3T3-L1 cell line,we performed non-targeted metabolomics and stable isotope tracing-based analyses.Our work aids in providing a novel perspective into the toxicity-related metabolome response to BPA and its alternative BPS.The main work of the thesis is as follows:1.Metabolome disturbance of 3T3-L1 preadipocyte differentiation associated with BPA and replacement BPS exposure.We performed non-targeted metabolomics analysis to study the comprehensive metabolome rewiring induced by BPA/BPS associated with differentiation of the3T3-L1 cell line.The results revealed the comprehensive metabolome disturbance induced by either BPA or BPS exposure.A total of 85 significant metabolites were identified,spanning amino acids,organic acids,amines,nucleotides,fatty acids and other categories.Pathway enrichment analysis combined with the topology analysis indicated the significant disturbance of BPA/BPS exposure to amino acid metabolism and the overall reduction of amino acid content.It would be related to BPA/BPS exposure to participate in cell penetration regulation,affecting cell oxidative stress response,energy metabolism and carbon metabolism.This study aids in supplying a novel perspective into the metabolic disturbance response to BPA and its alternative BPS.2.Stable isotope tracing of metabolic disturbance over the course of preadipocyte differentiation.We performed a stable-isotope tracing metabolomics/lipidomics study to cover metabolites as well as isotopologues in a non-targeted way.An in-house developed software enables high throughput processing of complex multi-dimensional data.Compared with standard non-targeted metabolomics studies,this strategy broadens the understanding of metabolism beyond the sole view on changes in the total amount of metabolites.Both classical ‘snapshots’ of total amount and dynamic information could be achieved simultaneously.The practicability is demonstrated analyzing 13C-U-glucose-based study of metabolome disturbance of 3T3-L1 preadipocyte differentiation associated with BPA and replacement BPS exposure.The key metabolome remodeling discovered in our previous studies was validated in this study to involve the cardiolipins(CLs),phosphatidylglycerols(PGs)and amino acids metabolic pathways,providing novel clues of potential mechanism in which both BPA and BPS exposure could be associated with decreased risk of glucose utilization.Metabolic pathway analysis revealed the BPS exposure induced patterns of metabolome changes similar to those of BPA,suggesting that the substitution of BPA by its structural analog BPS should be therefore performed with caution.