class: center, middle, inverse, title-slide # Molecular gatekeeper discovery for multiple exposure groups in adolescent girls ## Miao Yu ### ACS spring 2021 ### 2021-04-16 --- ## Background ### One compound, one outcome - regular epidemiology study ### One compound, multiple outcomes - regular toxicology study ### Multiple compounds, one outcome - regular metabolomics/non-targeted analysis ### Multiple compounds, multiple outcomes - exposomics --- ## Exposures-Metabolites-Disease model <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/EMD.png" style="display: block; margin: auto;" /> - What's the relationship between small molecule and health outcome? - What's the relationship between exposures and metabolites? - Which metabolites are the most important? --- ## Gatekeeper theory for EMD model <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/EMDG.png" style="display: block; margin: auto;" /> - The small molecule linked both exposures and other small molecule should be the frontier of biological process - Such molecules may regulate the adverse influences of exposures --- ## Gatekeeper molecular discovery ### Step 1: Correlation among metabolites/exposures ### Step 2: Association between metabolites and exposures ### Step 3: Screen the network structure to discover gatekeeper ### Step 4: Association between gatekeeper and health outcome --- ## Adolescent girls blood samples - Breast Cancer and the Environment Research Program (BCERP) - 163 girls with data on exposure, outcome, and potential confounding variables - Stages of puberty and menarche - PFCs (n-PFOS, n-PFOA, Sm-PFOS, PFHXS, PFNA2) and trace elements (BCD, Cadmium; BMN, Manganese; BPBLead, Lead; BSE, Selenium; THG, Mercury) were measured by CDC - 18750 (ZHP) and 25937 (RPN) features were found in plasma samples by LC-Q-TOF-MS --- ## Step 0: From metabolomics features to independent peaks <img src="https://yufree.github.io/presentation/figure/peakcom.png" width="70%" style="display: block; margin: auto;" /> - Remove redundant peaks by GlobalStd algorithm - 964 (ZHP) and 1784 (RPN) independent peaks as potential metabolites .half[ Yu, M., Olkowicz, M., & Pawliszyn, J. (2019). Structure/reaction directed analysis for LC-MS based untargeted analysis. Analytica Chimica Acta, 1050, 16–24. doi:10.1016/j.aca.2018.10.062 ] --- ## Step 1: Correlation among metabolites/exposures <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/mmnet.png" style="display: block; margin: auto;" /> - Cutoff for correlation: Spearman’s rho > 0.9 - 67 (ZHP) and 95 (RPN) metabolites correlation network clusters found - 787 out of 964 metabolites have no correlation with other metabolites (ZHP) and 1419 out of 1784 metabolites have no correlation with other metabolites (RPN) - No correlation above cutoff could be found among exposures --- ## Step 2: Association between metabolites and exposures <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/zhpset.png" style="display: block; margin: auto;" /> --- ## Step 2: Association between metabolites and exposures <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/rpnset.png" style="display: block; margin: auto;" /> --- ## Step 2: Association between metabolites and exposures <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/gkpnp.png" style="display: block; margin: auto;" /> - 36 (ZHP) and 47 (RPN) peaks connected with other peaks and exposures - 163 (ZHP) and 163 (RPN) peaks connected with exposures only --- ## Step 3: Screen the network structure to discover gatekeeper <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/gkapn.png" style="display: block; margin: auto;" /> - 15 (ZHP) and 11 (RPN) gatekeepers are associated with multiple environmental exposures - 5 annotated gatekeepers were associated with multiple environmental exposures --- ## Step 4: Association between exposure and health outcome <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/MilestonesStage.png" width="200%" style="display: block; margin: auto;" /> - Stages of puberty and menarche are associated with multiple environmental exposures - Pre-B2, B2, B3, B4 and B5 are the female breast developmental stages --- ## Step 4: Association between gatekeepers and health outcome <img src="https://raw.githubusercontent.com/yufree/presentation/gh-pages/figure/MSgk.png" style="display: block; margin: auto;" /> - 4 out of 5 gatekeepers were associated with stages of puberty and Menarche --- ## Conclusion - Gatekeeper discovery could be used to screen metabolites associated with exposures and other metabolites - Some gatekeepers are sensitive to multiple environmental exposures - Gatekeepers might reveal mechanistic aspects of relationships between environmental exposures and metabolome to generate hypothesis for future studies --- ## Acknowledgement .pull-left[ - Dr. Petrick's research group - Lam-ha Dang - Prof. Mary Wolff - Prof. Susan Teitelbaum - National Center for Environmental Health Laboratories at CDC ### Funding - NIEHS P30ES23515 - CHEAR pilot program - U2C ES026561 - 1U2CES030859 ] .pull-right[ <img src="../figure/mssmlabmember.jpg" width="300px" style="display: block; margin: auto;" /> ] --- class: inverse, center, middle # Thanks ## Q&A ## miao.yu@mssm.edu