Transgenerational effects of diet in mammals

描述（由申请人提供）：原则上，如果父母在幼崽受孕前告知它们所经历的环境条件，动物将更适合。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，因此可能在代际之间携带环境信息。人类流行病学证据表明，不良的父母饮食可使其后代易患心血管疾病。我们试图验证这样一种假设，即在代际之间传递的表观遗传信息可以为后代提供父辈所经历的环境条件的分子“知识”。因此，为了寻找跨代表观遗传，我们对小鼠中对父亲饮食有反应的基因进行了筛选。我们的初步数据表明，相对于对照组后代，当他们的父亲被喂食低蛋白饮食时，参与脂质生物合成和细胞增殖的基因表达显著增加。在这里，我们建议对哺乳动物基因表达的跨代控制机制进行全面的研究。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，这些实验构成了跨代饮食与表型联系的新途径的广泛表征。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：本建议涉及对哺乳动物基因表达跨代控制可能性的全面调查，使用小鼠模型去除人类群体中存在的混杂效应。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。如果最终证明，饮食的跨代记忆将意味着纵向研究不仅需要解决父母是否经历过某些环境，而且还需要解决与受孕相关的这种经历发生的时间。这将要求对糖尿病、心脏病、酗酒和癌症等复杂疾病的流行病学研究进行戏剧性的反思。因此，我们对一代人的饮食对下一代的影响的联系途径的识别和表征对于理解和最终治疗广泛的人类疾病至关重要。

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.