Oxidized Lipids as Potential Mediators and Markers of Disease in Pregnancy and Development

Abstract

Oxidized lipids derived from omega-3 (n-3) and n-6 polyunsaturated fatty acids (PUFAs)— collectively known as oxylipins—are bioactive mediators that affect functions of multiple organs. There are plausible mechanisms whereby excessive or inadequate exposures to specific oxylipins could adversely affect placenta, predispose to preterm birth and/or impact brain development. Yet there are large gaps in our understanding of the effects of oxylipins in pregnancy. The long-term objective of this research is to determine the impacts of oxylipins on human pregnancy and neurodevelopment. In this research I aimed to: (i) establish proof-of-concept that the largest alteration in dietary PUFAs in modern times (increased linoleic acid (LA) and preformed oxidized LA metabolite (OXLAM) consumption) alters brain biochemistry in a mammalian model; (ii) design and develop an assay for targeted profiling of oxylipins and precursor unesterified fatty acids; (iii) determine effects of delayed processing, typical of human studies, on oxylipin concentrations in plasma; (iv.) profile oxylipins and unesterified precursors in plasma from pregnant Australian participants in the Omega-3 fats to Reduce the Incidence of Prematurity (ORIP) study. ORIP samples were used to investigate: (a) concentrations of specific oxylipins throughout pregnancy, (b) effects of docosahexaenoic acid (DHA) supplementation on oxylipins; and (c) whether oxylipin concentrations measured in first and second trimesters predict risk of preterm birth. In study 1, increasing dietary LA in a mouse model increased n-6 and decreased n-3 fatty acids, and increased OXLAMs in brain. Dietary OXLAMs had no effect on brain oxylipins but decreased brain PUFAs. Thus, brain fatty acids are modulated by both dietary LA and OXLAMs, while brain OXLAMs are regulated by endogenous synthesis from LA, rather than incorporation of preformed OXLAMs. In study 2, I investigated effects of delayed blood processing typical of human studies, on oxylipin concentrations in plasma and established that most oxylipins were reasonably stable when blood is stored on wet ice for up to 2 hours prior to processing. The lone exception was substantial time-dependent increases in 12-lipoxygenase-derived and platelet-derived oxylipins. These findings gave me confidence to proceed with study 3. In study 3, I observed that in the placebo group without DHA supplementation unesterified arachidonic acid (AA) and several AA-derived oxylipins decreased between weeks 14-24 of pregnancy. DHA supplementation increased plasma unesterified DHA and DHA-derived oxylipins in plasma. Participants with higher concentrations of 5-lipoxygenase-derived oxylipins at 14 weeks, or unesterified AA at 24 weeks, had higher risk of preterm birth in exploratory analysis. The hypothesis that 5-lipoxygenase-derived oxylipins and/or unesterified AA could serve as mechanism-based biomarkers for preterm birth should be evaluated in larger, adequately powered studies. Collective findings stimulated and informed design and conduct of animal and human studies investigating the roles of oxylipins in pregnancy and development in humans. Findings suggest the need to move past the traditional measure of esterified fatty acid levels in blood and tissues and to measure the likely mediators of change – unesterified fatty acids their oxylipin derivatives – in humans. Such work could ultimately have important implications for human populations by informing strategies for manipulating oxylipins as in a manner to decrease the risk preterm birth and/or favorably impacting neurodevelopmental trajectory.