X‐ray‐induced chromosome aberrations in down lymphocytes: An explanation of their increased sensitivity

Abstract

Unstimulated lymphocytes from individuals with Down Syndrome (trisomy 21) are more sensitive to the induction of dicentric and ring aberrations by X rays than normal lymphocytes. Several explanations involving the more rapid rejoining of X-ray--induced lesions in Down cells have been offered. It is shown here that the repair of the DNA damage converted into chromosome aberrations is more rapid in Down cells than normal cells. This more rapid repair results in a higher probability of producing chromosomes aberrations, and hence higher aberration frequencies in Down than normal cells.

The use of inhibitors of DNA repair in the study of the mechanisms of induction of chromosome aberrations

“…This expectation is exemplified by our data with lymphocytes from individuals with Down's syndrome (Preston, 1981). It was shown by Sasaki and Tonomura (1969) and by E vans and A dams (1970) that Go lym phocytes from Down's syndrome individuals were more sensitive to the induction of chro mosome aberrations by X-rays than normal cells.…”

“…In the case of ara-C the inhibition is reversed by dcoxycytidine. This has been used by us (Preston, 1980(Preston, , 1981(Preston, , 1982 to study the mechanism of aberration induction by X-rays.…”

Clonal origin of Ph1-positive cells in a case of 46,XX/47,XXX/48,XXXX mosaicism associated with chronic myelocytic leukemia.

“…It has been reported that individuals with certain constitutional chromosome abnormalities, such as Down syndrome, are associated with a high risk of malignant diseases including leukemia (Sandberg 1980), and that somatic cells of such patients are hypersensitive in terms of the yield of chromosome aberrations or sister chromatid exchanges induced by radiation (Sasaki et al 1970;Higurashi and Conen 1972;Countryman et al 1977;Crossen and Morgan 1980;Preston 1981), viruses (Higurashi et a1.1973), andchemicals (O'Brien et al 1971;Kaina et al 1977;Sugimoto et al 1982). Although the unique occurrence of Ph1 in the XXX cells of our patient might be related to a certain genetic predisposition of such aneuploid cells, Ph1-positive leukemic cells in other cases of sex-chromosome mosaic have been reported to occur in chromosomally normal as well as abnormal cells, irrespective of the proportion of cell lines involved in a given mosaicism as mentioned before.…”

Intrinsic Factors that can Affect Sensitivity to Chromosome Aberration Induction

“…It was found that the increase in frequency of chromosome-type aberrations as a function of ara-C incubation time was more rapid in Down cells than normal cells (Preston, 1981). Thus, for example, the frequency of dicentri.cs in Down cells for 1 h. post-treatment in ara-C is about the same as the frequency after 2 h. ara-C incubation for normal cells.…”

“…It is also particularly important to note that the studies to date on specific heterozygotes are for obligate heterozygotes, and where the homozygous condition is known to be especially sensitive. The question of particular importance is whether or not it is possible to identify persons who might be only very slightly more sensitive to chromosome aberration or mutation induction by specific agents, and for whom there is no available genetic information that would indicate Our initial results on the use of DNA repair inhibitors for studying the mechanism of aberration induction by radiation and chemicals have been published (Preston, 1980;Preston, 1981;Preston & Gooch, 1981;Preston, 1982a;Bender and Preston, 1982;Preston, 1982b) and will not be presented in detail here. The conclusions from these studies are, however, important for the subsequent discussion.…”