Taming Chemical Space: Open and FAIR Workflows for Metabolomics and Exposomics

Prof. Dr. Emma L. Schymanski (plus many, many colleagues and collaborators!) Environmental Cheminformatics Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg [email protected] / https://gitlab.com/uniluxembourg/lcsb/eci https://wwwen.uni.lu/lcsb/research/environmental_cheminformatics/ Taming Chemical Space: Open and FAIR Workflows for Metabolomics and Exposomics Slides available at DOI: 10.5281/zenodo.17943795 UK Metabomeeting 2025 – 16-18 December 2025 The British Library and The Francis Crick Institute, London The Exposome meets the Metabolome 2 Mod. from Vermeulen, Schymanski et al. (2020). Science. DOI: 10.1126/science.aay3164, Miller & Jones (2014) DOI: 10.1093/toxsci/kft251. “The cumulative measure of environmental influences and associated biological responses throughout the lifespan, including exposures from the environment, diet, behaviour and endogenous processes” (Miller & Jones, 2014) Performing Exposomics Over Lifetimes 3 Source: Begoña Talavera Andújar, https://hdl.handle.net/10993/61575. Performing Exposomics Over Lifetimes 4 Source: Begoña Talavera Andújar, https://hdl.handle.net/10993/61575. Video: J. Perera. Fig. Arp, Aurich et al. 2023 DOI: 10.1021/acs.est.3c01735 Performing Exposomics Over Lifetimes 5 Source: Begoña Talavera Andújar, PhD Thesis Defense. https://hdl.handle.net/10993/61575 Performing Exposomics Over Lifetimes 6 Source: Begoña Talavera Andújar, PhD Thesis Defense. https://hdl.handle.net/10993/61575. Environmental Cheminformatics @ LCSB, Uni.lu FAIR chemical data Open source mass spectral library HRMS NTS TP workflows Slide inspired by B. Talavera Explore chemical space Browse transformations 7 Disease impacts 123 million The Vast Chemical Space of Exposomics … Numbers updated 13 Dec. 2025. Mod. from Escher et al (2020). Science. DOI: 10.1126/science.aay6636 Image: ESO/IDA/Danish 1.5 m http://www.eso.org/public/images/potw1015a/ 123 million 20,206 compounds < 0.01% of PubChem The Vast Chemical Space of Exposomics … Target Analysis Numbers updated 13 Dec. 2025. Mod. from Escher et al (2020). Science. DOI: 10.1126/science.aay6636 Image: ESO/IDA/Danish 1.5 m http://www.eso.org/public/images/potw1015a/ Suspect List(s) (NORMAN-SLE) (NORMAN SusDat) NORMAN Database System (NDS) Mohammed Taha et al. (2022) DOI: 10.1186/s12 302-02200680-6 16 Mohammed Taha et al. (2022) DOI: 10.1186/s12302-022-00680-6 17 123 million The Vast Chemical Space of Exposomics … 566,625 133,655 suspects Non-target Screening Suspect Screening Target Analysis Numbers updated 13 Dec. 2025. Mod. from Escher et al (2020). Science. DOI: 10.1126/science.aay6636 Image: ESO/IDA/Danish 1.5 m http://www.eso.org/public/images/potw1015a/ 20,206 compounds < 0.01% of PubChem Grand Challenge: HR-MS “Chemical Space” is too Big! 290 million 123 million 129 million Candidates with high information content Candidates with low information content 1.25 million …and prohibitive run times! 19 Creating Informative Subsets of 20 Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 Schymanski et al. (2021) DOI: 10.1186/s13321-021-00489-0 Creating Informative Subsets of ~500,000 entries “small” Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 Schymanski et al. (2021) DOI: 10.1186/s13321-021-00489-0 21 Elapavalore et al. (2025) DOI: 10.1021/acs.estlett.4c01003 & Schymanski et al. (2021) DOI: 10.1186/s13321-021-00489-0 22 : Fewer and more relevant candidates – with context for Exposomics – Website 23 http://pubchemlite.lcsb.uni.lu/ caffeine Database: for Exposomics 24 https://pubchemlite.lcsb.uni.lu/e/compound/2519 caffeine Database: for Exposomics 25 https://pubchemlite.lcsb.uni.lu/e/compound/2519 caffeine Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 32 Environmental Factors & Reduced Penetrance in PD House Dust Summarizes Indoor Exposure / Influences 33 Haglund et al. (2024) Comprehensive characterization of European house dust contaminants. DOI: 10.1016/j.scitotenv.2024.177639 Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 34 Reduced Penetrance: PD, LRRK2 – Multi-omics