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应激所编程的。已经在豚鼠身上进行了研究，因为这种物种会生下成熟的幼崽，这与较大的哺乳动物相似。然而，到目前为止，主要关注的是母亲的压力，对父亲的关注很少。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着后代的行为、神经内分泌和新陈代谢功能。在最近对小鼠的初步研究中，我们发现，在交配前，父亲的糖皮质激素暴露(模拟应激)会改变精子中的DNA甲基化和后代海马区的基因表达，为父亲的表观遗传传递提供了证据。*目标：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播。这项建议将确定怀孕前父亲的压力如何改变男性和女性后代的压力反应和行为。我们将确定相关的机制，并确定父性压力的影响是否会跨越多代人。*假设：1)怀孕前父亲的压力会导致HPA功能失调和应激相关行为的程序化。2)这些表型与边缘系统、下丘脑和垂体中DNA甲基化、染色质结构和miRNA水平的基因调控有关。3)父性应激后的跨代程序是通过精子的表观遗传修饰来调节的，精子在多个世代之间传递。*研究方法：将使用活体实验以及内分泌、行为和分子分析方法的组合来检验这些假说。我们对父亲应激暴露相关的DNA甲基化和基因转录变化的评估将极大地促进在我目前的NSERC资助期间在豚鼠身上开发的技术。*影响：父亲的逆境可能导致应激反应和应激相关行为，这一事实对野生动物种群和动物生产产生了重大影响，特别是因为雄性与多只雌性繁殖了许多后代，而且体外受精在动物育种中的广泛使用。这项研究将极大地促进我们对相关机制的理解，以及这些影响在一个物种中的跨代性质，这个物种的神经发育特征与较大的哺乳动物相似。这一新知识将为制定干预措施提供机会，以防止与逆境有关的结果在几代人之间向前传播。**

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. **