Importance of genetic differences in developmental programming: gene by environment interactions in models of maternal dietary restriction

Human epidemiological studies have clearly established long-term effects on postnatal health of the offspring of mothers who are under-nourished during gestation (McMillen & Robinson, 2005). Studies in animal models using both global caloric restriction and restriction of defined nutrients during specific windows of development in mice, rats and sheep have begun to provide firm experimental evidence of the mechanisms involved (Armitage et al. 2004). Currently there is great interest in the underlying mechanisms whereby maternal nutrient restriction (NR) alters the trajectory of fetal development and produces persistent effects on phenotype that alter life-long health. Elucidation of these mechanisms requires analysis of the type and timing of environmental challenges, as has been done in these various animal models, and analysis of genes that respond to these challenges. Gene by environment interactions in the setting of maternal NR that affect development have been demonstrated even in utero. In different breeds of sheep (Vonnahme et al. 2006), exposure to 50% global maternal NR for a flock of sheep selected for a normal husbandry setting resulted in decreased fetal weight, fetal blood glucose concentrations and placental efficiency half-way through gestation. In contrast a breed selected for survival under very adverse conditions at altitude did not show a decline in these three variables in the presence of the same decrease in maternal nutrition. It is likely that the observed differences between the two breeds of ewes are both genetic and epigenetic, i.e. the sheep may have bred for adaptation to their high altitude and the multigenerational, low calorie environment and additional epigenetic mechanisms may play a role in these adaptations. To answer the question of genetic or epigenetic mechanisms that play a role in gene by environment interactions in offsprings' response to an in utero maternal NR environment, Knight et al. (2007) describe in this issue of The Journal of Physiology a murine model that provides the foundation for studies of gene by environment interactions in developmental programming. The authors conducted a maternal NR study in two strains of laboratory mice: the A/J strain and the C57BL/6J (B6) strain. NR pregnant mice were fed 70% of the feed given to controls between 6.5 and 17 days of gestation. The authors observed strain specific and sex specific differences in offspring of NR mothers. In A/J offspring, maternal NR did not affect the postnatal growth trajectory up to 35 days postnatal age compared with strain and sex matched controls. A/J males from NR mothers maintained a growth trajectory comparable to controls up to 182 days postnatal age; however, A/J females were significantly heavier than controls up to 182 days postnatal age. Both B6 males and B6 females differed from A/J mice; B6 mice weighed significantly less than strain and sex matched controls up to 28 postnatal days but by day 63 B6 mice equalled controls and by day 182 B6 male NR mice were significantly heavier than controls. The strain specific body weight differences were investigated in more detail by measuring body composition, including lean body mass, fat mass, bone mineral density and bone mineral content. As with body weight, body composition was affected by both strain and sex. The authors also measured glucose tolerance and found significant strain and sex effects. A/J offspring and B6 female offspring showed no differences between CON and NR mice, whereas B6 male offspring showed significant increases in glucose intolerance in NR mice compared with controls. Thus, maternal NR has greater effects on B6 offspring than A/J offspring and greater effects on male B6 mice than female B6 mice. These data are consistent with results from studies in adult A/J and B6 strains where mice were fed a high fat diet; B6 mice developed more severe metabolic syndrome symptoms than A/J mice (see Knight et al. 2007). The results from this study are both exciting and provide a cautionary tale. The observations clearly demonstrate strain specific effects of maternal NR on postnatal offspring phenotypes not only because they reinforce the relationship between maternal NR and offspring bone mass, glucose intolerance and obesity, but also because these studies were performed in well characterized strains of mice. Consequently, numerous genetic tools are available to dissect the observed gene by environment interactions. The C57BL/6J strain included in this study was used to construct the mouse genome sequence (Waterston et al. 2002). In addition, whole genome SNP mapping has been performed for the A/J strain and bioinformatics tools for genetic comparison of these two strains are publicly available (Bogue et al. 2007). Thus, in silico comparisons of B6 and A/J strains' genomes will reveal sequence specific differences that underlie different gene by environment responses. These results will inform detailed molecular genetic studies to define the specific roles of the factors that encode the observed phenotypic differences such as DNA sequence, RNA sequence and expression, transcription factors, and epigenetic mechanisms such as DNA methylation and packaging. Further animal studies will throw light on the causes of differential maternal responses to challenges during pregnancy and variety of offspring outcomes for which hitherto no better explanation has been supplied other than ‘normal variation’. It will also be valuable to use various human studies involving specific ethnic populations, of which the San Antonio Family Heart Study of Mexican Americans is an example, where data from multigenerational, genetically defined, pedigreed populations inform gene by environment interactions in developmental programming. These issues are of fundamental importance to an understanding of both human health and individual resistance to diseases both acute and chronic.