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PubMed1978

[Quantitative description of the process of cellular radiation inactivation. IX. Remarks on the relative biological effectiveness of ionizing radiations in the reproductive death of diploid and polyploid cells].

The relative biological effectiveness (RBE) has been considered for three kinds of cell radiation damages: subdamages (sublethals), one-track, and two-track lethal damages. In contrast to the "dual theory", which postulates the square relation between the lethal damage yield and the specific energy, it is assumed that the one-track lethal yield is linearly related to the specific energy per cell nucleus. As a result, the identical dependence has been obtained of both one-track lethals and subdamages on specific energy and absorbed dose. It is established that RBE for all three kinds of damages does not depend on the radiation dose. It is shown that RBE for subdamages and one-track lethals depends on LET of radiation only, and involves molecular parameters of sensitive cell structures. Within the limits of this assumption, the relations are general for all the types of eukaryotic cells. These can be used for a further development of the RBE theory, with spectra of LET, the track structure of charged particles, the contribution of delta-electrons etc being taken into consideration.

Cell Division↗
PubMed1995

[The polyploidization characteristics of the hepatocytes of the mouse-like hamster Calomyscus mystax].

A cytophotometric measurement of DNA content in hepatocytes of maturing mouse-like hamsters was made. Cells belonging to ordinary mammalian ploidy classes 2c, 2c x 2, 4c, and 4c x 2 made about 90% of the hepatocyte population. The share of binucleated cells wa high (about 80%), the majority of these cells being 2c X 2 hepatocytes. Binucleated cells with tetraploid and diploid nuclei occur in almost every animal. An average hepatocyte ploidy level in mouse-like hamster is 4.6c. The main peculiarity of parenchymal liver cell populations is that up 5% of hepatocytes contain 3--11 nuclei of different ploidy classes. Multinucleated cells increase in number from 1.5% to 4% within the period from one year (the age of maturation) to two years. Later on their percentage does not change. It is found that in binucleated and multinucleated hepatocytes DNA synthesis can proceed asynchronously. Asynchrony in DNA synthesis elevates as the number of nuclei increases. Among the 2c x 2 and 2c x 3 cells an uneven distribution of 3H-thymidine label can occur, respectively, in 5 and in 50% cases, whereas all the cells with more than 3 nuclei display an uneven an uneven 3H-thymidin label distribution. The formation of multinucleated cells is supposed to be associated with asynchrony in DNA-synthesis in binucleated cells and with the restitution of mitosis.

Aging↗
PubMed1996

A brief staurosporine treatment of mitotic cells triggers premature exit from mitosis and polyploid cell formation.

At any point during the progression of many tumor types, cells can develop a hyperploid DNA content. Hyperploid tumors are significant more aggressive, with a higher growth rate and a poor patient prognosis. Yeast genetics have implicated three important genes involved in DNA ploidy changes: cdc2, cyclin b, and a specific inhibitor of the p34(cdc2)/cyclin B kinase, rum1. Mutations in these genes uncoupled the dependence mitosis on DNA replication in the fission yeast, Saccharomyces pombe. It was proposed that the inactivation of the mitotic kinase complex, p34(cdc2)/cyclin B, induces a G(1), state wherein the cells re-replicate their DNA without an intervening mitosis. We show in this report that treatment of only M phase-arrested mouse cells, with the protein kinase inhibitor staurosporine, induced polyploidy. Nocodazole-arrested metaphase FT210 cells were pulsed with 100 ng/ml of staurosporine for 1 h. This 1-h treatment results in the inhibition of the mitotic p34(cdc2) kinase. The inhibition of the mitotic kinases leads to a reduction in the histone H1 and H3 mitotic-associated phosphorylations, chromosome decondensation and nuclear membrane reformation. When released into normal growth medium, these cells are reset to a G(1)state, re-replicate their DNA without completing mitosis, and become octaploid.

Alkaloids↗
PubMed1977

[Characteristics of the regeneration process in the liver deprived of polyploid hepatocytes].

