Environment Industrial

While damage of cellular DNA by environmental chemicals has been shown to be a key causal event in the etiology of certain human cancers, there are endogenous cellular processes that also damage DNA.  These endogenous processes could contribute to spontaneous mutagenesis and might also be carcinogenic (Loeb, 1989).  Many processes that damage DNA and therefore could logically contribute to background or so called “spontaneous mutagenesis” have been identified.  As in the case of DNA damage by exogenous chemical agents, spontaneous damage would need to occur at a high enough frequency to exceed the cell’s capacity for DNA repair.  Only unrepaired DNA damage could be responsible for spontaneous mutations and, following the same logic, spontaneous cancers.  Thus, spontaneous mutations in somatic cells might have the same potential for inducing cancer as mutations caused by exogenous agents.

Among endogenous reactive species generated in cells with high potential for damaging DNA are oxygen free radicals.  Cellular processes that result in oxygen radicals include: respiration, phagocytosis, ischemic cell injury and drug metabolism (Klebanoff, S.J., 1988).  Extensive damage to DNA in cells y oxygen free radicals appears to occur in all cells.  Based on urinary excretion of two major products of DNA damage by oxygen free radicals, thymine glycol and 8-hydroxyguanosine, it has been estimated that oxygen introduces twenty thousand lesions in DNA in each somatic cell per day (Cathcart, R., et., 1984).  It seems probable that not every one of these 20,000 DNA alterations per cell is repaired prior to the onset of DNA replication.

Considering the potential importance of DNA damage and mutagenesis by oxygen free radicals, progress in this field has been notably slow.  Studies on DNA damage by oxygen free radicals have been hampered by the reactivity of the different active oxygen species and most importantly by the multiplicity of DNA modifications that have been characterized in nucleosides and DNA following exposure to oxygen free radicals (Cadet and Berger, 1985; Hutchinson, 1985).  It has been estimated that over one hundred different types of modifications in DNA are produced by oxygen free radicals, and it has been difficult to assign a particular type of oxygen free radical or a specific modification in DNA to a specific type of mutation.  To surmount this complexity, we have taken an inverse approach.  We have established the types of mutations produced by exposure of biologically active DNA to oxygen free radicals in vitro (McBride et al., 1991).  We are now investigating which of the oxygen generated chemical lesions is responsible for the specific mutations we observe.  With this knowledge, we will analyze cellular SNA for the types of damage and mutations that might be the result of oxygen free radicals.