Transgenerational effects of diet in mammals

描述（由申请人提供）：原则上，如果父母在怀孕前告诉后代他们所经历的环境条件，动物会更适合。虽然DNA序列的遗传在很大程度上不受环境的影响，但一些表观遗传信息可以通过哺乳动物生殖系遗传，因此可能在两代之间携带环境信息。人类的流行病学证据表明，父母的不良饮食会使他们的后代容易患心血管疾病。我们试图检验这样一个假设，即在两代人之间传递的表观遗传信息可以为后代提供关于其父母所经历的环境条件的分子“知识”。为了寻找跨代的表观遗传，我们因此在小鼠中进行了对父亲饮食有反应的基因的筛选。我们的初步数据表明，当父亲喂食低蛋白饮食时，相对于一组对照后代，参与脂质生物合成和细胞增殖的基因表达急剧增加。在这里，我们建议进行全面的调查机制的基因表达的跨代控制在哺乳动物。我们将进一步探索饮食影响后代表型的能力，并确定跨代信息是否由精子、精液或其他信息载体携带。总之，这些实验构成了一个新的途径连接饮食表型跨代的广泛表征。这些结果将对人类心血管疾病、癌症以及更广泛的复杂疾病的流行病学产生重要影响。公共卫生相关性：该提案涉及对哺乳动物基因表达跨代控制的可能性进行全面调查，使用小鼠模型消除人类群体中存在的混淆效应。文献中有一些证据表明，饮食变化确实会影响人类后代的疾病风险。如果得到结论性的证明，饮食的代际记忆将意味着纵向研究不仅需要解决父母是否经历过某种环境，而且还需要解决这种经历相对于受孕发生的时间。这就需要对糖尿病、心脏病、酗酒和癌症等复杂疾病的流行病学研究进行深刻的反思。因此，我们对将一代人的饮食与对下一代的影响联系起来的途径的识别和表征对于理解和最终治疗各种人类疾病至关重要。

DESCRIPTION (provided by applicant): In principle, animals would be more fit if parents informed their offspring of the environmental conditions they experienced before the conception of their young. Although inheritance of DNA sequence is largely unaffected by the environment, some epigenetic information can be inherited through the mammalian germ line and may therefore carry environmental information between generations. Epidemiological evidence in humans suggests that poor parental diets can predispose their offspring to cardiovascular disease. We sought to test the hypothesis that epigenetic information transferred between generations can provide offspring with molecular "knowledge" of the environmental conditions experienced by their parents. To search for transgenerational epigenetic inheritance, we therefore carried out a screen for genes in mice that respond to paternal diet. Our preliminary data demonstrate that the expression of genes involved in lipid biosynthesis and cell proliferation increased dramatically, relative to a cohort of control offspring, when their fathers were fed a low-protein diet. Here, we propose to pursue a comprehensive investigation of the mechanisms of transgenerational control of gene expression in mammals. We will further explore the ability of diet to affect offspring's phenotype, and we will determine whether transgenerational information is carried by sperm, seminal fluid, or some other information carrier. Together, these experiments constitute an extensive characterization of a novel pathway linking diet to phenotype across generations. These results will have important implications for human cardiovascular disease, cancer, and more broadly for the epidemiology of complex diseases. PUBLIC HEALTH RELEVANCE: This proposal concerns a comprehensive investigation of the possibility of transgenerational control of gene expression in mammals, using a mouse model to remove confounding effects present in human populations. There is some evidence in the literature that dietary variation can indeed affect disease risk in subsequent generations in humans. If demonstrated conclusively, transgenerational memory of diet would imply that longitudinal studies need to address not only whether parents experienced some environment, but also when this experience occurred relative to conception. This would call for a dramatic rethinking of epidemiological studies in complex diseases such as diabetes, heart disease, alcoholism, and cancer. Thus, our identification and characterization of pathways linking diet in one generation to effects on the next generation is of key importance for understanding and eventually treating a wide range of human diseases.