Bleomycin-induced chromosomal aberrations in Down's syndrome lymphocytes

Blood samples from 4 Down's syndrome (DS) patients with a 47,XY,21 + karyotype and from 4 normal male probands were cultured for 72 h in the presence of BrdU and lymphocytes analysed at their first mitosis for chromosomal aberrations. The frequencies of spontaneous aberrations and the proportions of cells in the first or later mitoses in culture were not different between the groups. Treatment with various doses of bleomycin in vitro resulted in similar delays in cell development for both DS and normal lymphocytes and dose-dependent increases in the incidence of chromosome-type aberrations. However, the induction of both dicentric aberrations and acentric fragments was significantly enhanced in DS cells relative to cells of normal karyotype.     

Radiosensitivity of chromosomes in lymphocytes from Down's syndrome patients

A study was made of the yield of chromosome aberrations in gamma-irradiated G0 peripheral blood lymphocytes from 6 patients with different forms of Down's syndrome. The doses used were from 0.25 to 3.0 Gy. Seven healthy donors of different age made the control group. There was a significant increase in the yield of chromosome exchanges in lymphocytes from all the patients as compared to control. The spontaneous level of chromosome aberrations and the frequency of radiation-induced fragments did not differ from the control values. The yield of exchanges in diploid and trisomic cells from patients with the mosaic form of Down's syndrome did not change significantly as the time of cultivation was raised. The origin of DNA repair defects leading to the increased chromosome radiosensitivity in Down's syndrome is discussed.     

Sister-chromatid exchanges in lymphocytes from infants with Down's syndrome

Sister-chromatid exchange (SCE) frequencies were studied in blood lymphocytes from 12 patients (3 females and 9 males) with Down's syndrome (DS). The mean frequency of SCE per metaphase for the patients (both sexes) was 9.2 +/- 0.8 which was significantly higher (P less than 0.01) than the mean SCE value (5.1 +/- 0.2) scored for 16 healthy infants (8 females and 8 males). A significant increase in the mean frequency of SCE in 12 parents of infants with DS (8.7 +/- 0.9 SCE/cell) was noticeable when compared with 20 parents of normal infants (6.3 +/- 0.1 SCE/cell). Increases in cellular division with reduction in their replication were also observed in patients with DS. Treatment with mitomycin C (0.05 micrograms/ml), hycanthone (0.1 micrograms/ml) and gamma-radiation (0.1 Gy) revealed a significant (P less than 0.01) increase in frequencies of SCE in DS lymphocytes and in those of their parents as compared to controls. These data may reveal a familial hypersensitivity reaction to these agents. The results indicate a genomic instability and deranged DNA-repair mechanisms which are accentuated by exposure to mutagenic agents, the underlying causal factor for which might be genetic.     

Age-related increase of mitomycin C-induced micronuclei in lymphocytes from Down's syndrome subjects

Peripheral blood lymphocytes from 7 patients with Down's syndrome (DS; trisomy 21) and 14 healthy age-matched controls were studied for the induction of micronuclei (MN) by the cytokinesis-block method. The spontaneous incidence of MN in lymphocytes from DS subjects was lower than that of control cultures. When lymphocytes were treated with mitomycin C (MMC) at the beginning of the culture period, an increase in MN formation was found in cells from both DS and control subjects. In DS subjects this increase was much more marked than in control donors. This effect had to be ascribed to cells from older DS subjects (37-55 years old), which showed an MMC-induced MN formation that was markedly and significantly higher than that observed in cells from younger (9-16 years old) DS subjects. These data indicate that age has to be considered a major variable when studies on the genetic instability of DS subjects are performed.     

The influence of cell cycle kinetics on the radiosensitivity of Down's syndrome lymphocytes

In agreement with previous work, [60Co]gamma-irradiation shortly after phytohemagglutinin (PHA) stimulation, induces higher frequencies of chromosomal aberrations in trisomy 21 lymphocytes compared to normal controls. However, equal frequencies of chromatid aberrations are induced in fully-stimulated trisomy 21 and normal lymphocytes by irradiation during G2. We have observed that trisomic lymphocytes respond more rapidly to PHA stimulation than normal lymphocytes. Furthermore, we have observed that chromosomal radiosensitivity increases as a function of time after PHA stimulation in normal lymphocytes. When normal lymphocytes are irradiated 8 h after PHA stimulation, the frequencies of chromosomal aberrations induced are comparable to those induced in trisomy 21 lymphocytes irradiated 30 min after PHA stimulation.     

Absence of radiation-induced adaptive response in lymphocytes of patients with Down's syndrome]

The adaptive syndrome and response (AR) in lymphocytes from 6 patients with Down syndrome (DS) were investigated. No AR was found to occur in all cases in DS cells pre-exposed to 3 rad of X-rays in S phase of cell cycle and then irradiated with 150 rad of gamma rays in G2 whereas the chromosome aberrations yield in cells from control donors was decreased twice under such conditions of the experiment.     

Satellite association in Down's syndrome

Summary The frequency of association of acrocentric chromosomes is examined in 20 Down's syndrome children, their parents, and 60 controls. Chromosome 21 enters into satellite associations most frequently, and chromosome 15 least. The parents of Down's syndrome children do not show any increased tendency for satellite association of chromosome 21 or indeed any other acrocentric.