By applying autoradiography with 3H-thymidine hepatocytes of young adult guinea pigs were found to enter the DNA-synthesis phase 25 hours after partial hepatectomy. Peaks of nuclei labeling were revealed 30, 45, and 60 hours after the operation. By calculating mitotic figures on squash preparations two waves of mitosis were found (in 40 and 55 hours) after hepatectomy. Cytophotometric study of DNA content showed practically all mononuclear and binuclear hepatocytes to contain diploid nuclei in 3 and 5 days after the operation. By the end of the 7th regeneration day there were revealed 6% mononuclear tetraploid cells. The percentage of binuclear cells during the period of regeneration under study decreased from 16 to 8%. A conclusion was drawn that the main cytologicalmechanism of the guinea pig liver regeneration was full-fledged mitosis ending by cell division.

Age Factors↗
PubMed1997

[Genome multiplication in the development of albumen gland polyploid cells of Succinea lauta (Gastropoda:Pulmonata).VII. Transcriptive activity of the nuclei in the endomitotic cycle].

Using 3H-uridine autoradiography and electron microscopy a study was made of the activity of RNA synthesis in the interphasic nuclei, mitoses and endomitoses of different ploidy classes (4c-32c) in the albumen gland cells of Succinea lauta. The incorporation of 3H-uridine into mitotic and endomitotic condensed chromosomes was temporarily stopped or kept at the lowest level: 0.7% in normal and abnormal mitoses and about 3-4% in endomitoses, as calculated from the highest possible level in the resting nuclei of the respective ploidy classes. In the interphasic nuclei, chromatid and chromonemal structures are revealed at the ultrastructural level, in addition to thin euchromatinous fibres with perichromatia granules, which makes the brushy appearance of chromonemes and chromocentres. During endomitosis the chromosomes become compacted and free from granules, which well compares with autoradiographical data on transcription stopping. The results obtained corroborate once again that endomitosis is a real endoreproductive mechanism, and allow to make distinctions between real endomitosis and pseudoendomitotic nuclei.

Animals↗
PubMedDate not supplied

[The organizational characteristics of the nucleolar region in the diploid and polyploid nuclei of neoplastic hepatocytes during dipin-induced carcinogenesis].

The use of the number of nucleoli as a criterion allowed us to identify significant differences in the organization of nucleoli in newly formed hepatocytes under the conditions of dipine-induced carcinogenesis 8-10 weeks after its initiation, as compared with normal liver cells of adult mice. The number of nucleoli in tetraploid new hepatocytes was equal to that in the diploid nuclei of normal liver (on average 3.5 and 3.6, respectively) and the number in the new octaploid nuclei was equal to that in tetraploid (6.2 and 6.4, respectively). A higher extent of association of nucleolar organizers under the conditions of endoreproduction or the association of homologous chromosomes in G1 period of the cell cycle is discussed as a possible mechanism responsible for the decrease in the number of nucleoli.

Animals↗
PubMed1993

Analysis of cell ploidy in histological sections of mouse tissues by DNA-DNA in situ hybridization with digoxigenin-labelled probes.

DNA-DNA in situ hybridization, with two digoxigenin-labelled, chromosome-specific DNA probes, was used to determine the number of copies of a given chromosome in interphase nuclei and so identify putatively polyploid nuclei in histological sections of several mouse tissues. One hybridization site per diploid genome was expected for tissues with hemizygous markers: male mice hybridized with a Y chromosome probe (pY353/B) or hemizygous transgenic mice hybridized with a beta-globin probe (pM beta delta 2). Nuclei with more than one hybridization site were considered putative polyploids. Three groups of experiments were undertaken: (1) evaluation of the method, using mouse liver sections; (2) studies of tissues already known to contain polyploid nuclei, and (3) studies that resulted in the discovery that the mouse ovary contains polyploid nuclei. First, control studies showed that the ability to detect the target DNA sequences was affected by section thickness. Studies of nuclear ploidy in the developing mouse liver revealed a pattern similar to that established by previous studies using DNA content as a criterion for ploidy. At birth, only about 5% of the liver nuclei were polyploid; this increased to 10-15% by 10-20 days and was followed by a sharp increase in the frequency of tetraploid nuclei between 20 and 40 days (to about 35%) and a more gradual increase in higher order polyploid nuclei. Secondly, this technique was used to confirm that polyploid (mostly tetraploid) nuclei were present in the bladder epithelium, heart, uterine decidua and placental trophoblast. Higher order polyploidy was seen in large bone marrow cells (megakaryocytes) but not in the even larger trophoblast giant cells of the placenta, thus confirming previous claims that these cells are polytene rather than polyploid. Thirdly, putatively tetraploid nuclei were found in the ovarian follicle and corpus luteum. As far as we are aware, this is the first time polyploid nuclei have been reported for the mouse ovary.

