Abstract
Here we demonstrate that conditional deletion of mouse uterine Trp53 (p53d/d), molecularly linked to mTORC1 activation and causally linked to premature uterine senescence and preterm birth, results in aberrant lipid signatures within the heterogeneous cell types of embryo implantation sites on day 8 of pregnancy. In situ nanospray desorption electrospray ionization mass spectrometry imaging (nano-DESI MSI) was used to characterize the molecular speciation of free fatty acids, monoacylglycerol species, unmodified and oxidized phosphatidylcholine (PC/Ox-PC), and diacylglycerol (DG) species within implantation sites of p53d/d mice and floxed littermates. Implantation sites from p53d/d mice exhibited distinct spatially resolved changes demonstrating accumulation of DG species, depletion of Ox-PC species, and increase in species with more unsaturated acyl chains, including arachidonic and docosahexaenoic acid. Understanding abnormal changes in the abundance and localization of individual lipid species early in the progression to premature birth is an important step toward discovering novel targets for treatments and diagnosis.
Highlights
The tumor suppressor p53 maintains genomic stability by triggering cell cycle arrest, DNA repair or apoptosis in response to cellular stresses such as DNA damage, in addition to broader cellular functions
We showed a decrease of enzymes in the β-oxidation pathway, the process by which fatty acids are metabolized in the mitochondria[7]
The 12-μm thick tissue sections from the central part of the p53d/d and p53f/f implantation sites containing the embryo were collected on day 8 of pregnancy
Summary
The tumor suppressor p53 maintains genomic stability by triggering cell cycle arrest, DNA repair or apoptosis in response to cellular stresses such as DNA damage, in addition to broader cellular functions. To investigate regional lipid alterations of p53d/d implantation sites on day 8 of pregnancy, we used nanospray desorption electrospray ionization mass spectrometry imaging (nano-DESI MSI)[8,9,10]. We have previously used nano-DESI MSI for three-dimensional and MS/MS imaging of lipids and metabolites in mouse embryo implantation sites on day 6 of pregnancy[11,12]. We employed nano-DESI MSI for examining molecular signatures of preterm birth by comparing the localization and abundance of lipids and lipid metabolites in uterine tissue sections of p53f/f and p53d/d mice. The significant alterations in DG and Ox-PC abundances between control and p53 knockout mice indicate that Trp[53] deficiency is associated with a severely altered lipid metabolism at an early stage of pregnancy
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