Multiparametric Detection and Preventive Approaches of Cancer Treatment-induced Epigenetic Instability in the Male Germline.

Advances in cancer treatments are raising new health questions for young survivors of the disease. Cancer itself and DNA-targeted treatments can have long-term effects on reproductive health. In men, spermatogenesis may remain impaired even years after recovery, with consequences for fertility and the health of offspring. It is important to note that sperm production can recover after cancer remission. However, men are advised to wait at least one year after the end of treatment before attempting natural conception, as gamete quality may influence reproductive capacity and offspring health. Yet, regardless of the mode of conception (natural or assisted reproduction), the question of whether a history of cancer and its treatment may affect the health of their offspring remains a fundamental issue that has not yet been clearly answered. In-depth studies are needed for this growing population of young cancer survivors who wish to have healthy children.

Where possible, the use of alkylating agents-known for their long-term systemic harmful effects-is being reduced, and less reprotoxic compounds, such as anthracyclines, are favored. Anthracyclines are widely used to treat various cancers prevalent in young men with a favorable survival prognosis and are classified as weakly reprotoxic (i.e., causing a temporary reduction in sperm count). However, they are suspected of having long-term effects on sperm chromatin and epigenome. The establishment of the sperm epigenome is a complex process resulting from multiple nuclear events during spermatogenesis, including chromatin remodeling and compaction that occur during spermiogenesis. These represent windows of opportunity for alteration by xenobiotics. Furthermore, genomic regions undergoing chromatin rearrangements may be more vulnerable to alterations; if these regions are located on key genes for embryonic development or fetal programming, they may predict adverse effects on offspring. In fact, emerging evidence suggests that sperm epigenetic marks could be used clinically to predict fertility and male-mediated developmental toxicity.

Here, we focus on young men with Hodgkin lymphoma (HL), one of the most commonly diagnosed malignant tumors at a young age, with a good prognosis and low risk of relapse, and for which treatment is well characterized using an anthracycline-containing protocol: doxorubicin. This pathology thus represents a large and relevant population of young cancer survivors who will consider parenthood after cancer. Due to interindividual variability, human studies aiming to determine the effects of chemotherapy must be able to compare samples before and after treatment in the same individual. Such published prospective longitudinal studies are rare and often include very few cases, as they require substantial resources, strong links between oncology and reproduction services, and the ability to follow patients over time, even after the end of oncological treatment. A (non-longitudinal) study of the long-term effects of HL treatments demonstrated persistent abnormalities in chromatin structure and DNA integrity. In the study proposed here, we will analyze epigenetic modifications in sperm from HL patients and their evolution after chemotherapy. We hypothesize that HL and its treatment induce persistent alterations up to 2 years after remission.