Rethinking tissue reactions to radiation exposure: The tissue-sparing effect as a threshold for radiation-induced male infertility

The principle of microbeam radiotherapy (MRT) is the delivery of a single high-dose fraction to a large treatment area divided into several smaller fields, to reduce the treatment's overall toxicity. Since the fundamental concept of MRT was first established, a notable tissue-sparing effect (TSE) has been confirmed in a large variety of species and tissue types, although the underlying biological mechanism in this process remains unclear. By coupling high-precision MRT with an ex-vivo mouse spermatogenesis model, we demonstrated the significant testicular TSE for maintaining spermatogenesis following MRT. To our knowledge, this was the first TSE identified in reproductive tissue. Our high-precision microbeam analysis also revealed that an efficient TSE for spermatogenesis relies on the size of the non-irradiated germ stem cell pool in the irradiated testicular tissues, suggesting the involvement of stem cell migration/competition. These findings of testicular TSE indicate that radiation infertility is not dose-dependent, but instead depends on micro-dosimetric conditions, and that the limit of the TSE is a potential threshold for radiation-induced male infertility.