Transgenerational Effects of Undernutrition on Children

描述(由申请人提供)：营养不良对儿童的跨代影响在40年的时间里，巴巴多斯营养研究系统地跟踪了巴巴多斯的312人(G1队列)，从出生到成年。一组参与者在出生后的第一年患有蛋白质-能量营养不良，另一组包括来自相同社区和教室的没有营养不良病史的配对对照组。这项研究广泛记录了这些人的发展历程。先前营养不良的人群表现出严重的不良发育后果，即使在控制了多种环境和生态因素后，这种不良后果也会持续到成年。这些人中的大多数人，现在38-43岁，都有孩子(G2代)。动物模型的研究，包括我们自己对老鼠代际营养不良的研究表明，营养不良具有长期影响，即使在父母一代得到营养康复的情况下，这种影响也会持续两到四代，这引发了人们对我们这一群体的后代的担忧。继发于早期营养不良暴露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(目标1，N=200)的认知、行为和健康结果(表型)，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后代及其G1母亲(目标2，N=200)的子组的表观遗传学变化。最后，我们将检查在G1和G2代中任何表观遗传学变化和表型之间的关系(探索性目标3)。关于营养不良对人类代际影响的研究有限，也没有涉及行为结果。因此，我们记录良好的巴巴迪亚主题及其后代的可用性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成人研究中，我们已经确定了188个G2后代可供研究，并估计随着成人研究在明年接近完成，还会增加98个G2。因此，我们有机会确定先前营养不良的成年人的后代是否与对照组的后代不同，更重要的是，我们有机会探索潜在的表观遗传机制，这些机制可能导致长期和跨代的行为和认知结果。这一信息可能有助于阐明旨在防止长期不良后果和未来世代传播的未来干预措施。营养不良影响了全球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，突显了这项研究的潜在公共卫生益处。由于表观遗传学改变可能是可逆的，识别表观遗传学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.