SPONTANEOUS GENETIC-DAMAGE IN MAN - EVALUATION OF INTERINDIVIDUAL VARIABILITY, RELATIONSHIP AMONG MARKERS OF DAMAGE, AND INFLUENCE OF NUTRITIONAL-STATUS

The 'spontaneous' frequency of genetic damage (normal background) and the possible relationship of this damage to nutritional variables in h umans were investigated in 22 subjects using several indices of geneti c damage. The subjects were chosen, out of 122 initially analyzed, for being at the extremes of the highest and lowest values of one index o f genetic damage, the frequency of micronucleated erythrocytes in peri pheral blood. This index reflects chromosomal damage and loss in bone marrow erythropoietic cells. The assay for micronuclei is convenient b ut is restricted to splenectomized individuals because the human splee n removes micronucleated cells. The initial 122 subjects were splenect omized, but all were normal and healthy at the time of this study and none had a previous history of neoplastic disease. Factors investigate d were stability of micronucleus frequency as a function of time, corr elations among multiple markers of genetic damage, and influence on da mage indices of nutritional variables, including blood levels of folat e, B-12 and antioxidant vitamins. Among different individuals, the ran ge of values was 10-fold or more in the erythrocyte micronucleus, glyc ophorin A, plasma ascorbate and urinary 8-hydroxydeoxyguanosine (oxo(8 )dG) assays, was approximately 6-fold in the lymphocyte micronucleus a ssay, and was 2-fold in the lymphocyte sister chromatid exchange (SCE) assay. Red blood cell folate and plasma folate, B-12 and alpha-tocoph erol values varied by up to 10-fold among individuals. Micronucleus fr equencies in erythrocytes and peripheral blood lymphocytes ranged from < 0.3 to 16.9/1000 in mature red blood cells, < 1 to 33/1000 in retic ulocytes, and 2.5 to 15/1000 in binucleate lymphocytes. Frequencies of glycophorin A variant erythrocytes ranged from 5.6 to 77.3 x 10(6) N/ 0 cells and 3.2 to 16.2 x 10(6) N/N cells, and oxo(8)dG excretion vari ed from 32 to 397 pmol/kg/day. Although a wide range of values was obs erved in each genetic endpoint, the extreme values for various endpoin ts of genetic damage were not observed in the same individuals. The fr equency of micronucleated erythrocytes varied over time within individ uals and indicated that individuals with the highest levels of damage exhibit greater variability than those with lower levels. In some subj ects, frequencies of micronucleated erythrocytes changed dramatically over an interval of 2-3 years: four subjects with initial micronucleat ed reticulocyte frequencies of 20.4, 5.9, 6.4 and 33/1000 changed to 2 .5, 20.5, 18.5 and 12/1000, respectively. Among more than 150 individu als we have studied, including the 64 individuals studied by Everson e t al. [(1988) J. Natl. Cancer Inst., 80, 525-529] and Smith et al. [(1 990) Cancer Res., 50, 5049-5054], the seven individuals with the highe st observed frequencies of micronucleated erythrocytes all had excepti onally low values of plasma folate, red cell folate, or plasma B-12, s uggesting that folate and B-12 status are the major determinants of th e types of damage that lead to spontaneous micronucleus formation in e rythrocytic cells.