Intergenerational neurocognitive effects of intrauterine hyperglycemia on male offspring

Abstract Background Studies on human and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, researches have focused on the neurodevelopment consequences of the first filial (F1) offspring. We hypothesize that the intrauterine hyperglycemia exposure will alter epigenetic reprogramming in F1 sperm, and carry risks of passing on molecular defects to the second filial (F2). Results We found that intrauterine hyperglycemia exposure resulted in memory impairment in both F1 and F2 males from the F1-GDM male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes were enriched in learning, memory, cognition, neurotransmission, synaptic plasticity, and postsynaptic specialization. Again, enrichment curves computed by Gene set enrichment analysis (GSEA) of F1 hippocampi were highly consistent with F2. Interestingly, combined analysis of F1 sperm methylome and gene expression of F2 hippocampi screened out several hypermethylation-low expression genes which are associated with abnormal central nervous system development (particularly synapse development and homeostasis), such as Camk2b, Dlgap1, Wnt5a, Tubb2b and so on. Conclusions These findings implicate that the male germ line is a major player in transgenerational phenotypic transmission. Taken together, our results for the first time suggest that intrauterine hyperglycemia leads to transgenerational cognitive impairment, and, sperm methylome is a potential epigenetic mechanism for the effects of GDM.