Effect of in utero exposure to Lipotropic (One-Carbon) nutrients on mammary developmental genomic signals in rat offspring

Abstract Text:

Lipotropes are methyl group-containing essential nutrients (including methionine, choline, folic acid, and vitamin B₁₂) that play key roles in one-carbon metabolism. One-carbon metabolism provides methyl groups for biological methylation pathways, including DNA methylation which regulates the expression of genes. The objective of this study was to investigate the effect of maternal dietary lipotropes fortification on global DNA methylation and mRNA expression of genes involved in mammary gland development in female rat offspring. Pregnant Sprague-Dawley rats were divided into two groups and fed the control diet or lipotropes supplemented diet until parturition, at which point, all rats were fed the control diet until weaning. The control diet was AIN-93G rodent diet, while the lipotropes supplemented diet was designed to provide approximately 5 times the level of choline, folic acid, and vitamin B₁₂, whereas methionine was only 1.8 times greater than that of the control diet to avoid methionine toxicity. At weaning, female offspring were randomly selected from each group and kept on the control diet until they were bred for collection of the mammary tissues at weaning. Tissues were analyzed for global DNA methylation and gene expression by a colorimetric assay and RT-PCR, respectively. Intrauterine exposure to dietary methyl nutrients significantly enhanced global DNA methylation in mammary tissues of offspring as compared with the control diet (4.6% vs. 3.9%; P=0.04). In addition, lipotropic diet significantly increased transcription of DNA methyltransferase 1 (DNMT1) [P=0.02], while also significantly decreasing the expression of methyl CpG binding protein 2 (MECP2) [P=0.05] in mammary tissues. While DNMT1 is responsible for maintenance and propagation of DNA methylation status, MECP2 plays a role in DNA methylation-directed repression of gene transcription. Taken together, data suggests that dietary lipotropes influences mammary development via alteration of DNA methylation and the expression of genes involved in chromatin structure remodeling.  The extent to which these maternal one-carbon nutrients-induced genomic changes affect lactation performance needs to be investigated.

Keywords:

One-carbon nutrients, mammary development, global DNA methylation