Epigenomic drugs and the germline: Collateral damage in the home of heritability?

The testis and ovary provide specialised environments that nurture germ cells and facilitate their maturation, culminating in the production of mature gametes that can found the following generation. The sperm and egg not only transmit genetic information, but also epigenetic modifications that affect the development and physiology of offspring. Importantly, the epigenetic information contained in mature sperm and oocytes can be influenced by a range of environmental factors, such as diet, chemicals and drugs. An increasing range of studies are revealing how gene-environment interactions are mediated through the germline. Outside the germline, altered epigenetic state is common in a range of diseases, including many cancers. As epigenetic modifications are reversible, pharmaceuticals that directly target epigenetic modifying proteins have been developed and are delivering substantial benefits to patients, particularly in oncology. While providing the most effective patient treatment is clearly the primary concern, some patients will want to conceive children after treatment. However, the impacts of epigenomic drugs on the male and female gametes are poorly understood and whether these drugs will have lasting effects on patients' germline epigenome and subsequent offspring remains largely undetermined. Currently, evidence based clinical guidelines for use of epigenomic drugs in patients of reproductive age are limited in this context. Developing a deeper understanding of the epigenetic mechanisms regulating the germline epigenome and its impact on inherited traits and disease susceptibility is required to determine how specific epigenomic drugs might affect the germline and inheritance. Understanding these potential effects will facilitate the development of informed clinical guidelines appropriate for the use of epigenomic drugs in patients of reproductive age, ultimately improving the safety of these therapies in the clinic.