Paternal Stress Programs Endocrine Function and Behaviour in Offspring

背景：我的nserc资助的研究已经确定，后代的下丘脑-垂体-肾上腺（HPA）功能和行为是由母亲在怀孕期间的急性和慢性心理压力决定的。在豚鼠身上进行了研究，因为这种物种会产下成熟的幼崽，这与大型哺乳动物相似。然而，到目前为止，主要关注的是母亲的压力，很少关注父亲。强有力的证据表明，父亲的压力在整个生命过程中深刻地影响后代的行为、神经内分泌和代谢功能。在最近的一项小鼠初步研究中，我们发现，在交配前，父亲的糖皮质激素暴露（模拟应激）改变了精子中的DNA甲基化和后代的海马基因表达，为父亲的表观遗传传递提供了证据。***目的：我的研究计划的长期愿景是确定压力如何影响后代的生理，以及如何防止这种传递。该建议将确定受孕前的父亲压力如何改变雄性和雌性后代的压力反应和行为。我们将确定所涉及的机制，并确定父亲压力的影响是否会延伸到多代。假设：1)怀孕前的父亲压力导致HPA功能失调和压力相关行为的编程。2)这些表型与边缘系统、下丘脑和垂体的DNA甲基化、染色质结构和miRNA水平上的基因调控修饰有关。3)父亲压力后的跨代编程是通过精子的表观遗传修饰介导的，这种修饰在多代之间传播。***研究方法：这些假设将通过体内实验和结合内分泌、行为和分子分析方法进行验证。我们对与父亲压力暴露相关的DNA甲基化和基因转录变化的评估将极大地促进我目前在NSERC资助期间在豚鼠身上开发的技术。***影响：事实上，父亲逆境可以编程应激反应和应激相关行为，对野生动物种群和动物生产产生重大影响，特别是因为雄性从多个雌性繁殖许多后代，并且因为试管婴儿在动物育种中的广泛使用。这项研究将极大地促进我们对所涉及的机制以及这些影响在物种中的跨代性质的理解，这些物种具有与大型哺乳动物相似的神经发育概况。这一新的知识将为干预措施的发展提供机会，以防止与逆境相关的结果在几代人之间向前传递。**

BACKGROUND: My NSERC-funded studies have established that hypothalamo-pituitary-adrenal (HPA) function and behaviours in offspring are programmed' by maternal acute and chronic psychological stress during pregnancy. Studies have been undertaken in the guinea pig, as this species gives birth to mature young, and this is similar to larger mammals. However, to date, major focus has been placed on maternal stress, with little focus on fathers. Strong evidence is emerging that paternal stress profoundly influences behavioural, neuroendocrine and metabolic function in offspring across the life-course. In a recent preliminary study in mice, we showed that paternal glucocorticoid exposure (simulating stress), prior to mating, modifies DNA methylation in sperm and hippocampal gene expression in offspring, providing evidence for paternal epigenetic transmission. ***OBJECTIVES: The long-term vision of my research program is to define how stress influences the physiology of subsequent generations, and how such transmission can be prevented. This proposal will establish how paternal stress prior to conception modifies stress-responsiveness and behaviours in both male and female offspring. We will determine the mechanisms involved and establish whether the effects of paternal stress extend across multiple generations. ***HYPOTHESES: 1) Paternal stress prior to conception results in programming of dysregulated HPA function and stress-related behaviours. 2) These phenotypes are associated with modified gene regulation at the level of DNA methylation, chromatin structure and miRNA in the limbic system, hypothalamus and pituitary. 3) Transgenerational programming after paternal stress is mediated through epigenetic modification in sperm that is transmitted across multiple generations. ***RESEARCH APPROACH: These hypotheses will be tested using in vivo experimentation and combinations of endocrine, behavioural and molecular analytical approaches. Our assessment of DNA methylation and gene transcription changes associated with paternal stress exposure will be greatly facilitated by techniques developed in the guinea pig during my current NSERC grant. ***IMPACT: The fact that paternal adversity can program stress responsiveness and stress-related behaviour has major ramifications for wild animal populations and in animal production, particularly since males sire many offspring from multiple females, and because of the widespread use of IVF in animal breeding. This study will greatly advance our understanding of the mechanisms involved and the transgenerational nature of these effects in a species, which has a similar neurodevelopmental profile to larger mammals. This new knowledge will provide opportunity for the development of interventions to prevent the forward transmission of adversity-related outcomes across generations. **