Intrauterine undernutrition alters patterns of DNA methylation in the next generation offspring through the male line

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Martinez, D. | Pentinat, Thais | Davidaud, C. | Ribo, S. | Cebria, J. | Diaz, R. | Tost, Jörg | Jimenez-Chillaron, J.C

Edité par CCSD ; Springer Verlag -

International audience. Background and aims: Human and experimental data show that malnutrition during early development may increase diabetes risk into the second generation offspring. These transgenerational effects might be mediated by epigenetic mechanisms. We have previously reported a mouse model of intrauterine growth restriction (IUGR) by reducing to 50% global caloric availability to pregnant females. IUGR mice developed metabolic syndrome with ageing. Strikingly, the diabetic phenotypes progressed to the next generation offspring (IUGR-F2) through the paternal lineage, despite IUGR-F2 mice had not been exposed to nutritional stress during their development. Here we aim to test: a) whether in utero malnutrition influences the epigenome in the next generation offspring and b) whether such transgenerational effects are mediated by epigenetic modifications inherited through the gametes (sperm).Materials and methods: Here we analyzed global DNA methylation patterns in liver samples from control and IUGR-F2 mice (385K, Roche-NimbleGene). Next, we validated positive loci identified in the array by PyroSequencing (liver and sperm).Results: In utero undernutrition altered the methylation of 1,207 regions in livers from IUGR-F2 mice. Bioinformatics analysis showed enrichment in loci belonging to the Wnt (P= 0.01) and Hedgehog signaling pathways (P=0.04). Remarkably, no statistic enrichment in loci belonging to metabolic pathways was observed. Next, we confirmed a set of positive candidate genesfrom the array (Wnt2b, Wnt7a, Wnt9a, Sfrp1 and Gsk3b) by Pyrosequencing. These epigenetic modifications might be inherited from their progenitors (IUGR-F1) through the germ line or develop as a consequence of progressive metabolic dysfunction. To address this, we analyzed DNA methylation of the candidate loci in sperm samples from IUGR-F1 mice. Strikingly, the epigenetic signatures for Wnt2b and Wnt7a were already present in sperm samples from IUGR-F1 male mice, thus suggesting that early nutritional stress maycause transgenerational epigenetic inheritance of epigenetic marks.Conclusion: Early malnutrition may induce epigenetic modifications in cells from the germ line. Next, these alterations remain stable during gametogenesis and can be inherited into the following generation offspring thus influencing disease risk.Supported by: EFSD/ Novo Nordisk., MINECO

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