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

Abstract

Background 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. Results A cross-fostering model using a/a and A vy /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. Conclusion Our 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.

Got Milk? Maternal immune activation during the mid-lactational period affects nutritional milk quality and adolescent offspring sensory processing in male and female rats

“…A total of 829 genes were differently expressed on P10 between saline and MIA milk samples ( Figure 3A ). We analyzed clusters of gene networks that are involved in maternal milk nutrition, immune activation, and offspring brain development (Quintana et al, 2019; Oakley & Cidlowski, 2013; Polman et al, 2012; Zhu et al, 2016; Ozkan et al, 2020; Zhang et al, 2013; Bowen et al, 2013; Borish & Steinke, 2003; Figure 3B). Heatmap clustering revealed a general upregulation of genes related to nutrient transport and inflammation, while genes related to epigenetic modifications, parvalbumin interneuron development, and glucocorticoid signaling were largely downregulated by MIA on P10 ( Figure 3B ).…”

Milking it for all it’s worth: The effects of environmental enrichment on maternal nurturance, lactation quality, and offspring social behavior

“…RNA-seq revealed several differently expressed genes involved with milk triglyceride and nutrient transport downregulated by EE, including Ghr (p = .024, FC = −0.671), Igf1 (p = 0.03, FC = −0.671), Slc27a4 (p= 0.032, FC = −0.447), Gpat4 (p<.001, FC = −0.613), and Cs1s2b (p = 0.009, FC = −0.838; Velmala et al, 1995; Figure 3B, C ). We broadened the scope of our analyses further to include gene pathways related to oxytocin (Quintana et al, 2019), glucocorticoid receptor (GR) signaling (e.g., events that occur when glucocorticoids bind to the GR receptor; (Oakley & Cidlowski, 2013), GR binding (e.g., genes which bind the glucocorticoid receptor; Polman et al, 2012), and epigenetic modifiers (Zhu et al, 2016; Figure 3D, E, F, G ) given their crucial implication in milk production and offspring development (Ozkan et al, 2020; Zhang et al, 2013). Heatmap clustering showed that EE rats displayed a major downregulation of genes encoding for triglycerides and nutrient transport (Figure 3B, C) , while genes related to oxytocin and GR (Figure 3D, E) signaling were mostly upregulated compared to SD rats.…”

Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

“…Accumulating evidence supports the concept that milk functions as an epigenetic modifier suppressing the activity of DNA methyltransferase 1 (DNMT1) [ 107 , 108 , 109 , 110 , 111 , 112 ]. Fresh and pasteurized cow’s milk transfers bioactive milk exosomes (MEX) (50–100 nm in diameter) to the milk recipient [ 113 , 114 , 115 , 116 , 117 ].…”