Hyponutrition during pregnancy after insemination alters the progenies’ behavior and DNA methylation of their brain

Recent epidemiological studies suggest that hyponutritional stress during fetal period increase risks of adult-onset diseases, such as type 2 diabetes and mental diseases. Rodent models have demonstrated that hyponutrition during pregnancy alters epigenetic status of neuronal genes in the fetal brains; this implicate fatal environment contributes to susceptibility to mental disorders. However, in these studies, progenies were generated with natural mating and effects of hyponutrition during egg formation have not been eliminated. Therefore, we conducted experiments in order to finely evaluate the hyponutritional effects during fatal life using in vitro fertilization. We divided three experimental groups such as control diet (CD (AIN93G)), protein-restricted diet (PR), and PR diet with supplemental folic acid (FA) and compared body weight of mother and progenies, clinical-blood biochemistry, DNA methylation and gene-expression pattern in adult brain of the progenies, behavioral phenotypes of the progenies, and DNA methylation profile in brain of the progenies. The progenies of the PR group and the FA group exhibited increased activity in the home cage, decreased contact to a novel object, and decreased social behavior compared with the CD group. Increased home-cage activity in the PR group was rescued in the FA group. The progenies of the PR group and the FA group showed different patterns of mRNA expression and genomic methylation in the brain compared with the CD group. These results suggest that hyponutrition after insemination sufficiently induced phenotypic and epigenetic changes in the progenies. In addition, supplemental nutrition to mothers should rescue the epigenetic and phenotypic changes induced with hyponutrition. For methylation study, there were in total 22 samples: 11 Input files (3 controls diet (CD) sammples, 4 protein-restricted diet (PR) samples, 4 PR diet with supplemental folic acid (FA) samples). In addition, gene expression profiles were analyzed to identify the effects of prenatal maternal diet and to the next generation. Four male mice of three experimental conditions (CD, PR and FA) were analyzed.