Personalised Risk Assessment of Low-dose Radiation Effects on Spermatogenesis

Abstract

Since the large-scale nuclear disasters of Chernobyl in 1986 and Fukushima in 2011, serious public concern has arisen about the health effects of long-term, low-dose environmental radiation exposure and contamination. From the point of view of radiation microdosimetry, the energy deposition of radiation from low-dose exposure (such as from environmental radiation) is localised along its track, resulting in a non-uniform distribution of exposed and unexposed cells in the irradiated tissue. To establish a personalised risk assessment for the effects of low-dose radiation on spermatogenesis, we investigated significant alterations in spermatogenesis in response to non-uniform radiation distributions at low doses and estimated the genetic diversity of radiation sensitivity at the population level. To investigate non-uniform, radiation-induced effects on cell survival in vitro, we used 15P-1 Sertoli cells that retain the morphological and functional features of primary Sertoli cells, which helps germ cells in the process of spermatogenesis. Also, with the technical combination of synchrotron X-ray microbeams and a unique ex vivo testes organ culture, we investigated tissue-level responses in non-uniform radiation fields, such as environmental radiation. Our data revealed the non-targeted effects, including the radiation-induced bystander effects and the tissue-sparing effect (TSE), on spermatogenesis at the cell and tissue levels. We also found that an effective TSE for spermatogenesis requires the survival and repopulation of non-irradiated spermatogonial cells during the process of spermatogenesis in non-uniform radiation fields. Using a population-based genome database, we investigated variants of the ATM and MSH5 genes, including MSH5 85C>T (p.Pro29Ser) (rs2075789), that are responsible for radiotherapy-related spermatogenic impairment. We found regional differences in the frequency of rs2075789. We also demonstrated the diversity of ATM gene variants at the population level and found four novel variants that are predicted to lead to a loss of ATM protein functionality. In conclusion, the cell and tissue responses induced by non-uniform, temporospatial radiation exposure and affected by individual differences in radiation sensitivity are essential in creating a personalised risk assessment of the effects of low-dose radiation on spermatogenesis. In the next steps, we will investigate which molecular signals of cell migration are involved in the TSE during the long process of spermatogenesis. We will also seek to further identify the rigorous predictors of individual radiation sensitivity using population-based genomics approaches.

Date of Award	Dec 2019
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Kevin Prise (Supervisor) & Karl Butterworth (Supervisor)