Paternal Stress Programs Endocrine Function and Behaviour in Offspring

背景技术背景：我的NSERC资助的研究已经确定，下丘脑-垂体-肾上腺（HPA）功能和行为的后代是'编程'的母亲在怀孕期间的急性和慢性心理压力。在豚鼠中进行了研究，因为该物种生育成熟的幼仔，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。有力的证据表明，父亲的压力深刻地影响行为，神经内分泌和代谢功能的后代在整个生命过程中。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（模拟压力）会改变后代精子中的DNA甲基化和海马基因表达，为父亲的表观遗传传递提供证据。* 酒店：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。这项建议将建立父亲的压力如何在怀孕前修改压力反应和行为的男性和女性后代。我们将确定所涉及的机制，并确定父亲压力的影响是否会跨越多代人。* 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、下丘脑和垂体中DNA甲基化、染色质结构和miRNA水平上的基因调控相关。3)父亲压力后的跨代编程是通过精子中的表观遗传修饰介导的，该修饰在多代人之间传递。* 研究方法：这些假设将使用体内实验和内分泌，行为和分子分析方法的组合进行测试。我们的DNA甲基化和基因转录的变化与父亲的压力暴露的评估将大大促进技术开发的豚鼠在我目前的NSERC赠款。* 影响：事实上，父亲的逆境可以编程压力反应和压力相关的行为对野生动物种群和动物生产有重大影响，特别是因为雄性从多个雌性中产生了许多后代，并且因为IVF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一个物种中的跨代性质的理解，该物种与大型哺乳动物具有相似的神经发育特征。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代际之间的向前传播。**

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. **