Transgenerational Effects of Undernutrition on Children Over a 40 year period, the Barbados Nutrition Study has systematically followed 312 individuals (G1 cohort) in Barbados from birth through adulthood. One group of participants suffered from protein-energy malnutrition during the first year of life and the other group includes matched controls from the same neighborhoods and classrooms who do not have histories of malnutrition. This study has extensively documented the developmental course of these individuals. The previously malnourished group displayed significant adverse developmental consequences that persisted into adulthood even after controlling for multiple environmental and ecological factors. Most of these individuals, now 38-43 years of age, have children (G2 offspring). Studies in animal models, including our own studies of intergenerational malnutrition in rats, indicate that malnutrition has long-term effects that persist for two to four generations even when the parent generation is nutritionally rehabilitated, raising concerns about the offspring of our cohort. Epigenetic changes secondary to the early malnutrition exposure are likely candidates for explaining these long-term transgenerational effects. We now propose to study cognitive, behavioral and health outcomes (phenotype) of these G2 offspring (Aim 1, N=200), allowing us to document transgenerational effects of malnutrition. We will then use state-of-the- art techniques to document epigenetic changes in a subgroup of G2 offspring and their G1 mothers (Aim 2, N=200) with different nutritional histories. Finally, we will examine the relationship between any epigenetic changes and phenotype in both the G1 and G2 generations (Exploratory Aim 3). Research on the intergenerational effects of undernutrition in humans is limited and has not addressed behavioral outcomes. The availability of our well-documented Barbadian subjects and their offspring thus presents an exciting and unique translational opportunity. In our current NIH-funded study of the G1 adults, we have already identified 188 G2 offspring who are available for study and estimate adding 98 more G2s as the adult study nears completion this coming year. Thus, we have the opportunity to determine whether the offspring of the previously malnourished adults differ from those of controls and, importantly, to explore potential epigenetic mechanisms underlying long-term and transgenerational behavioral and cognitive outcomes. This information may elucidate future interventions aimed at preventing long-term adverse outcomes and future generational transmission. Malnutrition impacts 25-30% of children world-wide and 1.3% of US children, and limits the developmental potential of all of these children, underscoring the potential public health benefits of this research. Since epigenetic changes are potentially reversible, identifying an epigenetic mechanism could be of significant clinical relevance. PUBLIC HEALTH RELEVANCE: We will determine whether the offspring of the previously malnourished adults differ from the offspring of controls and, importantly, will explore potential epigenetic mechanisms that may explain continuing adverse effects into the next generation. Malnutrition impacts 25-30% of children world-wide and 1.3% of US children and limits the developmental potential of these children and possibly their children. Because epigenetic changes are potentially reversible, identifying an epigenetic mechanism is of significant clinical relevance, underscoring the potential far-reaching public health benefits of this research.