Epigenetic Programming Through Breast Milk and Its Impact on Milk-Siblings Mating

Hasan Ozkan,Peyda Korhan,Nuray Duman,Funda Tuzun,Yusuf Özkul,Pınar Akokay,Abdullah Kumral,Osman Yılmaz,Erdener Özer,Serpil Taheri,Esra Tufan

doi:10.3389/fgene.2020.569232

Abstract

BackgroundThe epigenetic effects of transmission of certain regulatory molecules, such as miRNAs, through maternal milk on future generations, are still unknown and have not been fully understood yet. We hypothesized that breastfeeding regularly by adoptive-mother may cause transmission of miRNAs as epigenetic regulating factors to the infant, and the marriage of milk-siblings may cause various pathologies in the future generations.ResultsA cross-fostering model using a/a and Avy/a mice had been established. F2 milk-sibling and F2 control groups were obtained from mating of milk-siblings or unrelated mice. Randomized selected animals in the both F2 groups were sacrificed for miRNA expression studies and the remainings were followed for phenotypic changes (coat color, obesity, hyperglycemia, liver pathology, and life span). The lifespan in the F2 milk-sibling group was shorter than the control group (387 vs 590 days, p = 0.011) and they were more obese during the aging period. Histopathological examination of liver tissues revealed abnormal findings in F2 milk-sibling group. In order to understand the epigenetic mechanisms leading to these phenotypic changes, we analyzed miRNA expression differences between offspring of milk-sibling and control matings and focused on the signaling pathways regulating lifespan and metabolism. Bioinformatic analysis demonstrated that differentially expressed miRNAs were associated with pathways regulating metabolism, survival, and cancer development such as the PI3K-Akt, ErbB, mTOR, and MAPK, insulin signaling pathways. We further analyzed the expression patterns of miR-186-5p, miR-141-3p, miR-345-5p, and miR-34c-5p and their candidate target genes Mapk8, Gsk3b, and Ppargc1a in ovarian and liver tissues.ConclusionOur findings support for the first time that the factors modifying the epigenetic mechanisms may be transmitted by breast milk and these epigenetic interactions may be transferred transgenerationally. Results also suggested hereditary epigenetic effects of cross-fostering on future generations and the impact of mother-infant dyad on epigenetic programming.

Highlights

The epigenetic effects of transmission of certain regulatory molecules, such as miRNAs, through maternal milk on future generations, are still unknown and have not been fully understood yet
Human milk provides abundant amounts of miRNA-148a, miR-152, miR-29b, and miR-21, which all target DNA methyl transferases (DNMTs) that potentially affect whole genome DNA methylation patterns leading to genome-wide DNA hypomethylation, and modifies gene expression (Bodo and Melnik, 2017; Melnik and Gerd, 2017)
Based on our data showing that F2 milk-siblings had higher body weight and shorter life expectancy compared to control counterparts (Table 1 and Figure 2), we focused on the signaling pathways regulating lifespan and metabolism (Figures 4– 6)

Summary

Introduction

The epigenetic effects of transmission of certain regulatory molecules, such as miRNAs, through maternal milk on future generations, are still unknown and have not been fully understood yet. We hypothesized that breastfeeding regularly by adoptive-mother may cause transmission of miRNAs as epigenetic regulating factors to the infant, and the marriage of milk-siblings may cause various pathologies in the future generations. Breast milk provides growth factors, immune factors, microbiota, stem cells, and microRNAs (miRNAs) (Kosaka et al, 2010; Hassiotou et al, 2012; Alsaweed et al, 2016; Melnik and Gerd, 2017). Human milk provides abundant amounts of miRNA-148a, miR-152, miR-29b, and miR-21, which all target DNA methyl transferases (DNMTs) that potentially affect whole genome DNA methylation patterns leading to genome-wide DNA hypomethylation, and modifies gene expression (Bodo and Melnik, 2017; Melnik and Gerd, 2017). Continued uptake of milk-derived exosomes that carry DNMTs targeting miRNAs may promote diabesity, allergy, neurodegenerative diseases, and cancer later in life (Melnik and Schmitz, 2017)

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Discussion

Conclusion