A Chemical Structure and Machine Learning Approach to Assess the Potential Bioactivity of Endogenous Metabolites and Their Association with Early Childhood Systemic Inflammation

Mario Lovrić*, Tingting Wang, Mads Rønnow Staffe, Iva Šunić, Kristina Časni, Jessica Lasky-Su, Bo Chawes, Morten Arendt Rasmussen

*Corresponding author af dette arbejde

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Abstract

Metabolomics has gained much attention due to its potential to reveal molecular disease mechanisms and present viable biomarkers. This work uses a panel of untargeted serum metabolomes from 602 children from the COPSAC2010 mother–child cohort. The annotated part of the metabolome consists of 517 chemical compounds curated using automated procedures. We created a filtering method for the quantified metabolites using predicted quantitative structure–bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines. The metabolites measured in the children’s serums are predicted to affect specific targeted models, known for their significance in inflammation, immune function, and health outcomes. The targets from Tox21 have been used as targets with quantitative structure–activity relationships (QSARs). They were trained for ~7000 structures, saved as models, and then applied to the annotated metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation.
Keywords: metabolomics; QSAR; inflammation; cortisol; cortisone; vitamin A; CRP
OriginalsprogEngelsk
Artikelnummer278
TidsskriftMetabolites
Vol/bind14
Udgave nummer5
Antal sider16
ISSN2218-1989
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
B.C. received funding from the European Research Council (ERC) under the European Union\u2019s Horizon 2020 research and innovation program (grant agreement No. 946228). J.L.S. received funding from the National Heart, Lung, and Blood Institute (NHLBI) grants R01HL123915 and R01HL141826. COPSAC is funded by private and public research funds, all listed on www.copsac.com (access date 25 April 2024). The Lundbeck Foundation, the Novo Nordisk Foundation, the Danish Ministry of Health, the Danish Council for Strategic Research, and the Capital Region Research Foundation provided core support for COPSAC. M.A.R. has funding from the Novo Nordisk Foundation (grant nb: NNF21OC0068517). M.L., K.\u010C., I.\u0160. have funding from the European Commission (grant agreement ID: 101057497).

Publisher Copyright:
© 2024 by the authors.

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