Mechanisms for induction of mutations and chromosome alterations.

Abstract

Genotoxic agents induce chromosomal alterations, such as aberrations, micronuclei, and sister chromatid exchanges as well as mutations both in vivo and in vitro. Ionizing radiation and typical radiomimmetic agents such as bleomycin are very efficient inducers of chromosomal aberrations. The type of aberrations induced by these agents are cell-cycle dependent, i.e., chromosome type in pre-replication stages and chromatid type in post-replication stages of the cell cycle. Under optimal DNA repair conditions, DNA double-strand breaks (DSBs) appear to be the most important lesion responsible for the production of aberrations. In human lymphocytes, fast-repairing DSBs lead to exchange-type aberrations. The fact that the dose-response curves for induction of exchange aberrations induced by ionizing radiation are similar in vitro and in vivo allows one to use the yield of induced aberrations to estimate absorbed radiation dose in the case of accidents. In this respect, frequencies of translocations detected by the chromosome painting technique appear to be more sensitive. Mutations do not express immediately after exposure and require an expression time before they can be detected. In humans, it is estimated that for the mutations induced in bone marrow, it takes about 2 months for them to express and to be detected in peripheral blood lymphocytes. Hence, frequency of mutations is of limited value for estimating radiation doses immediately after an accident. This holds true for chemical exposure as well. Most of the lesions induced by chemical mutagens (such as alkylating agents) are converted into aberrations only during the S phase of the cell cycle, and therefore an intervening DNA synthesis following exposure is necessary for the visualization of aberrations. These agents induce mainly the chromatid-type aberrations and are also very efficient in inducing sister chromatid exchanges. Chemical mutagens are more efficient in inducing gene mutations than ionizing radiations. In monitoring human populations, mutations in the hprt locus in peripheral lymphocytes and hemoglobin mutations as well as glycophorin mutations in erythrocytes can be studied. The hprt mutations and glycophorin mutations can arise from single base-pair changes to large deletions, whereas hemoglobin mutations arise from changes in a single codon.

Evaluation of DNA damage in white blood cells of healthy human volunteers using the alkaline comet assay and the chromosome aberration test.

“…During the life-time everyone "accumulates" some level of radiation exposure, mainly due to background radiation in the environment, diagnostic exposures, or small amounts of radioisotopes ingested with food. From the studies on subjects occupationally exposed to ionizing radiation it is known that the consequence of an in vivo exposure to ionizing radiation also might be complex unstable chromosome aberrations, such as dicentric or ring chromosomes (Bender et al, 1988a;Natarajan, 1993;Hagelström et al, 1995). However, these aberration types were not observed in our study; on the contrary, most of chromosome aberrations detected in peripheral blood lymphocytes were of chromatid-type.…”

“…However, these aberration types were not observed in our study; on the contrary, most of chromosome aberrations detected in peripheral blood lymphocytes were of chromatid-type. Such aberration type is mostly induced by chemical mutagens and carcinogens in lymphocytes during S-phase or post-replicative stages (Bender et al, 1988a;Natarajan, 1993).…”

Chromosomal Aberrations in Lymphocytes of Healthy Subjects and Risk of Cancer

“…The role of some chemicals and ionizing radiation in inducing DNA double-strand breaks that, if not repaired, are transformed into CAs during cell division is well established (Bryant 1998; Natarajan 1993; Obe et al 2002; Palitti 1998; Savage 1998). Measuring the frequency of chromosomal damage in humans exposed to occupational and environmental clastogens has been a priority in public health studies for decades, and an increased level of CAs in population groups is currently interpreted as evidence of genotoxic exposure and early biologic effects on DNA (Albertini et al 2000; Šrám 1981; Šrám et al 1983; Waters et al 1999).…”

Genetic variation associated with chromosomal aberration frequency: A genome‐wide association study

“…However, no loci were found to be associated with CSA frequency. CSAs are also known to be affected to a lesser extent by chemical mutagens as compared to CTAs (Natarajan 1993). The SNPs in CAtot category were selected from the logistic model as it provided stronger associations.…”