Animals↗
PubMed2004

The bioreductive agent RH1 and gamma-irradiation both cause G2/M cell cycle phase arrest and polyploidy in a p53-mutated human breast cancer cell line.

PURPOSE: RH1 is a newly developed bioreductive agent, and its bioactivation is mediated by the enzyme DT-diaphorase (DTD). We have shown previously that RH1 is highly cytotoxic against cells expressing high DTD, using the p53-mutated MDA231 human breast cancer cell line transfected with the DTD gene (D7 cells). We now report that both RH1 and gamma-irradiation cause D7 cells to arrest in the G2/M cell cycle phase and undergo polyploidy. The latter is a way of p53-mutated cells responding to DNA-damaging agents. Only a small proportion of the polyploid cells are clonogenic, hence polyploidy may contribute to the reproductive failure of the cells after RH1 and irradiation. Thus, we investigated the effect of RH1 and gamma-irradiation on the formation of polyploid cells and a sub-G1 population (as a measure of apoptosis) in relation to the G2/M cell cycle block. METHODS AND MATERIALS: MDA231 D7 cells were treated using a range of RH1 doses. The cells were irradiated using 2 Gy or 5 Gy gamma-rays either as a single dose or in combination with RH1. An IC(90) dose (dose to kill 90% of the cells) of RH1 was administered for 3 h followed by irradiation after a further 24 h. Subsequent changes in cell cycle and polyploidy (DNA content in excess of that of G2/M cells) were examined. RESULTS: Treatment of D7 cells with the RH1 resulted in 60-70% of cells arrested in the G2/M phase of the cell cycle by 24 h, which decreased to control levels by 48 h. Irradiation with 2 Gy and 5 Gy caused a similar G2/M block at 12-24 h, which was followed by a sharp decline at 24-48 h. In contrast, the same dose of radiation combined with RH1 held the cells in the G2/M phase up to 48 h, and this pattern reached pretreatment levels at 72-96 h. Most control cells were found to contain a small number of spontaneously arising polyploid cells. The development of polyploid cells was evident from 12 h after all treatments and showed a significant increase at 48 h and subsequently. As opposed to this, apoptosis measured by the sub-G1 cell population in DNA analyses showed a tendency to increase according to the elapsed time for each group of treatments. Single treatments with RH1 caused a significant increase in the apoptotic population between 48 and 120 h. The first significant increase in apoptosis was observed at 48 h for 5 Gy, 2 Gy + RH1, and 5 Gy + RH1 treatments, and showed a tendency to increase further at later times, but the 2 Gy dose gave an earlier apoptotic peak at 24 h, which decreased to 96 h. The addition of RH1 to the irradiation did not increase the formation of polyploid cells or apoptosis compared with radiation alone (2 Gy vs. RH1 + 2 Gy or 5 Gy vs. RH1 + 5 Gy). The higher dose of irradiation (5 Gy vs. 2 Gy) resulted in a significantly higher proportion of polyploid cells (but not of apoptotic cells) when used alone or in combination (5 Gy + RH1 vs. 2 Gy + RH1). CONCLUSIONS: Both RH1 and gamma-irradiation, individually and in combination, showed a significant G2/M block in MDA231 D7 breast cancer cells. The formation of polyploid cells was dependent more on the radiation dose rather than on the pretreatment with RH1. The polyploid cell population was observed after the G2/M cell cycle phase arrest, and it preceded the late increase of the apoptotic cell population. The role of polyploidy in cell reproductive failure in the total cell population is not known, but it appears to contribute to cytotoxicity in cells released from the G2/M cell cycle phase block.

Apoptosis↗
PubMed2004

Paradoxical relationship between protein content and nucleolar activity in mammalian cardiomyocytes.

