Dietary Protein Restriction during F0 Pregnancy in Rats Induces Transgenerational Changes in the Hepatic Transcriptome in Female Offspring

Samuel P Hoile,Mark A Hanson,Nicola A Thomas,Graham C Burdge,Karen A Lillycrop,Catherine M Suter

doi:10.1371/journal.pone.0021668

Abstract

There is considerable evidence for non-genomic transmission between generations of phenotypes induced by environmental exposures during development, although the mechanism is poorly understood. We investigated whether alterations in expression of the liver transcriptome induced in F1 offspring by feeding F0 dams a protein-restricted (PR) diet during pregnancy were passed with or without further change to two subsequent generations. The number of genes that differed between adult female offspring of F0 protein-restricted (PR) and protein-sufficient (PS) dams was F1 1,684 genes, F2 1,680 and F3 2,062. 63/113 genes that were altered in all three generations showed directionally opposite differences between generations. There was a trend toward increased proportions of up-regulated genes in F3 compared to F1. KEGG analysis showed that only the Adherens Junctions pathway was altered in all three generations. PR offspring showed altered fasting glucose homeostasis and changes in phosphoenolpyruvate carboxykinase promoter methylation and expression in all three generations. These findings show that dietary challenge during F0 pregnancy induced altered gene expression in all three generations, but relatively few genes showed transmission of altered expression between generations. For the majority of altered genes, these changes were not found in all generations, including some genes that were changed in F3 but not F1, or the direction and magnitude of difference between PR and PS differed between generations. Such variation may reflect differences between generations in the signals received by the fetus from the mother as a consequence of changes in the interaction between her phenotype and the environment.

Highlights

Variations in the quality of the early life environment can induce, through epigenetic changes, multiple phenotypes from a single genotype
The daughters of women exposed to nutrient restriction and stress during pregnancy as a result of the Dutch Hunger Winter showed decreased birth weight and an increased risk of insulin resistance, and, in turn, their granddaughters were born with a lower birth weight despite adequate nutrition during their daughter’s pregnancy [8,9]
The administration of dexamethasone to dams in late pregnancy induced an increased expression of the glucocorticoid receptor (GR) and of its target gene phosphoenolpyruvate carboxykinase (PEPCK) in the liver of the F1 and F2 offspring, these effects were lost in F3 offspring [14]

Summary

Introduction

Variations in the quality of the early life environment can induce, through epigenetic changes, multiple phenotypes from a single genotype. Anway et al [18] showed transmission essentially without further change of altered male fertility and changes in promoter methylation of specific genes in testis up to F4 generation offspring of F0 dams exposed to the endocrine disruptor vinclozolin. Such germline effects involved altered expression of DNA methyltransferases [19]. We investigated for specific genes whether any differences in expression between offspring of F0 dams fed a protein-sufficient (PS) or PR diet during pregnancy were associated with altered promoter methylation

Results

Discussion

Materials and Methods