The double hit of growth restriction: its origins and outcome on this generation and the next.

The study by Gallo et al. (2012) in a recent issue of the Journal of Physiology tested the hypothesis that the physiological challenge of growth restricted pregnancy enhances programming of cardiovascular (CV), renal and metabolic risk, and impacts fetal growth in the next generation. However, the importance of this study is not limited to the transmission of intrauterine growth restriction (IUGR) to the next generation, or the effect of pregnancy and its related physiological impact on adverse adult health risk in female growth restricted offspring. A crucial aspect of this study is that it highlights the complexity of the ‘Developmental Origins of Health and Disease’ and underscores the importance of further investigation into the mechanisms that program the long-term effect of growth restriction on later metabolic health. There is compelling evidence from numerous epidemiological and experimental studies that an increased CV, renal and metabolic risk can be programmed in response to adverse influences during early development (Godfrey et al. 2007). Furthermore, transmission of heritable risk to the next generation is also strongly implicated (Godfrey et al. 2007). Epigenetic processes that induce heritable changes in gene expression without altering the underlying DNA sequence are emerging as a key non-genomic means of developmental programming of chronic disease and are also implicated as a potential mechanism in the passage of heritable risk to the next generation (Godfrey et al. 2007). Thus, transmission of the effects of growth restriction from one generation to the next as observed in the study by Gallo et al. was not totally unexpected. However, the mechanisms involved may be complex and epigenetic processes initiated during the mother's fetal life may be confounded by influences induced by the mother's gestational metabolic health (Fig. 1). Figure 1 A summary highlighting the need for further study of the potential mechanisms that program growth restriction and impaired metabolic health in one generation and the next. Numerous alterations in glucose and insulin metabolism occur during normal pregnancy to meet the needs of the growing fetus (Lind, 1979). Women born with low birth weight are at higher risk for development of gestational diabetes mellitus (GDM) (Innes et al. 2002). This major complication of pregnancy is defined as any degree of glucose intolerance with onset or first recognition during pregnancy and is associated with altered fetal growth including growth restriction (Yogev & Visser, 2009). In the study by Gallo et al., basal insulin secretion and pancreatic β-cell mass were reduced in female growth restricted offspring (Gallo et al. 2012). Pregnancy restored these metabolic disturbances, but elicited impaired glucose tolerance in female growth restricted offspring (Gallo et al. 2012). Thus, growth restriction in the next (F2) generation may be the consequence of transgenerational transmission of environmentally induced epigenetic changes that originated during the fetal life of the mother (F1). However, growth restriction in the next (F2) generation may also be the consequence of direct exposure to the maternal milieu of a diabetic pregnancy (Fig. 1). GDM also imparts a high risk for development of type 2 diabetes in the mother's later life (Yogev & Visser, 2009). Whether permanent alterations in carbohydrate metabolism in female growth restricted offspring persisted after pregnancy, and/or whether ageing exacerbated impaired glucose control in the female growth restricted offspring remains to be elucidated (Fig. 1). Furthermore, the long term effect of growth restriction compounded by GDM on metabolic health in the F2 generation from this study is not yet known (Fig. 1). Appropriate experimental models to examine the potential mechanisms that link GDM and the long-term impact on health and fetal growth of the offspring are limited. Pregnancy in the fetal growth restricted dam provides an ideal experimental model for further in-depth investigation into the potential and multifaceted mechanisms that mediate maternal transmission of growth restriction and metabolic risk to the next generation. In addition, insight from future studies utilizing this model may determine the mechanisms by which metabolic risk in female growth restricted offspring is augmented by an additional physiological challenge such as pregnancy (Fig. 1).