Predictors of oxylipins in a healthy pediatric population

Abstract

Background: Oxylipins are formed from oxidation of omega-6 (n6) and omega-3 (n3) fatty acids (FAs). Evidence for inflammatory effects comes mostly from adults.

Methods: Oxylipins from n6 FA (27 n6-oxylipins) and n3 FA (12 n3-oxylipins) were measured through ultra-high-performance liquid chromatography-mass spectrometry (LC-MS/MS) in plasma from 111 children at risk of type 1 diabetes (age 1-17 years) studied longitudinally. Oxylipin precursor FAs (arachidonic acid, linoleic acid, alpha-linolenic acid, docosahexaenoic acid, eicosapentaenoic acid) were measured in red blood cell (RBC) membrane and plasma. Precursor FAs dietary intake was measured through food frequency questionnaire and environmental tobacco smoke (ETS) through questionnaires. Linear mixed models were used to test oxylipins with predictors.

Results: Age associated with 15 n6- and 6 n3-oxylipins; race/ethnicity associated with 3 n6- and 1 n3-oxylipins; sex associated with 2 n6-oxylipins. ETS associated with lipoxin-A4. Oxylipins associated with precursor FAs in plasma more often than RBC. RBC levels and dietary intake of precursor FAs more consistently associated with n3-oxylipins than with n6-oxylipins.

Conclusions: In healthy children, oxylipin levels change with age. Oxylipins associated with precursor FAs more often in plasma than RBC or diet, suggesting that inflammatory regulation leading to FA release into plasma may also be a determinant of oxylipin generation.

Impact: This is the first study to examine predictors of oxylipins in healthy children at risk of type 1 diabetes. In healthy children at risk of type 1 diabetes, many oxylipins change with age, and most oxylipins do not differ by sex or race/ethnicity. Environmental tobacco smoke exposure was associated with the presence of lipoxin A4. Omega-6- and omega-3-related oxylipin levels were consistently associated with their respective precursor fatty acid levels measured in the plasma. Proportionally more omega-3 compared to omega-6 oxylipins were associated with dietary intake and red blood cell membrane levels of the respective precursor fatty acid.

Figure 1:

Relationships between precursor fatty acids and oxylipins. Boxes represent oxylipins and ovals represent precursor FA. Shaded boxes represent metabolites that were measured by this study, and unshaded boxes represent unmeasured metabolites. Biosynthetic enzymes for the formation of oxylipins (CYP450 sEH, 12/15-LOX, 5-LOX, 15-LOX, COX) are indicated above the oxylipin formed by the enzyme. Full names of oxylipins are presented in supplementary table 1.

Figure 2:

Changes in oxylipin values by age in DAISY children without islet autoimmunity or T1D (age range 1–17 years). Oxylipin values were box-cox transformed and standardized. Each open circle represents a visit rather than an individual. Solid lines represent slope of oxylipin change over age, with estimates derived from the model presented in table 2. 95% confidence limit of the estimated slope is shown by the shaded area. Of the 22 oxylipins significantly associated with age, we present three examples to demonstrate a quadratic relationship (A), and oxylipins that decrease (B) and increase (C) with age. A: 12(13)-EpOME (Precursor FA: LA). B: 19,20-DiHDPE (Precursor FA: DHA). C: 14-HDoHE (Precursor FA: DHA).

Figure 2:

Changes in oxylipin values by age in DAISY children without islet autoimmunity or T1D (age range 1–17 years). Oxylipin values were box-cox transformed and standardized. Each open circle represents a visit rather than an individual. Solid lines represent slope of oxylipin change over age, with estimates derived from the model presented in table 2. 95% confidence limit of the estimated slope is shown by the shaded area. Of the 22 oxylipins significantly associated with age, we present three examples to demonstrate a quadratic relationship (A), and oxylipins that decrease (B) and increase (C) with age. A: 12(13)-EpOME (Precursor FA: LA). B: 19,20-DiHDPE (Precursor FA: DHA). C: 14-HDoHE (Precursor FA: DHA).

Figure 2:

Changes in oxylipin values by age in DAISY children without islet autoimmunity or T1D (age range 1–17 years). Oxylipin values were box-cox transformed and standardized. Each open circle represents a visit rather than an individual. Solid lines represent slope of oxylipin change over age, with estimates derived from the model presented in table 2. 95% confidence limit of the estimated slope is shown by the shaded area. Of the 22 oxylipins significantly associated with age, we present three examples to demonstrate a quadratic relationship (A), and oxylipins that decrease (B) and increase (C) with age. A: 12(13)-EpOME (Precursor FA: LA). B: 19,20-DiHDPE (Precursor FA: DHA). C: 14-HDoHE (Precursor FA: DHA).

Figure 3:

Differences in 9,12,13-TriHOME (precursor FA: LA) between NHW and other ethnicities. 9,12,13-TriHOME was higher in NHW children compared to those with other race/ethnicity (p-value 0.0221). Oxylipin values were box-cox transformed and standardized.

Figure 4:

Differences in 8,9-DiHETrE values (precursor FA: ARA) between those exposed and not exposed to ETS. 8,9-DiHETrE was higher in those not exposed to ETS (p-value 0.0006). Oxylipin values were box-cox transformed and standardized.