Inhalation exposure to TiO2 nanoparticles has been shown to produce a pulmonary inflammatory response and to influence downstream microvascular dysfunction. However, the molecular mechanisms relating pulmonary inflammation with systemic microvascular dysfunction in addition to differential responses of vascular tissues have yet to be fully elucidated. Comprehensive comparative proteomics of aorta and small resistance vasculature tissue as well as plasma reveal differences in protein abundances for control and exposed rat cohorts. Biopathway analysis of the aorta and plasma proteins revealed “acute phase response signaling,” “LXR/RXR activation,” and “FXR/RXR activation” as being significant (p ≤ 0.05). However, “ILK signaling,” “D-myo-inositol (1,3,4)-trisphosphate biosynthesis,” and “1D-myo-inositol hexakisphosphate biosynthesis II (mammalian)” pathways are observed to be significant (p ≤ 0.05) in the vasculature. Comparative metabolomics analyses provided only a limited number of species exhibiting a significant difference in abundance and, when included, did not enhance the biopathway analysis. In part, the problem with the use of metabolites results from challenges associated with their identification. To improve identification capabilities, an analytical approach employing ion mobility spectrometry coupled with gas-phase hydrogen deuterium exchange and mass spectrometry is being developed. Proof-of-principle experiments are presented to demonstrate the ability to generate a highly parameterized database of compounds from which high-confidence assignments can be obtained in comparative metabolomics analyses. The parameters are highly orthogonal and provide distinguishing information about separate physicochemical properties of individual compounds. Several examples of the usage of such a set of parameters for compound identification is provided for real-world metabolite samples. The results are promising for integrative ‘omics analyses directed at deciphering molecular mechanisms responsible for microvascular dysfunction resulting from TiO2 nanoparticle exposure.

Enhancing integrative ‘omics studies of nanoparticle exposure using ion mobility spectrometry-hydrogen deuterium exchange-mass spectrometry techniques

254th National Meeting (2017)

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