Cations are important for the functionality of chromatin in old people. Our results indicate that heavy metals cause remodeling of heterochromatin in cultured lymphocytes from aged individuals. In particular, 50 μM Cu(II) caused an increase in chromosome aberrations and led to an additional level of heterochromatin heterochromatinization, whereas 100 μM Cd(II) caused deheterochromatinization of facultative and constitutive heterochromatin.
Changes in chromosome structure are key aspects in the epigenetic regulation of gene expression. Hypermethylation may cause heterochromatinization and, thus, result in gene silencing (Mazin 1994
). It was demonstrated that progressive heterochromatinization of chromosomes (condensation of eu- and heterochromatic regions) occurs during aging, followed by inactivation of the genes that functioned actively at younger ages (Lezhava 2001
). Using the DSC method, our data support the statement that lymphocytes from old individuals exhibit increased chromosome heterochromatinization compared with the level of heterochromatin in young individuals.
There is abundant experimental evidence indicating that structural lesions caused by mutagens develop more frequently in heterochromatic than in the euchromatic regions. To explain the prevalence of accumulation of damage in heterochromatin and in regions of heterochromatinization, it has been assumed that the repair of lesions that are capable of causing aberration is possible only in areas of DNA that are actively involved in transcription and are physically accessible to reparative enzymes, i.e., euchromatin areas. It is known that the condensed (heterochromatic) regions of chromosomes are physically inaccessible to repair enzymes (Prokofieva-Belgovskaya 1986
Heterochromatinization of chromatin by 3d transition metals is a potential mechanism of metal-mediated gene regulation (Ellen et al. 2009
). Aluminum and copper accumulate in the tissues of old humans and animals and presumably act as binding agents that mediate eu- and heterochromatin condensation. Thus, they may explain rising mutation rates and structural changes of chromosomes (Jokhadze and Lezhava 1994
; Kawanishi et al. 2002
; Theophanides and Anastassopoulou 2002
). Cu(II) induces conformational changes (condensation) in the chromosomes exposed on the cells of Chinese hamster ovaries. This decreases the availability of antibodies to the chromosomal histone H2b (Turner and Koehane 1986
). Chromosome condensation requires posttranslational modification and the action of an ATP-dependent complex termed “condensing,” which introduces positive DNA supercoils into DNA substrates, in the presence of topoisomerases (Uhlmann 2001
Our data pertaining to the increase of chromosome aberrations and the presence of additional heterochromatinization of heterochromatin induced by Cu(II) in old individuals are in good agreement with these findings. We explain the additional heterochromatinization of heterochromatin by the Cu(II)-induced additional crosslinking of the chromatin 30-nm fiber with the nuclear matrix.
Regarding the mutagenic action of Cd(II) ions, chromosomal changes under the influence of this element have not been observed (Jokhadze and Lezhava 1994
). However, it was shown that exposure of cells to CdCl2
for 6 h causes decondensation of chromosomes in bone-marrow cells of rodents (Muramatsu et al. 1980
). Moreover, Cd(II) has been shown to cause a significant effect, as extremely low doses reportedly stimulate progesterone biosynthesis, whereas high doses inhibit this process (Henson and Chedrese 2004
). Our studies demonstrated that low doses of Cd(II) induced the deheterochromatinization of eu- and heterochromatin regions in individuals aged 80–93 years.
Thus, our results indicate that the transition metals Cu(II) and Cd(II) induce remodeling of heterochromatin in cultured lymphocytes of aged individuals. Cu(II) causes additional heterochromatinization of heterochromatin, and Cd (II) causes deheterochromatinization of the facultative and constitutive heterochromatin.
The proposed remodeling of the heterochromatin induced by the heavy metals Cu(II) and Cd(II) in aging, aging pathology, and pathology linked with metal ions may help evaluate the importance of external and internal factors in the development of diseases and enable the development of proper therapeutic tools.