on Dust Control (n=11) iPD (n=11) PD-/LRRK2+ (n=8) PD+/LRRK2+ (n=11) Control (n=8) iPD (n=3) PD-/LRRK2+ (n=8) PD+/LRRK2+ (n=5) Dust sample collection Serum sample collection Liquid-liquid extraction Bile acids extraction DNA extraction Monophasic extraction DNA sequencing HRMS LC MTBE MeOH+ H 2 O Non-polar metabolites Polar metabolites RP (CSH C18) Q Exactive HF HRMSLC EXPLORIS 240 NextSeq500 (Illumina) HILIC RP (BEH C18) HILIC Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 35 Exposomics Workflows – Best of Many Worlds! Chemical Classification: PD, LRRK2 Penetrance & Dust Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 36 Is Regrettable Substitution Impacting Neurodegeneration? Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 37 Control iPD PD-/LRRK2+ PD+/LRRK2+ -2 -1 0 1 2 BPS Normalized peak intensity p=0.0117 p=0.0591 p=0.0620 Emerged as a “safer” alternative to bisphenol A (BPA) Control iPD PD-/LRRK2+ PD+/LRRK2+ -3 -2 -1 0 1 2 3 PFBuS Normalized peak intensity p=0.0184 p=0.0069 p=0.0649 PFBuS is a substitute for perfluorooctanesulfonate (PFOS) 1,003 chemicals Perfluorobutane Sulfonic Acid Bisphenol S Use and manufacturing (549) Associated Disease/Disorder (543) Pathways (331) Hazardous chemical replacements (2) Compound TOC 38 15-Dec-25 BPS Impacting Mitochondria in Patient-Derived Neurons Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 39 Significant Chemicals: PD, LRRK2 Penetrance & Dust Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 40 A) BPS B) PFBuS C) BThSO 3 D) 2PP ** * * * * * * Is Traffic Impacting Neurodegeneration? Talavera Andújar et al. (2024). Environment International DOI: 10.1016/j.envint.2024.109151 41 Persistent Substructures in Emerging Contaminants Chirsir et al (2024). ESEU. DOI: 10.1186/s12302-024-00919-4 48 Concerns due to mobility and persistence Persistent Substructures in Emerging Contaminants 49 Biotransformer v4.0 beta Predicted TPs Literature TPs Analogous TPs Chirsir et al (2025). ChemRxiv. DOI: 10.26434/chemrxiv-2025-l4gkg https://gitlab.com/uniluxembourg/lcsb/eci/pubchem-docs/-/tree/main/taxonomy/Danio_rerio Example: Potentially Persistent Triazine Substructures Chirsir et al (2025). ChemRxiv. DOI: 10.26434/chemrxiv-2025-l4gkg 50 Example: Potentially Persistent Triazole Substructures Chirsir et al (2025). ChemRxiv. DOI: 10.26434/chemrxiv-2025-l4gkg 51 Introducing FAIR-TPs 52 Mayahi, Palm & Schymanski (in prep.). https://fairtps.lcsb.uni.lu/ & https://fairtps.lcsb.uni.lu/about/ Substructure Searching with FAIR-TPs 53 Mayahi, Palm & Schymanski (in prep.). https://fairtps.lcsb.uni.lu/substructure_search/?l=all-lists&depth=20&sid=4YF3lRP4&page=2 Substructure Searching with FAIR-TPs 54 Mayahi, Palm & Schymanski (in prep.). https://fairtps.lcsb.uni.lu/stats/ & https://fairtps.lcsb.uni.lu/about/ Substructure Searching with FAIR-TPs 55 Mayahi, Palm & Schymanski (in prep.). https://fairtps.lcsb.uni.lu/stats/ & https://fairtps.lcsb.uni.lu/about/ 56 Mayahi, Palm & Schymanski (in prep.). https://fairtps.lcsb.uni.lu/stats/ & https://fairtps.lcsb.uni.lu/about/ Shortest Pathway with FAIR-TPs 57 Mayahi, Palm & Schymanski (in prep.). https://fairtps.lcsb.uni.lu/stats/ & https://fairtps.lcsb.uni.lu/about/ Predicting Dead-End Transformation Products 64 Source: Emma Palm. Palm et al. (2025) Presentation at SETAC Europe, 13 May 2025 . DOI: 10.5281/zenodo.15574837 Number of precursors: 29 Coverage of Exposomics Resources and Open Data 65 Source: Talavera Andújar & Schymanski, accepted, Exposome. https://gitlab.com/uniluxembourg/lcsb/eci/exposomics-plots. Triglycerides Nucleotides EU Pesticides PFOS and related substances Environmental Cheminformatics @ LCSB, Uni.lu FAIR chemical data Open source mass spectral library HRMS NTS TP workflows Slide inspired by B. Talavera Explore chemical space Browse transformations 66 Disease impacts Email: emma.schymans[email protected] in:emma-schymanski / @[email protected] https://wwwen.uni.lu/lcsb/research/environmental_ cheminformatics/ https://gitlab.com/uniluxembourg/lcsb/eci/ https://pubchemlite.lcsb.uni.lu/ Merci/Danke schön/Thank you! H2020: 101036756 67