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Maternal Dietary Docosahexaenoic Acid Alters Lipid Peroxidation Products and (n-3)/(n-6) Fatty Acid Balance in Offspring Mice.

ABSTRACT: The abundance of docosahexaenoic acid (DHA) in the mammalian brain has generated substantial interest in the search for its roles in regulating brain functions. Our recent study with a gene/stress mouse model provided evidence to support the ability for the maternal supplement of DHA to alleviate autism-associated behavior in the offspring. DHA and arachidonic acid (ARA) are substrates of enzymatic and non-enzymatic reactions, and lipid peroxidation results in the production of 4-hydroxyhexenal (4-HHE) and 4-hydroxynonenal (4-HNE), respectively. In this study, we examine whether a maternal DHA-supplemented diet alters fatty acids (FAs), as well as lipid peroxidation products in the pup brain, heart and plasma by a targeted metabolite approach. Pups in the maternal DHA-supplemented diet group showed an increase in DHA and a concomitant decrease in ARA in all brain regions examined. However, significant increases in 4-HHE, and not 4-HNE, were found mainly in the cerebral cortex and hippocampus. Analysis of heart and plasma showed large increases in DHA and 4-HHE, but a significant decrease in 4-HNE levels only in plasma. Taken together, the DHA-supplemented maternal diet alters the (n-3)/(n-6) FA ratio, and increases 4-HHE levels in pup brain, heart and plasma. These effects may contribute to the beneficial effects of DHA on neurodevelopment, as well as functional changes in other body organs.

SUBMITTER: Yang B

PROVIDER: S-EPMC6468482 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Maternal Dietary Docosahexaenoic Acid Alters Lipid Peroxidation Products and (n-3)/(n-6) Fatty Acid Balance in Offspring Mice.

Yang Bo B Li Runting R Woo Taeseon T Browning Jimmy D JD Song Hailong H Gu Zezong Z Cui Jiankun J Lee James C JC Fritsche Kevin L KL Beversdorf David Q DQ Sun Grace Y GY Greenlief C Michael CM

Metabolites 20190301 3

The abundance of docosahexaenoic acid (DHA) in the mammalian brain has generated substantial interest in the search for its roles in regulating brain functions. Our recent study with a gene/stress mouse model provided evidence to support the ability for the maternal supplement of DHA to alleviate autism-associated behavior in the offspring. DHA and arachidonic acid (ARA) are substrates of enzymatic and non-enzymatic reactions, and lipid peroxidation results in the production of 4-hydroxyhexenal ...[more]

PMID: 30832208

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Project description:Abstract Objectives To assess if maternal fatty acid desaturase (FADS) single nucleotide polymorphism (SNP) rs174602 modifies the effect of prenatal DHA supplementation on the offspring metabolome at age 3 months. Methods Data were obtained from POSGRAD, a double-blind randomized controlled trial in Mexico in which 1094 women received 400 mg/day of algal DHA or a placebo (corn and soy oil) from mid-gestation until delivery. Genotyping was performed using maternal blood samples collected from women at baseline. Using liquid chromatography with high-resolution mass spectrometry, untargeted metabolomics was performed on plasma samples obtained from a random subsample of 112 offspring of POSGRAD participants at 3 months of age. Discriminatory metabolic features were selected via linear regression (P < 0.05); false discovery rate (FDR) was controlled for using the Benjamini-Hochberg method (q = 0.2). Analyses were adjusted for infant sex. Effect modification by FADS SNP rs174602 was assessed using two-way analysis of variance. Pathway enrichment analysis was performed with Mummichog (P < 0.05). Subgroup analyses were performed by rs174602, where the study population was grouped into carriers (TT, TC; n = 70) and non-carriers (CC; n = 42) of the minor allele. Results We identified 279 metabolic features that differed significantly between infants whose mothers received prenatal DHA (n = 59) versus placebo (n = 53); however, zero features remained significant after FDR correction. In the DHA * SNP rs174602 interaction analysis, following FDR correction, 346 differentially expressed features were identified. In the subgroup analysis, positively enriched fatty acid metabolism and decreased amino acid and vitamin B3 metabolism pathways were seen among carriers in the DHA group compared to placebo, whereas differentially enriched TCA cycle and omega-6 fatty acid metabolism pathways were observed by treatment group among non-carriers. Conclusions Maternal SNP rs174602 modified the effect of prenatal DHA supplementation on the infant metabolome at 3 months of age, particularly with regards to fatty acid metabolism. These findings provide additional support for the suggestion that differences in FADS genotype may explain inconsistent results observed across DHA supplementation trials. Funding Sources NIH, Nutricia Foundation, Laney Graduate School, and Conacyt, Mexico.

Project description:Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either 18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Δ6 and Δ5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro-constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Δ6 and Δ5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG -394 bp 5' to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis.

Dataset Information

Maternal Dietary Docosahexaenoic Acid Alters Lipid Peroxidation Products and (n-3)/(n-6) Fatty Acid Balance in Offspring Mice.

Publications

Maternal Dietary Docosahexaenoic Acid Alters Lipid Peroxidation Products and (n-3)/(n-6) Fatty Acid Balance in Offspring Mice.

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