Intrauterine hyperglycemia exposure results in intergenerational inheritance via DNA methylation reprogramming on F1 PGCs

Abstract

BackgroundThe existing reports about intergenerational or transgenerational effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, while the impact of intrauterine hyperglycemia per se has not been assessed alone. A number of studies suggest DNA methylation reprogramming of gametes plays a crucial role in the metabolic inheritance, but it is unclear when and how DNA methylation patterns are altered when exposed to intrauterine hyperglycemia. In this study, we selected nondiabetic F1- and F2-gestational diabetes mellitus (GDM) male mice as founders to examine metabolic changes in the next generation and performed methylome sequencing of day 13.5 primordial germ cells (PGCs) from F1-GDM to explore the underlying epigenetic mechanism.ResultsWe found that intrauterine hyperglycemia exposure resulted in obesity, insulin resistance, and/or glucose intolerance in F2 male mice, but no metabolic changes in F3 male mice at 8 weeks. Using reduced representation bisulfite sequencing, we found DNA methylome of day 13.5 PGCs from F1-GDM fetuses revealed differently methylated genes enriched in obesity and diabetes. Methylation validation of the insulin resistance and fat accumulation gene Fyn showed a consistent hypomethylation status in F1 PGCs, F1 fetal testes, sperm from F1/C-GDM mice, and somatic cells from F2-GDM male mice. In contrast, no methylation alteration was observed in F2-GDM male germ cells and F3-GDM somatic cells.ConclusionWe provide evidence that intrauterine hyperglycemia exposure per se contributes to intergenerational metabolic changes in the F2 but not F3 generation. And the aberrant DNA methylation reprogramming occurs as early as day 13.5 in PGCs of the F1 generation. Our findings suggest that intrauterine exposure alone is sufficient to cause the epigenetic inheritance in F2 offspring, and the epigenetic memory carried by DNA methylation pattern could be erased by the second wave of methylation reprogramming in F2 PGCs during fetal development.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0192-2) contains supplementary material, which is available to authorized users.

Intergenerational neurocognitive effects of intrauterine hyperglycemia on male offspring

“…In our previous study, we found that impaired glucose tolerance (IGT) in male offspring was more obvious than females, with parental characteristics and sex-speci c transmission [4]. Our further study showed that the aberrant DNA methylation reprogramming occurs as early as day 13.5 in primordial germ cells (PGCs) of the rst lial generation (F1), suggesting that intrauterine exposure alone is su cient to cause the epigenetic changes in the second lial generation (F2) [5].…”

“…Dysregulation of imprinted genes is a plausible mechanism linking maternal stressors with fetal growth [42]. For mechanism of transmission to F2 offspring, based on our previous research that intrauterine exposure alone is su cient to cause the epigenetic inheritance in F2 offspring [4,5], we mainly investigated the methylation status of F1 sperm, nding 56 genes down-regulated in F2-GDM hippocampus hypermethylated in F1-GDM sperm. Our result con rmed that the epigenetic memory carried by DNA methylation pattern could be reprogrammed in F1 germcell during fetal development in uterus.…”

“…The nal PCR products were sequenced on HiSeq 2500 (Illumina Inc., San Diego, CA, USA). Differentially methylated loci (DML) and differentially methylated regions (DMRs) were analyzed based on a Bayesian approach [23], summarized as follows as our previous study [5]: two groups were modeled according to the Bayesian strati cation model, and the Wald test was applied to each locus to get a p value for each CpG site. For each CpG site, a difference in methylation value between two groups ≥ 5% and a posteriori probability of Wald test ≥ 0.95 was considered to be a DML.…”

Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations during Mammalian Development

“…In utero exposure to a high-fat diet induces paternal obesity and insulin resistance accompanied by changes in sperm micro RNA content and germ cell methylation in two generations of offspring [149]. Intrauterine hyperglycemia exposure contributes to intergenerational metabolic changes in the F2 but not the F3 generation [150].…”

“…Primordial germ cells ICR mice Obesity and insulin resistance [150] Paternal diet restriction significantly changed the DNA methyltransferase, Dnmt1 and the transcript of methyl CpG binding protein 2 (Mecp2) in F1, not in F2 and F3 generations. An increase in the expression of histone modification gene, histone deacetylase 1 (Hdac1) in fetus liver was found in F1 and F2.…”