Why does one person get cancer while other people do not, even though all have been exposed to approximately the same environment? Does genetic variability play a role in the susceptibility of each individualís cells to radiation damage, toxic chemical exposure, and possible cancer induction? ORNL researchers are conducting studies with mice, which are genetically similar to humans, to help address these questions about human susceptibility. For example, the Department of Energy wants to know which parts of the human and mouse genomes cause individuals to differ in their responses to radiation. Which genes may be overexpressed (overactive in producing proteins) or underexpressed (turned down or off) in individuals whose DNA is more susceptible to radiation damage than others'?
Ed Michaud and his colleagues in ORNL's Life Sciences Division (LSD) are studying ORNL mouse mutants that are more susceptible to skin cancer. He is using gene microarrays to identify the networks of genes that are altered in mice that are more susceptible to skin cancer compared with normally resistant mice. "We are interested in determining which genes are involved in the normal development of the skin and its function as a barrier to protect our bodies from various environmental agents," Michaud says. "By determining the networks of genes that specify healthy skin, and how subtle changes in these genes make mice more susceptible to skin cancer following exposure to environmental stresses and toxins, we hope to gain a better understanding of the molecular mechanisms underlying human susceptibility to cancer and other diseases of the skin."
LSD's Gene Rinchik and his colleagues are beginning to study differences in the genetic responses of the skin, lymphoid, and reproductive tissues of mice from different strains as a result of exposure to low-level X rays. By studying in specific tissues the responses of many genes to low-dose radiation in different strains of mice, or in descendants of mice treated with a chemical mutagen, Rinchik hopes to identify individuals that differ in their cellular response to such low radiation doses. He and his colleagues can then study whether such variation is significant in the animals'susceptibility to various diseases, including cancer.
Using microarrays, they are looking at which genes are overexpressed or underexpressed in exposed versus nonexposed tissues in these different strains of mice. By looking at gene-expression ratios, they can identify variants in the response. Future genetic mapping and mutation-finding techniques (such as temperature-gradient capillary electrophoresis) can compare DNA from the mutant mouse with the draft sequence of the mouse genome, to identify mutant genes responsible for the differential response to radiation.
ORNL Corporate Fellow Liane Russell of LSD, in studying the risk of damage to a mouseís health from parental exposure to radiation or chemicals, has found that the developmental stage at which the parental reproductive cells are exposed is of paramount importance not only to the frequency but also to the nature of the transmitted genetic damages. Thus, the interval between exposure of an individual to a given mutagenic agent and the conception of offspring has a major influence on the likelihood that genetic damage will be inherited. While different environmental agents had been found to exert their maximum effects at various developmental stages, ranging from stem cells to mature sperm or ova, no chemical had been discovered to be especially active during stages critical for chromosome pairing and segregation. Recently, Russell found that the topoisomerase-II inhibitor "etoposide" not only induces mutations during that interval but also alters the frequency with which genes on homologous chromosomes recombine.
LSD's Bem Culiat is conducting a study to determine why some mice are more susceptible than others to DNA damage from toxic chemicals. Some 20 years ago retired biologist Walderico Generoso found evidence suggesting that eggs from some mouse strains can correct damage in sperm from male mice exposed to a toxic chemical, thereby reducing the percentage of embryo deaths. By using a combination of genetic, cytological, and gene expression studies in newly fertilized eggs, Culiat hopes to determine whether the egg repairs damaged DNA (Generoso's hypothesis) or whether the egg's extracellular coat can screen for normal sperm and keep damaged sperm out (an alternative Culiat hypothesizes). Early results have neither ruled out nor substantiated either hypothesis.
It thus appears that susceptibility to diseases or to exposures depends at least partly on multiple, genetically programmed internal responses of the body to external influences.
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