MSACL 2017 US Abstract

A Multi-Omic Analysis of Pre-Eclampsia and Related Conditions using Ion Mobility-Mass Spectrometry

Christopher Chouinard (Presenter)
Pacific Northwest National Laboratory

Bio: Chris Chouinard received his Ph.D. in analytical chemistry from the University of Florida in 2016. While at UF, Chris worked under advisor Richard Yost to develop ion mobility-mass spectrometry methods for studying isomeric steroids and clinically relevant compounds such as vitamin D epimers. Chris then began his post-doctoral studies at Pacific Northwest National Laboratory (PNNL) where he works to implement innovative ion mobility technologies, including Structures for Lossless Ion Manipulations (SLIM), for improving analysis of biological samples.

Authorship: Christopher D. Chouinard (1); Xueyun Zheng (1); Jennifer E. Kyle (1); Yehia M. Ibrahim (1); Richard D. Smith (1); Brandie D. Taylor (2); Kristin E. Burnum-Johnson (1); Erin S. Baker (1)
(1) Pacific Northwest National Laboratory, Richland, WA; (2) Department of Epidemiology & Biostatistics, School of Public Health, Texas A&M Health Science Center, College Station, TX

Short Abstract

Pre-eclampsia, gestational diabetes mellitus (GDM), and other complications arising during pregnancy lead to increased morbidity and mortality in both pregnant women and their fetuses, potentially causing long-term effects. Such conditions have been studied extensively and, although some treatments have been determined, the precise cause of these conditions remains uncertain. However, there appears to be a link with pre-existing conditions such as obesity. In this study, ion mobility-mass spectrometry (IMS-MS) was used to investigate plasma metabolomic, lipidomic, and proteomic changes in pregnant women that developed GDM or preeclampsia compared with control pregnancies. Ion mobility allowed an additional mode of identification and separation for potential biomarkers in these samples.

Long Abstract

Introduction: Pre-eclampsia is a condition that affects 3-5% of pregnancies and presents with hypertension and elevated proteinuria [1,2]. Failure to effectively monitor and treat pre-eclampsia significantly increases morbidity in pregnant women (stroke, liver rupture) and fetuses (prematurity, intrauterine growth restriction), and leads to increased mortality. Incidence of this condition has risen in the USA, and although the precise cause of pre-eclampsia remains unknown, its risk is believed to be elevated by pre-disposing conditions such as chronic hypertension, diabetes, and obesity.

Understanding the development of pre-eclampsia may provide insight into its cause(s) and ultimately improve diagnosis and prevention. Due to the correlation with many pre-existing conditions, development and/or progression of these conditions during gestation is of great interest to clinicians. Specifically, the progression of gestational diabetes mellitus (GDM) into pre-eclampsia and other hypertensive disorders may shed light on the increased risk associated with pre-pregnancy conditions.

Metabolomic [3], lipidomic [4], and proteomic [5] studies have been undertaken to investigate pre-eclampsia biomarkers before and during pregnancy. Many of these studies have utilized combinations of gas chromatography (GC) and liquid chromatography (LC) coupled with high-resolution and/or tandem mass spectrometry (MS) methods. Alternatively, ion mobility spectrometry (IMS) is a rapidly growing technique that has recently been applied to several biological systems and disease states. IMS allows separation based on gas-phase size and shape of compounds, referred to as collision cross section (CCS). When coupled with chromatography (retention time) and mass spectrometry (m/z), this technique can provide additional information and resolution of isomeric species. However, commercial high-throughput IMS instrumentation often lacks the resolution necessary to separate multiple components of complex biological mixtures.

Recent instrumental advances, including the introduction of Structures for Lossless Ion Manipulations (SLIM), have attempted to overcome this barrier. SLIM uses printed circuit board (PCB) technology to form low-cost ion mobility devices capable of moving ions around corners rather than only in simple straight lines. This allows serpentine path lengths in excess of an order of magnitude greater than commercial instrumentation. Additionally, SLIM is capable of multiple pass separations, further increasing the mobility length and the potential resolution of similar mobility species; all of this can be achieved without increasing the footprint of the device. In this way, SLIM offers tremendous potential for investigation of changes in disease state by increasing breadth of data collection.

