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Test-system for Individual Radiosensitivity Analysis

#2028


Development of Highly Precise Test-System for Individual Human Radiosensitivity Analysis in Cohorts of Occupationally Exposed People

Tech Area / Field

  • BIO-RAD/Radiobiology/Biotechnology
  • MED-OTH/Other/Medicine
  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology

Status
8 Project completed

Registration date
30.10.2000

Completion date
23.08.2010

Senior Project Manager
Latynin K V

Leading Institute
VNIIEF, Russia, N. Novgorod reg., Sarov

Supporting institutes

  • Institute of General Genetics, Russia, Moscow\nResearch Center for Medical Genetics, Russia, Moscow

Collaborators

  • University of Maryland / School of Medicine / Department of Radiation Oncology, USA, MD, Baltimore\nThe Foundation for Advancements in Science and Education, USA, CA, Los-Angeles

Project summary

The recent technological progress of society and political situation have increased the group of countries that make, store and test nuclear weapons (NW). This, in turn, results in more people to work permanently in radiologically hazardous environments. In addition, the category of chronically exposed to low-dose ionizing radiations (IR) also includes people that populate areas to NW-related production facilities and nuclear power stations. Therefore, it becomes increasingly more topical to study the impact of long-term exposure to low-dose radiation on the human genome. This is essential:

– for predicting of low dose irradiation remote effects on human body;


– for developing a package of measures to mitigate the consequences of human exposure to IR;
– for development of scientifically sound quotas for radiation protection, based on a real risk.

It is impossible to evaluate the remote effects of the human body exposure to radiation without doing analysis of the inpidual radiosensitivity in conjunction with the genetic distinction of inpiduals.

Inpidual radiosensitivity of the body strongly depends on the ability of its sells to repair radiation-induced damages in their genetic substrate – DNA and/or eliminate the cell death due to apoptosis, in particular.

In nuclear industry no facility has practised inpidual radiosensitivity and genotype analyses for its personnel. It is necessary for timely taking of prophylactic measures for the insuring safety for personnel.

It is the goal of the project proposal to develop a precise test system to analyze and predict inpidual human radiosensitivity in cohorts of occupationally exposed people on the base of correlation between:

– characteristics of gеnotype;


– genome instability parameters;
– inpidual radiosensitivity parameters;
– health status of occupational nuclear personnel and their posterity.

For this purpose it would be the first investigation of damages induced in the genome of occupationally exposed people by different types of IR (a, b and g-neutron) using the combination analysis of the most promising molecular-genetic methods:

1. For inpidual radiosensitivity analysis:

– study of DNA-repairing activity in the human body based on exstraordinary DNA synthesis with original modification of RCMG RAMS;


– detection of certain DNA fragments in biological liquids (for example blood plasma). In particular it may be a DNA fragment of the transcribed region of ribosomal RNA gene. This region is one of the most stable in respect of degradation. The presence of such DNA fragments in biological liquids may indicate either DNA-reparation system defects or increased death of cells, in particular, by means of an apoptosis. Method is developed in the laboratory of professor D.Spitkovski.
– the anomalous viscosity time dependence technique (АVTDT) for investigating the cell chromatin response to IR.

The methods mentioned above are the most modern and perspective for inpidual human radiosensitivity analysis in cohorts of occupational nuclear personnel, their posterity and the population of exposure-risk areas

around nuclear facilities, because they take into consideration genetic peculiarities of each human being at most. The methods result in accurate dose-effect ratios for low-dose irradiation (0–25 sGy) in all indices studied.

2. For comprehensive estimation of genotype and for search for the markers of early development of various diseases in occupational nuclear personnel and their posterity it is planned to investigate:

– enzyme loci polymorphism using electrophoretic separation of blood proteins, a method that proved excellent in genetic studies;


– microsatellite loci polymorphism using the modern modification of electrophoretic method, based on the application of polymeraze chain reaction (PCR) for microsatellite DNA fractions.

3. For the estimation of genome instability in the cohort of people with low DNA-repairing activity, revealed in the result of the project, it is planned to determine frequencies of chromosome aberrations in human peripheral blood lymphocytes (spontaneous level and induced by IR).

