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Prenatal Glucocorticoid Exposure Results in Changes in Gene Transcription and DNA Methylation in the Female Juvenile Guinea Pig Hippocampus Across Three Generations.

ABSTRACT: Synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery, to mature the fetal lung and decrease neonatal morbidity. sGC also profoundly affect the fetal brain. The hippocampus expresses high levels of glucocorticoid (GR) and mineralocorticoid receptor (MR), and its development is affected by elevated fetal glucocorticoid levels. Antenatal sGC results in neuroendocrine and behavioral changes that persist in three generations of female guinea pig offspring of the paternal lineage. We hypothesized that antenatal sGC results in transgenerational changes in gene expression that correlate with changes in DNA methylation. We used RNASeq and capture probe bisulfite sequencing to investigate the transcriptomic and epigenomic effects of antenatal sGC exposure in the hippocampus of three generations of juvenile female offspring from the paternal lineage. Antenatal sGC exposure (F₀ pregnancy) resulted in generation-specific changes in hippocampal gene transcription and DNA methylation. Significant changes in individual CpG methylation occurred in RNApol II binding regions of small non-coding RNA (snRNA) genes, which implicates alternative splicing as a mechanism involved in transgenerational transmission of the effects of antenatal sGC. This study provides novel perspectives on the mechanisms involved in transgenerational transmission and highlights the importance of human studies to determine the longer-term effects of antenatal sGC on hippocampal-related function.

SUBMITTER: Constantinof A

PROVIDER: S-EPMC6890750 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The nutritional factors acting during early life can affect the development of the organism. It has been hypothesized that such programmed traits can be inherited by later generations. In this work, we present for the first time the effect of food deprivation in pregnant dams and its consequences for the transcription and DNA methylation profiles in the offspring of the next three generations. We used a 50% reduction in dietary intake during pregnancy in the rat and determined whether this altered the hepatic DNA methylation and transcription levels in female fetuses over three generations. Targeted next-generation sequencing (tNGS) was used in the first generation for 1748 genes associated with six selected biological processes. The selected cytosines were then studied by pyrosequencing in F1-F3. The transcript level of the selected genes was determined by the real-time PCR. The tNGS approach indicated 394 cytosines, in close proximity to 374 genes, with a statistically significant difference in methylation levels between the control and restricted groups. A gene clustering analysis revealed 23 molecular pathways to which the studied genes were assigned. Only seven cytosines were differently methylated to more than 10%, and so these sites were studied next using pyrosequencing. The observation from NGS was confirmed for only one cytosine located near the St6galnac5 gene, though this was with the opposite effect. A difference was also observed for the Usp30 gene, though in proximity to the cytosine selected from NGS. In F3, the differences were observed for the Oxct2b gene. We also found differences in methylation levels between generations for the Grb10 and St6galnac5 genes, but independently of the diet used. The transcript levels of selected genes (Usp30, Grb10, Pld1, St6galnac5, Oxct2b, Khk, and Acsl4) were not altered in F1, while changes were detected for Pld1 and Oxct2b in F2 and F3, respectively. Prenatal food deprivation did not induce broad changes in hepatic DNA methylation of the genes involved in lipid or carbohydrate metabolism, and did not result in alterations in their transcription. Thus, the hypothesis that transgenerational inheritance is induced by dietary restriction was not confirmed.

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Prenatal Glucocorticoid Exposure Results in Changes in Gene Transcription and DNA Methylation in the Female Juvenile Guinea Pig Hippocampus Across Three Generations.

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