In this study, a novel multi-omic approach with ion mobility-mass spectrometry (IMS-MS) is used to compare the metabolome, lipidome, and proteome of pregnant women suffering from gestational diabetes and pre-eclampsia with those of control pregnancies. Both commercial and homebuilt IM-MS instrumentation is used for resolution of structural and stereoisomers that may be of biological significance but are unresolved with conventional GC- and LC-MS methods.

Experimental Design: Plasma samples were collected at a single time point (at delivery) from control women (100 samples), those presenting with gestational diabetes mellitus (49 samples), and those with pre-eclampsia (50 samples). These samples were then extracted using the MPLEx protocol for metabolomic, lipidomic, and proteomic analyses [6]. For the metabolomic analyses, an Agilent RapidFire automated SPE system was coupled with IMS-MS instrumentation for rapid (<10 seconds) SPE-IMS-MS analyses and LC-IMS-MS measurements were performed for both the lipidomic and proteomic studies. Features from each of the studies were identified based on collision cross section, m/z, and LC elution times (when available) and compared with an in-house database.

For further investigation of targeted features of interest, a home-built system incorporating a traveling wave (TW) Structures for Lossless Ion Manipulations (SLIM) was used for high-resolution multi-pass mobility separation. This setup was coupled to an Agilent 6500 series QTOF, similar to that previously reported in literature [7]. This instrumentation allows the user to “zoom in” on mobility peaks of interest by allowing multiple passes for targeted features within a narrow mobility window, such as potential metabolite or lipid isomers, enabling separation and identification of previously unresolved species.


References & Acknowledgements:

References

(1) Steegers, E. A. P.; von Dadelszen, P.; Duvekot, J. J.; Pijnenborg, R. The Lancet 2010, 376, 631-644.

(2) Mol, B.W.J.; Roberts, C.T.; Thangaratinam, S.; Magee, L.A.; de Groot, C.J.M.; Hofmeyr, G.J. The Lancet 2016, 387, 999-1011.

(3) Odibo, A.O.; Goetzinger, K.R.; Odibo, L.; Cahill, A.G.; Macones, G.A.; Nelson, D.M.; Dietzen, D.J. 2011, Prenat Diagn. 2011, 31, 990-994.

(4) Korkes, H.A.; Sass, N.; Moron, A.F.; Camara, N.O.S.; Bonetti, T.; Cerdeira, A.S.; Da Silva, I.D.C.G.; De Oliveira, L. PloS One, 2014, 9, doi:10.1371/journal.pone.0110747

(5) Wong, F.; Cox, B. J Proteomics Bioinform. 2014, S10: 001. doi:10.4172/jpb.S10-001

(6) Nakayasu E.S.; Nicora, C.D.; Sims, A.C.; Burnum-Johnson, K.E.; Kim, Y.M.; Kyle, J.E.; et al. Am Soc. Microbiol. 1(3):e00043-16 doi:10.1128/mSystems.00043-16.

(7) Deng, L.; Ibrahim, Y.M.; Baker, E.S.; Aly, N.A.; Hamid, A.M.; Zhang, X.; Zheng, X.; Garimella, S.V.B.; Webb, I.K.; Prost, S.A.; Sandoval, J.A.; Norheim, R.V.; Anderson, G.A.; Tolmachev, A.V.; Smith, R.D. Chemistry Select 2016, 1, 2396-2399.

Acknowledgments

This research utilized capabilities developed by the Pan-omics program (funded by the U.S. Department of Energy Office of Biological and Environmental Research Genome Sciences Program). This work was performed in the W. R. Wiley Environmental Molecular Sciences Laboratory (EMSL), a DOE national scientific user facility at the Pacific Northwest National Laboratory (PNNL). PNNL is operated by Battelle for the DOE under contract DE-AC05-76RL01830.


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