Sex-biased transgenerational transmission of betaine-induced epigenetic modifications in glucocorticoid receptor gene and its down-stream BDNF/ERK pathway in rat hippocampus

Objectives:Glucocorticoid receptor (GR) expressed in hippocampus is critical for the homeostasis of stress responses and susceptible to epigenetic modulation caused by maternal factors. Here we show that maternal methyl nutrition causes sex-biased changes in hippocampal expression of GR exon 1 mRNA variants, associated with promoter DNA methylation, across two offspring generations in rats. Methods:Three-month-old female Sprague-Dawley rats (F0) were fed a diet supplemented with 1% betaine throughout the gestation and lactation. F0 dams and their F1 and F2 offspring of both sexes at weaning were used in the study. Results:A sex-specific transgenerational effect was observed. F2 females, but not males, followed the same pattern of their grand dams showing increased mRNA expression of total GR and its exons 1.4, 1.7, 1.10 and 1.11 variants coincided with promoter DNA hypomethylation in the hippocampus. However, F1 females, but not males, exhibited an opposite pattern, showing decreased expression of GR and its mRNA variants accompanied with promoter hypermethylation. The protein content of phospho-GR and BDNF/ERK in the hippocampus displayed the same sex and generation specificity. Discussion:These results indicate that maternal betaine exerts transgenerational effects on hippocampal GR expression and BDNF/ERK pathway in female rat offspring, with generation-dependent patterns of DNA methylation on alternative GR promoters.

Automated summary

The study demonstrates that maternal betaine has transgenerational effects on hippocampal GR expression and BDNF/ERK pathway in female rat offspring, with generation-dependent patterns of DNA methylation on alternative GR promoters.