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Comparative metabolic profiles of total and partial body radiation exposure in mice using an untargeted metabolomics approach

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Abstract

Introduction

A large scale population exposure to ionizing radiation during intentional or unintentional nuclear accidents undoubtedly generates a complex scenario with partial-body as well as total-body irradiated victims. A high throughput technique based rapid assessment method is an urgent necessity for stratification of exposed subjects independent of whether exposure is uniform total-body or non-homogenous partial-body.

Objective

Here, we used Nuclear Magnetic Resonance (NMR) based metabolomics approach to compare and identify candidate metabolites differentially expressed in total and partially irradiated mice model.

Methods

C57BL/6 male mice (8–10 weeks) were irradiated total-body or locally to thoracic, hind limb or abdominal regions with 10 Gy of gamma radiation. Urine samples collected at 24 h post irradiation were examined using high resolution NMR spectroscopy and the datasets were analysed using multivariate analysis.

Results

Multivariate and metabolic pathway analysis in urine samples collected at 24 h post-radiation exhibited segregation of all irradiated groups from controls. Metabolites associated with energy metabolism, gut flora metabolism and taurine were common to partial and total-body irradiation, thus making them potential candidates for radiation exposure. Nevertheless, a distinct metabolic pattern was observed in partial-body exposed groups with maximum changes observed in the hind limb region indicating differential tissue associated radiation sensitivity. The organ-specific changes may provide an early warning regarding the physiological system at risk after radiation injury.

Conclusion

The study affirms potentiality of metabolite markers and comparative analysis could be an important piece of information for an integrated solution to a complex research question in terms of radiation biomarkers.

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Funding

This work was supported by Defence R & D Organsiation (DRDO), Ministry of Defence, India (INM 313). KM was supported by University Grant Commission (UGC), India.

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Authors and Affiliations

  1. Metabolomics Research Facility, Division of Behavioral Neuroscience, Institute of Nuclear Medicine and Allied Sciences (INMAS), DRDO, Delhi, India

    Kiran Maan, Ritu Tyagi & Poonam Rana

  2. Division of Radiation Biodosimetry, Department of Radiation Epigenetics, Institute of Nuclear Medicine and Allied Sciences (INMAS), DRDO, Delhi, India

    Ajaswrata Dutta

  3. Department of Biomedical Science, Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, Delhi, India

    Kiran Maan & Radhika Bakhshi

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  1. Kiran Maan
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  2. Ritu Tyagi
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  3. Ajaswrata Dutta
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  4. Radhika Bakhshi
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  5. Poonam Rana
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Contributions

PR and RB conceived the project and designed the study, PR supervised the NMR experiments and data analysis. PR, AD and KM involved in experimentation. KM and RT involved in analysis and interpretation of data and writing of manuscript. PR and RB evaluated the manuscript critically and all the authors reviewed the manuscript.

Corresponding author

Correspondence to Poonam Rana.

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Research involving human and/or animal rights

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Electronic supplementary material

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Electronic supplementary material 1 (TIF 5841 kb)

Fig. 1: PCA Loading plots of (PC1 and PC2): (a) Control and TI groups (b) Control and HI groups, (c) Control and AI groups (d) Control, TI, AI and HI groups, (e) Control and TBI groups and (f) Control, TBI and PI groups.

Electronic supplementary material 2 (TIF 3234 kb)

Fig. 2: Multivariate analysis in TI (Thoracic Irradiated) group (a) PCA score plot showing variation between control and TI groups, (b) PLS-DA score plot showing complete separation of metabolic profile of TI from control group. Group segregation is seen in component 1 with 55.7% (elliptical boundary shows 95% confidence interval), (c) VIP plot presenting top 15 metabolites responsible for observed discrimination between the groups, (d) Corresponding Heatmap showing comparison of metabolites between the groups. (C-Red, TI-Green).

Electronic supplementary material 3 (TIF 3595 kb)

Fig. 3: Multivariate analysis in HI (Hind Limb Irradiated) group: (a) PCA score plot showing variation between control and HI groups. (b) PLS-DA score plot showing complete separation of metabolic profile of HI from control group. Group segregation is seen in component 1 with 49.4% (elliptical boundary shows 95% confidence interval). (c) VIP plot presenting top 15 metabolites responsible for observed discrimination between the groups (d) Corresponding Heatmap showing comparison of metabolites between the groups. (C-Red, HI-Green).

Electronic supplementary material 4 (TIF 3282 kb)

Fig. 4: Multivariate analysis in AI (Abdominal region Irradiated) group (a) PCA score plot showing variation between control and AI groups, (b) PLS-DA score plot showing complete separation of metabolic profile of AI from control group. Group segregation is seen in component 1 with 46.8% (elliptical boundary shows 95% confidence interval), (c) VIP plot presenting top 15 metabolites responsible for observed discrimination between the groups, (d) Corresponding Heatmap showing comparison of metabolites between the groups (C-Green, AI-Red).

Electronic supplementary material 5 (TIF 3189 kb)

Fig. 5: Pattern recognition analysis of urine samples (a) PCA score plot showing variation between control, AI, HI and TI groups, (b) PLS-DA score plot showing separation of all irradiated groups from control group (elliptical boundary shows 95% confidence interval) (c) VIP plot presenting top 15 metabolites responsible for observed discrimination between the groups, (d) Corresponding Heatmap showing comparison of metabolites between the groups (C-Green, AI- Red, HI- Purple and TI-Blue).

Electronic supplementary material 6 (TIF 8113 kb)

Fig. 6: Relative levels of peak intensity of significantly perturbed metabolites in all irradiated groups (TI, AI, HI and Pooled Partial) compared to control group. Data is presented as mean ± standard deviation. (*p-value < 0.05, **p-value < 0.01 and ***p-value < 0.001).

Electronic supplementary material 7 (TIF 3422 kb)

Fig. 7: Pattern recognition analysis of urine samples (a) PCA score plot showing variation between control and TBI groups, (b) PLS-DA score plot showing complete separation of metabolic profile of TBI from control group. Group segregation is seen in component 1 with 54% (elliptical boundary shows 95% confidence interval), (c) VIP plot presenting top 15 metabolites are responsible for observed discrimination between the groups, (d) Corresponding Heatmap showing comparison of metabolites between the groups (C-Red, TBI-Green).

Electronic supplementary material 8 (TIF 5557 kb)

Fig. 8: Representative 1H NMR spectrum of urine showing identified metabolites (a) and comparative NMR spectra of control (C) and different irradiated groups (TBI, TI, AI and HI) (b).

Electronic supplementary material 9 (XLSX 141 kb)

Electronic supplementary material 10 (XLSX 21 kb)

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Maan, K., Tyagi, R., Dutta, A. et al. Comparative metabolic profiles of total and partial body radiation exposure in mice using an untargeted metabolomics approach. Metabolomics 16, 124 (2020). https://doi.org/10.1007/s11306-020-01742-7

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