Transgenerational Effects of Undernutrition on Children

在40多年的时间里，巴巴多斯营养研究系统地跟踪了312名巴巴多斯人（G1队列）从出生到成年。一组参与者在出生的第一年就患有蛋白质-能量营养不良，另一组则是来自相同社区和教室的没有营养不良史的对照组。这项研究广泛地记录了这些个体的发育过程。即使在控制了多种环境和生态因素后，先前营养不良的组仍表现出严重的不良发育后果，并持续到成年期。这些人中的大多数，现在38-43岁，有孩子（G2后代）。动物模型研究，包括我们自己对大鼠代际营养不良的研究，表明营养不良具有长期影响，即使父母一代营养恢复，也会持续两到四代，这引起了对我们队列后代的关注。继发于早期营养不良的表观遗传变化可能是解释这些长期跨代影响的候选因素。我们现在建议研究这些G2后代的认知、行为和健康结果（表型）（Aim 1， N=200），使我们能够记录营养不良的跨代影响。然后，我们将使用最先进的技术来记录具有不同营养史的G2后代亚组及其G1母亲（Aim 2， N=200）的表观遗传变化。最后，我们将研究G1代和G2代中任何表观遗传变化与表型之间的关系（探索性目标3）。关于人类营养不良的代际影响的研究是有限的，并且没有解决行为结果。因此，我们的巴巴多斯主题和他们的后代提供了一个令人兴奋和独特的翻译机会。在我们目前由美国国立卫生研究院资助的G1成年研究中，我们已经确定了188个G2后代可供研究，并估计随着明年成年研究接近完成，还会增加98个G2后代。因此，我们有机会确定以前营养不良的成年人的后代是否与对照组不同，重要的是，探索长期和跨代行为和认知结果背后的潜在表观遗传机制。这一信息可能阐明未来旨在预防长期不良后果和未来世代传播的干预措施。营养不良影响着全世界25-30%的儿童和1.3%的美国儿童，并限制了所有这些儿童的发展潜力，强调了本研究的潜在公共卫生益处。由于表观遗传变化可能是可逆的，因此确定表观遗传机制可能具有重要的临床意义。

DESCRIPTION (provided by applicant): 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.