A Metabolomics Study of Plasma Biological Changes Related to Polybrominated Biphenyl (PBB 153) Exposure in the Michigan PBB Cohort Público
Yano, Yukiko (2014)
Abstract
The accidental contamination of the food chain with polybrominated biphenyl (PBB), a brominated flame retardant, in Michigan (1973-1974) has resulted in the exposure of more than 4,000 individuals. PBBs are suspected to disrupt endocrine function, but the long-term health effects are unknown. In this study, newly collected blood plasma samples obtained from participants of the Michigan PBB registry were analyzed to investigate the long-term effects of PBB exposure on human metabolic pathways. Metabolic profiles were compared between different classes of PBB exposure, ranging from low to high body burdens of PBB, in order to identify biomarkers associated with the exposure or potential disease risk.
Metabolomic analysis was performed using liquid chromatography with Fourier-transform mass spectrometry (LCMS) on 179 plasma samples collected from subjects in the PBB registry. Metabolomic data were analyzed using various statistical and computational methods with R software package (MetBN) and the web-based tool, MetaboAnalyst. Samples were categorized into two or three classes of PBB exposure levels based on the measured plasma PBB 153 concentrations. Metabolic features (mass to charge ratios of ions and their retention time) that discriminated between different classes of PBB exposure were identified using False Discovery Rate (FDR) to account for multiple testing. The separation of the data based on these discriminatory features was visualized and assessed using principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and hierarchical clustering with heatmaps. Selected discriminatory features were tentatively identified using MetaboAnalyst's metabolite set enrichment analysis (MSEA) and metabolic pathway analysis (MetPA).
Of the features strongly correlated with PBB concentrations, 44 features were significantly different between low and high PBB exposure classes, and 119 discriminatory features were identified from the 11,202 total features detected by LCMS. Although the true identity of these features remains uncertain, it was suggested that these discriminatory features contained metabolites involved with lipid metabolism. Results of the study demonstrate that metabolomics can be used to discover biomarkers along the exposure-disease continuum and provides a powerful means to explore the human exposome, which has been coined as a cumulative measure of environmental exposures throughout the lifespan.
Table of Contents
1. Introduction... 1
2. Methods... 8
2.1 Materials... 8
2.2 Samples... 8
2.3 Metabolomic analysis... 9
2.4 Data analysis... 10
3. Results... 16
3.1 Descriptive analysis of PBB exposure among the sample cohort... 16
3.2 Metabolomic data... 17
3.3 Part 1. Biomarker discovery: Identification of discriminatory features associated with PBB exposure... 17
3.4 Part 2: Metabolome-wide identification of discriminatory features between PBB exposure classes... 34
4. Discussion... 61
5. Conclusion... 66
Appendix A: IRB Approval Letter... 67
Appendix B: Supplementary Figures... 68
Appendix C: Supplementary Tables... 88
References... 97
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