Germ cell DNA damage and its impact on early embryo development

An apparent decline in semen quality has occurred during the past half century which is most likely related to environmental exposure; however, the agent(s) responsible have not been identified. Endocrine disruptors acting prenatally may be responsible bu t have yet to be shown as relevant for humans. On the other hand, there are strong indications that the life style of adult men may affect their fertility and their offspring. Abortions are more frequent when the father is old, and smoking couples receivi ng assisted fertilisation have lower success rate if the father smokes. In recent years the NIPH research group has characterised chemically-induced DNA damage and its repair in male germ cells and established that, unexpectedly, human spermatogenic cells possess a low capacity to repair the highly mutagenic oxidative DNA lesion 8-oxoG, compared to rodent male germ cells which repair these lesions. The presence of increased levels of 8-oxoG is associated with reduced fertility. There are strong indication s that unrepaired DNA lesions may be transmitted to the fertilised egg from the sperm, interfering with the normal development of the zygote and leading to preimplantation loss. This is also a mechanism for increased mutation rates in live offspring. In t he present project we will study, in an extended time window, the fate of DNA lesions during spermatogenesis, fertilisation and development of the embryo. Repair of DNA lesions arising from the sperm, within the oocyte, will be studied using techniques sp ecifically developed for this purpose. DNA lesions resulting from polycyclic hydrocarbons (B(a)P) and food contaminants (acrylamide) exposure will be studied to establish the levels and nature of lesions affecting fertility and early embryo development. A transgenic mouse model will be used and validated. This project is part of a larger and integrated study, with collaborators within and outside Norway. The elements described here constitute a postdoctoral project.