Epididymis-derived RNAs in sperm affect the next generation: potential clinical implications

Until recently, the sole function of sperm was thought to be as delivery agents for the paternal contribution of zygote genes encoded in the DNA they carry. However, recent research has shown that sperm contribute substantially more information to oocytes upon fertilization through a select population of non-coding (nc)RNAs obtained while traversing the epididymis. Strikingly, their content can be altered by the environment in which males have lived, such as their exposure to various types of pollutants, traumas, addictive drugs, diet, and other factors. These changes in sperm ncRNA content can be responsible for transmitting the negative consequences of these environments to their offspring, via 'epigenetic inheritance', which is reminiscent of Lamarckian inheritance. This mini-review aims to provide an overview of the role of environment-regulated sperm ncRNAs in this process. We include studies on the relationship between specific paternal environments and the associated changes in sperm ncRNA content. These studies have been performed largely in rodent models, but we also describe evidence supporting the same processes occurring in humans. As an example, we focus on the epigenetic inheritance of stress phenotypes through changes in sperm miRNA profiles. We propose that identifying these specific ncRNAs carried by human sperm could lead to future diagnostic and treatment paradigms positively impacting ART. Screening out these potentially harmful sperm, or further research that provides approaches to reverse these changes before conception, may therefore prevent negative consequences related to epigenetic inheritance.