Using Drosophila melanogaster as model organism, which is considered a valuable model for the analysis of the biological consequences of radiation exposure, we have recently found that a pre-exposure to a dose of 40 cGy at dose rate of about 2.5 mGy/h (Low Dose Low Dose Rate (LDLDR)) confers radioresistance to chromosomal DNA damage after a challenging exposure of 10Gy. This revealed us that a radio-adaptive response also exists for Drosophila mitotic cells after a LDLDR treatment. In addition, our preliminary genetic and RNA seq data indicated that this response is mediated by DNA damage response pathway and strongly depends on modulations of lincRNAs and transcripts involved in ribosome biogenesis. Furthermore, we have also found that the permanence on a strongly reduced radiation environment, such as the INFN-LNGS underground laboratory can indeed affect Drosophila development and, depending on the genetic profile, may affect viability for several generations even when flies are moved back to the reference radiation environment. Collectively, our findings suggest that small variations of radiation dose/dose rate above and below background, can trigger significant biological responses on a complex multicellular organism and reinforce the view that the Linear No Threshold (LNT) model cannot be generally taken into account for the evaluation of radiation risks. My proposal aims at investigating the biological effects of LDLDR on Drosophila cells by tackling two main tasks: (TASK 1) Characterizing the LDLDR-induced resistance to dsDNA breaks; (TASK 2) Validating the RNA seq data in Drosophila to understand the molecular bases underlying the LDLDR-induced radio-adaptive response.
Understanding the biological consequences of exposures to low-dose radiation is becoming increasingly important for humans and other organisms. If small variations on radiation dose/dose rates doses compared to background are harmless (threshold model) or even protective (adaptive-response model), the standards of exposure could be relaxed, resulting in substantial savings. In addition, the adaptive response could prove useful in cancer therapy if normal and tumor cells are found to respond differently. However, until the mechanisms of these phenomena are revealed and their effects become predictable, a relaxation of standards will still remain a concept just for a few. The current uncertainties about the health risks of low doses of radiation are influencing many major daily decisions that impact almost every facet of our lives including medical care, homeland security, defense, energy, education etc. and create an increase of the costs. An incomplete understanding of the mechanisms of radiation action at low doses is one of the most contributor to the current uncertainty on low-dose risk estimates. While improved understanding of the mechanisms will not eliminate the uncertainty, it can help increase confidence in low-dose risk estimates. Animal studies play an important role in providing a link between molecular and cellular studies, tissue effects and epidemiological studies of low dose radiation related to human risk. But translating the data from a well-controlled animal study to human population is not without
limitations. However, moving to "systems biology" type approaches that incorporate multiple "omics" platforms to interrogate radiation responses in a complex tissue or animal models as a function of radiation dose and time after exposure would indeed provide more reliable information for addressing this delicate issue. My project, aimed at understanding the biological mechanisms of radiation actions at low doses using a multidisciplinary approach, will provide useful insights to solve some of the uncertainties associated to low-dose risks. The genetic and molecular characterization, as well as the validation of RNA seq data, of radio-adaptive response observed in Drosophila larval neuroblasts, will help unravel new mechanisms that underlie this phenomenon. As several publications indicate that adaptive response and radiation-induced instability are inter-related phenomena and share common mechanistic pathways, this study carried out on a model organism will contribute to solve the continuous debate about the impact of radiations at low doses on risk estimation.