Genetic Factors Affecting Susceptibility to Low-Dose Radiation

William F. Morgan
WFMorgan@som.umaryland.edu
University of Maryland 410-706-2475Website: http://medschool.umaryland.edu/departments/radiationoncology/rorl/morgan.html

The short-term effects of high doses of ionizing radiation on cellular responses are relatively well understood. Less clear are the long-term consequences of exposure to low dose/low dose-rate radiation and the effects of radiation exposure on the progeny of surviving cells. If a cell survives radiation, it is generally thought to have repaired all the radiation-induced insults and be capable of a "normal healthy life". At a certain frequency however, we have found that some cells surviving radiation grow normally, but will rearrange their genetic material during time in culture. We call this radiation-induced genomic instability. Many of the chromosome changes we see in genomic instability are similar to those seen in cancer cells as they change from being normal to acquiring the characteristics of cancer. Our studies to date have all been done with high doses of radiation, much higher than could ever be expected to occur in any normal occupational or environmental situation. We want to know if similar effects can be seen after exposure to low dose/low dose-rate radiation. Biological effects at very low doses of radiation are extremely rare, so we propose to develop a robust and reliable test for detecting potential genomic changes in human cells after exposure to low dose/low dose-rate radiation.

1. Develop a test to determine if radiation-induced rearrangement and genomic instability can be detected using a green fluoresent marker protein at low doses and a low dose rates
   
   
2. Develop a robust and stable test for detecting genomic instability that can be related to cancer risk
   
   
3. Determine if an adaptive response can be induced for genomic instability

We expose a human cell line to low dose and dose rates and measure genomic instability. To do this, we have integrated a marker gene into these cells which can be detected by the green fluorescent protein, and we will use this to detect whether low dose/low dose rate radiation can cause the genome to rearrange. If the genome does rearrange, we would expect that some of the daughter cells of a radiated cell would recombine with this marker gene and fluoresce green. We can use fluorescence microscopy and molecular biology techniques to identify the surviving cells that exhibit this form of radiation-induced genomic instability. We will then compare how instability measured by this method correlates with the previously used test for chromosome aberrations. Many cell types exposed to low doses of radiation become resistant to exposure to a second high dose of radiation. This is termed the adaptive response. There is a large body of evidence suggesting that the low dose pre-exposure induces a repair system in these cells that reduces the damage induced by the high challenge dose. We will investigate the molecular mechanism for this important protective effect of low dose/low dose-rate radiation and to determine whether the adaptive response occurs for delayed effects of radiation such as genomic instability.

1. Measure genomic environmentally relevant dose and dose rates with these new techniques.
   
   
2. Determine whether adaptive response occurs for delayed effects such as genomic instability that can modify the shape of the dose response at low doses and dose rates.
   
   
3. The project will advance the understanding of the relationships between genomic instability induced at low doses and radiation cancer risks.