Progressive, Transgenerational Changes in Offspring Phenotype and Epigenotype following Nutritional Transition

Graham C Burdge,Nicola A Thomas,Mark A Hanson,Tobias Uller,Karen A Lillycrop,Samuel P Hoile,Peter D Gluckman,Axel Imhof

doi:10.1371/journal.pone.0028282

Abstract

Induction of altered phenotypes during development in response to environmental input involves epigenetic changes. Phenotypic traits can be passed between generations by a variety of mechanisms, including direct transmission of epigenetic states or by induction of epigenetic marks de novo in each generation. To distinguish between these possibilities we measured epigenetic marks over four generations in rats exposed to a sustained environmental challenge. Dietary energy was increased by 25% at conception in F0 female rats and maintained at this level to generation F3. F0 dams showed higher pregnancy weight gain, but lower weight gain and food intake during lactation than F1 and F2 dams. On gestational day 8, fasting plasma glucose concentration was higher and β-hydroxybutyrate lower in F0 and F1 dams than F2 dams. This was accompanied by decreased phosphoenolpyruvate carboxykinase (PEPCK) and increased PPARα and carnitine palmitoyl transferase-1 mRNA expression. PEPCK mRNA expression was inversely related to the methylation of specific CpG dinucleotides in its promoter. DNA methyltransferase (Dnmt) 3a2, but not Dnmt1 or Dnmt3b, expression increased and methylation of its promoter decreased from F1 to F3 generations. These data suggest that the regulation of energy metabolism during pregnancy and lactation within a generation is influenced by the maternal phenotype in the preceding generation and the environment during the current pregnancy. The transgenerational effects on phenotype were associated with altered DNA methylation of specific genes in a manner consistent with induction de novo of epigenetic marks in each generation.

Highlights

Organisms respond to changes in their environment in a variety of ways, both adaptive and non-adaptive [1]
In the present study we investigated the effect of a sustained dietary change on the induced phenotype and associated epigenetic marks of female rats over four generations
Plasma glucose concentration was lower (generation F(1856,5.3) 25.6, P,0.0001) and b-hydroxybutyrate (generation F(1934712,164232) 11.8, P,0.0001) concentration was higher in F2 dams than F0 dams during this test suggesting that there was a transition towards greater glucose utilisation and increased glucose sparing by ketogenesis in F2 dams (Figure 3)

Summary

Introduction

Organisms respond to changes in their environment in a variety of ways, both adaptive and non-adaptive [1]. Plastic responses to environmental conditions can enhance fitness These mechanisms have the advantage that they are potentially reversible [2], which may be advantageous if the environmental change is not sustained. In mammals the signals that induce developmental plasticity are often mediated by the parents, mother during fetal and neonatal life [3,4,5,6,7] Such parental effects need not be adaptive, by allowing structural changes to be passed on to future generations they may facilitate the persistence of populations in stressful environments and affect the potential for natural selection [3,6,8,9,10,11]. Parental effects are likely to be important in mammals as the sustained, intimate relationship between mothers and offspring during gestation and suckling facilitates transference of environmentally induced variation between generations [5,7,12]

Methods

Results

Conclusion