van Steenwyk Gretchen, Roszkowski Martin, Manuella Francesca, Franklin Tamara B, Mansuy Isabelle M
Laboratory of Neuroepigenetics, Brain Research Institute, Faculty of Medicine, University of Zurich & Institute for Neuroscience, Department of Health Science and Technology, ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Department of Psychology and Neuroscience, Dalhousie University, Life Sciences Centre, 1355 Oxford Street, Halifax, NS B3H 4R2, Canada.
Environ Epigenet. 2018 Oct 16;4(2):dvy023. doi: 10.1093/eep/dvy023. eCollection 2018 Apr.
In the past decades, evidence supporting the transmission of acquired traits across generations has reshaped the field of genetics and the understanding of disease susceptibility. In humans, pioneer studies showed that exposure to famine, endocrine disruptors or trauma can affect descendants, and has led to a paradigm shift in thinking about heredity. Studies in humans have however been limited by the low number of successive generations, the different conditions that can be examined, and the lack of mechanistic insight they can provide. Animal models have been instrumental to circumvent these limitations and allowed studies on the mechanisms of inheritance of environmentally induced traits across generations in controlled and reproducible settings. However, most models available today are only intergenerational and do not demonstrate transmission beyond the direct offspring of exposed individuals. Here, we report transgenerational transmission of behavioral and metabolic phenotypes up to the 4th generation in a mouse model of paternal postnatal trauma (MSUS). Based on large animal numbers (up to 124 per group) from several independent breedings conducted 10 years apart by different experimenters, we show that depressive-like behaviors are transmitted to the offspring until the third generation, and risk-taking and glucose dysregulation until the fourth generation via males. The symptoms are consistent and reproducible, and persist with similar severity across generations. These results provide strong evidence that adverse conditions in early postnatal life can have transgenerational effects, and highlight the validity of MSUS as a solid model of transgenerational epigenetic inheritance.
在过去几十年里，支持获得性性状跨代传递的证据重塑了遗传学领域以及对疾病易感性的理解。在人类中，开创性研究表明，接触饥荒、内分泌干扰物或创伤会影响后代，这导致了对遗传的思维范式转变。然而，人类研究受到连续世代数量少、可研究的不同条件以及缺乏机制性见解的限制。动物模型有助于克服这些限制，并允许在可控且可重复的环境中研究环境诱导性状的跨代遗传机制。然而，如今现有的大多数模型只是代际的，并未证明性状能传递到受暴露个体的直接后代之外。在此，我们报告在父系产后创伤小鼠模型（MSUS）中，行为和代谢表型跨代传递至第四代。基于不同实验者在相隔10年进行的几次独立繁育中获得的大量动物数量（每组多达124只），我们表明，类似抑郁的行为会传递给后代直至第三代，冒险行为和葡萄糖调节异常会通过雄性传递至第四代。这些症状是一致且可重复的，并且在各代中以相似的严重程度持续存在。这些结果提供了强有力的证据，证明产后早期的不良状况会产生跨代效应，并突出了MSUS作为跨代表观遗传继承坚实模型的有效性。
