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Mass spectrometry imaging (MSI) of lipids within tissues has significant potential for both biomolecular discovery and histopathological applications. Conventional MSI technologies are, however, challenged by the prevalence of phospholipid regioisomers that differ only in the location(s) of carbon-carbon double bonds and/or the relative position of fatty acyl attachment to the glycerol backbone (i.e., sn position). The inability to resolve isomeric lipids within imaging experiments masks underlying complexity, resulting in a critical loss of metabolic information. Herein, ozone-induced dissociation (OzID) is implemented on a mobility-enabled quadrupole time-of-flight (Q-TOF) mass spectrometer capable of matrix-assisted laser desorption/ionization (MALDI). Exploiting the ion mobility region in the Q-TOF, high number densities of ozone were accessed, leading to similar to 1000-fold enhancement in the abundance of OzID product ions compared to earlier MALDI-OzID implementations. Translation of this uplift into imaging resulted in a 50-fold improvement in acquisition rate, facilitating large-area mapping with resolution of phospholipid isomers. Mapping isomer distributions across rat brain sections revealed distinct distributions of lipid isomer populations with region-specific associations of isomers differing in double bond and sn positions. Moreover, product ions arising from sequential ozone- and collision-induced dissociation enabled double bond assignments in unsaturated fatty acyl chains esterified at the noncanonical sn-1 position.

Lipidomics is a rapidly growing field with numerous examples showing the importance of lipid molecules throughout biology. It has also shed light onto the vast and complex functions performed by many lipids that possess an immense diversity in molecular structures. Mass spectrometry (MS) is the tool of choice for analyzing lipids and has been the key catalyst driving the field forward. However, MS does not yet permit true molecular lipidomics wherein the identification and quantification of lipids having defined molecular structures can be routinely achieved. Here we describe recent advances in MS-based lipidomics that allow access to higher levels of molecular information in lipidomics experiments. These advances will form a key piece of the puzzle as the field moves towards systems characterization of lipids at the molecular level.

Lipidomics is a rapidly growing field with numerous examples showing the importance of lipid molecules throughout biology. It has also shed light onto the vast and complex functions performed by many lipids that possess an immense diversity in molecular structures. Mass spectrometry (MS) is the tool of choice for analyzing lipids and has been the key catalyst driving the field forward. However, MS does not yet permit true molecular lipidomics wherein the identification and quantification of lipids having defined molecular structures can be routinely achieved. Here we describe recent advances in MS‐based lipidomics that allow access to higher levels of molecular information in lipidomics experiments. These advances will form a key piece of the puzzle as the field moves towards systems characterization of lipids at the molecular level.

Summary Sentinel species are playing an indispensable role in monitoring environmental pollution in aquatic ecosystems. Many pollutants found in water prove to be endocrine disrupting chemicals that could cause disruptions in lipid homeostasis in aquatic species. A comprehensive profiling of the lipidome of these species is thus an essential step toward understanding the mechanism of toxicity induced by pollutants. Both the composition and spatial distribution of lipids in freshwater crustacean Gammarus fossarum were extensively examined herein. The baseline lipidome of gammarids of different sex and reproductive stages was established by high throughput shotgun lipidomics. Spatial lipid mapping by high resolution mass spectrometry imaging led to the discovery of sulfate-based lipids in hepatopancreas and their accumulation in mature oocytes. A diverse and dynamic lipid composition in G. fossarum was uncovered, which deepens our understanding of the biochemical changes during development and which could serve as a reference for future ecotoxicological studies., Graphical Abstract, Highlights • Baseline lipidome profiling of G. fossarum of different sex and reproductive stages • Spatial localization of lipids in gammarid tissue by mass spectrometry imaging • SIMS imaging guided discovery of sulfate-based lipids in hepatopancreas epithelium • Disclosure of a dynamic lipid composition in maturing female oocytes, Environmental Science; Lipidomics; Metabolomics; Pollution; Zoology

Mass spectrometry imaging (MSI) enables the spatial distributions of molecules possessing different mass‐to‐charge ratios to be mapped within complex environments revealing regional changes at the molecular level. Even at high mass resolving power, however, these images often reflect the summed distribution of multiple isomeric molecules, each potentially possessing a unique distribution coinciding with distinct biological function(s) and metabolic origin. Herein, this chemical ambiguity is addressed through an innovative combination of ozone‐induced dissociation reactions with MSI, enabling the differential imaging of isomeric lipid molecules directly from biological tissues. For the first time, we demonstrate both double bond‐ and sn‐positional isomeric lipids exhibit distinct spatial locations within tissue. This MSI approach enables researchers to unravel local lipid molecular complexity based on both exact elemental composition and isomeric structure directly from tissues.

There are numerous reports demonstrating the heterogeneous spatial distributions of lipids throughout biology using mass spectrometry imaging (MSI). However, despite these and the biological significance of lipid alterations there remains a surprising lack of understanding regarding the underlying origins of the spatial distributions detected with MSI. With the rapid improvements in analytical capabilities of MSI instrumentation, it is now at the point that these biological questions can begin to be addressed. In this review we focus on (i) work providing insight into the biochemical origins of lipid spatial distributions, with an emphasis on the role of localised enzymatic processes in determining lipid compositions; (ii) use of stable isotope labelling to spatially-resolve the kinetics of lipid synthesis; and (iii) current challenges faced by the lipid MSI community and new analytical methods to overcome them. Combined, these topics highlight the added biological information that can be acquired from the MSI of lipids. (c) 2018 Elsevier B.V. All rights reserved.

There are numerous reports demonstrating the heterogeneous spatial distributions of lipids throughout biology using mass spectrometry imaging (MSI). However, despite these and the biological significance of lipid alterations there remains a surprising lack of understanding regarding the underlying origins of the spatial distributions detected with MSI. With the rapid improvements in analytical capabilities of MSI instrumentation, it is now at the point that these biological questions can begin to be addressed. In this review we focus on (i) work providing insight into the biochemical origins of lipid spatial distributions, with an emphasis on the role of localised enzymatic processes in determining lipid compositions; (ii) use of stable isotope labelling to spatially-resolve the kinetics of lipid synthesis; and (iii) current challenges faced by the lipid MSI community and new analytical methods to overcome them. Combined, these topics highlight the added biological information that can be acquired from the MSI of lipids. (c) 2018 Elsevier B.V. All rights reserved.