As a result of activities mentioned above correlation will be established between:


– frequencies and heterozygosity of polyloci genotypes (enzymatic and microsatellite DNA loci);
– velocity of exstraordinary DNA synthesis induced by additional UV-radiation;
– presence of a DNA fragment of the ribosomal RNA gene transcribed region in analysed blood samples;
– changes of chromatin viscosity in cell of occupational nuclear personnel in response to IR;
– frequencies of chromosome aberrations in peripheral blood lymphocytes of occupational nuclear personnel (spontaneous level and induced by IR);
– health status of occupational nuclear personnel (cancer and somatic diseases).

Based on these studies, risk groups will be identified including people with low DNA-repairing activity, higher radiosensitivity, higher genome instability. All characteristics under investigation are connected with possible undesirable health effects (higher risk of cancer and somatic diseases in occupational nuclear personnel and their posterity; reduction of life duration). Risk groups are necessary for study the character of low-dose and low-intensive IR influence on human organism and for prediction of remote effects.

Definitely, advantages of the proposed approach to inpidual radiosensitivity analysis are:


– the uniqueness of the contingent under investigation (occupational nuclear personnel and their posterity);
– comparative analysis for different types of IR (a, b and g-neutron) effects on DNA-repair activity, and stability of genome;
– combination of the most promising molecular-genetic methods for investigation;
– the screening possible simultaneously for a large group of people (up to 100 per day);
– employs compact, user-friendly and inexpensive equipment;
– environmentally safe facilities and equipment in use.

The following tasks will be accomplished as part of the project performance:


– polyloci genotype analysis for each survey case (enzymatic and microsatellite DNA loci);
– determination of inpidual radiosensitivity parameters for each survey case;
– sickness rate evaluated in each survey case over the entire survey time;
– estimation of genome instability for each survey case (frequencies of chromosome aberrations);
– grouping people into cohorts of different inpidual polyloci heterozygosity, radiosensitivity and genome instability;
– identification of polyloci genotypes, responsible for higher or lower inpidual radiosensitivity in their owns;
– correlation analysis of the genotype, inpidual radiosensitivity, genome instability and sickness rate for each survey case;
– risk groups singled out in terms of a variety of early diseases in people, chronically exposed to low IR doses and their posterity.

Each of the above tasks being accomplished will be of great scientific and applied importance, as long as:


– their achievements can be used in the future to evaluate health effects of low-dose radiation on the human generations to follow;
– the project performance will result in the development of a package of measures to mitigate the consequences of exposure to IR for personnel of NW-related production facilities and nuclear power stations, their posterity and people that populate surrounding areas;
– it is planned to bring up into health physics application a test-system to indicate a radiation damage that took place in various periods of time, remote included, based on evaluated activity of human DNA-repairing system.

Commerce importance of the project consists in receiving unique data for:


– the development of scientifically sound quotas for radiation protection, based on a real risk;
– the development of a scientifically sound genetic health prediction system for personnel of nuclear industry facilities, including nuclear power stations, and their posterity. It is essential for supporting safe operations in nuclear power industry;
– the vocational guidance of population and public education.

The project performance will result in:


– collected data of clinical (health status) and genetic (parameters of genotype, radiosensitivity and genome instability) inspectation for occupational nuclear personnel and their posterity;
– estimated remote effects for different types of IR (a, b and g-neutron) effects on DNA-repairing activity, and stability of genome;
– represented data for the development of scientifically sound quotas for radiation protection, based on a real risk;
– highly precise test system developed to analyze and predict inpidual human radiosensitivity in cohorts of occupationally exposed people;
– package of procedures developed to mitigate the impact of ionizing radiation on the health of the above-mentioned groups of people;
– test-system to indicate a radiation damage of different occurrence time, remote included, based on evaluated activity of human DNA-repairing system, developed to bring up into health physics application.

The project will be performed by highly competent personnel specialized in radiobiology, biochemical genetics, cytogenetics, mathematics and computing, and including scientists and engineering formerly involved in nuclear weapon research and development.


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