It was recently demonstrated that polyploidization of the avian myocardium is associated with a reduction of cardiac aerobic capacity evaluated by the heart mass to body mass ratio (heart index). To investigate possible cellular correlates of polyploidization, the protein content and nucleolar activity per cell and per genome were examined by image cytometry in 21 mammalian species, differing in the degree of heart polyploidization and heart index. We found that average cardiomyocyte ploidy level correlates negatively with the animal heart index (r = -0.75, p < 10(-4)), i.e., the large heart of athletic mammals is polyploidized to a lesser degree than the relatively smaller heart of sedentary species, which confirms the picture observed in birds. The protein content per genome decreased with the elevation of cardiomyocyte ploidy level. This inverse correlation was especially pronounced with the removed effect of body mass (r = -0.79, p < 10(-4)). Surprisingly, these changes were accompanied by the increase of nucleolar activity per genome (r = 0.61, p < 10(-3)). In the two species, for which the microarray gene expression data were available (human and mouse), this increase was paralleled by the elevated expression of ribosomal protein genes (but there was no increase in the expression of tissue-specific genes). Thus, in the polyploid cardiomyocytes there is a misbalance between protein content per genome and ribosome biogenesis. The reduction of protein content (per genome) of polyploid cardio my ocytes should further curtail heart functionality (in addition to reduction of heart index), because it is known that cardio myocyte protein content consists of more than 90% contractile proteins. This finding makes doubtful a widespread notion that polyploidization is necessary for cell function. Because somatic polyploidization is associated with stressful conditions and impaired energetics, we suppose that additional genomes can serve for cell regeneration and as a defense against oxidative damage in the organs that work at the limit of their metabolic capacity.

Animals↗
PubMed1979

Polyploidy in insect evolution.

Of all living organisms insects are the group with the highest number of existing species. It is, of course, true that a fraction of the total number of insects has been cytologically studied. Polyploid forms are rare exceptions among them. Polyploidy in insects is always associated with the parthenogenetic mode of reproduction. The cytologically verified cases are described. As for the geographic distribution of polyploid insects, they have successfully colonized vast land areas. Their distributions are, in general, northern and montane. The polyploid races are in general far more widespread than their diploid bisexual ancestors. The possible models of origin of polyploid insects are covered as well as data on their gaenetic variability. There are apparent environmental correlations in the distribution of certain forms. Most polyploid insects have life cycles extending over two (or more) years. They are also in general flightless forms. Hypotheses on the relation between heterozygosity in polyploids as well as the consequences of mutations in polyploid lineages are also presented.

Animals↗
PubMed2002

High rate of mixoploidy among human blastocysts cultured in vitro.

OBJECTIVE: To determine the incidence and type of mixoploidy in human blastocysts produced in vitro. DESIGN: A laboratory study of spare blastocysts from an IVF program. SETTING: University hospital laboratory. PATIENT(S): Thirty-nine couples undergoing IVF or intracytoplasmic sperm injection. INTERVENTION(S): A total of 103 blastocysts were classified as good- or poor-quality blastocysts based on morphology. A total of 6,927 interphase nuclei, 5,015 from 59 good-quality and 1,912 from 44 poor-quality blastocysts, were assessed for ploidy by fluorescence in situ hybridization with chromosome-specific DNA probes. MAIN OUTCOME MEASURE(S): The percentage and the type of polyploid cells present in each blastocyst. RESULT(S): Mixoploidy (mixture of diploid and polyploid cells) was found in 86% of good-quality and 82% of poor-quality blastocysts analyzed. The type of polyploidy ranged from 3N to 14N, with tetraploidy being the most common between both groups. The proportion of polyploid cells per mixoploid blastocyst ranged from 1% to 88%. The percentage of polyploid nuclei within most good-quality mixoploid blastocysts was small (10%) and significantly lower than in poor-quality blastocysts (19%). CONCLUSION(S): Most human blastocysts produced in vitro contain polyploid, predominantly tetraploid cells. The proportion of polyploid cells in the majority of good-quality blastocysts is low. The small numbers of blastocysts with a high percentage of polyploid cells may have implications for blastocyst transfer.

Blastocyst↗
PubMed2001

Genesis of clone size heterogeneity in megakaryocytic and other hemopoietic colonies: the stochastic model revisited.

OBJECTIVE: We previously showed that the distributions of the numbers of doublings (NbD) undergone by individual megakaryocyte progenitors before commitment to polyploidization are markedly skewed and can consistently be fitted to straight lines when plotted on semilogarithmic coordinates. The slope of such lines, which yields the probability of polyploidization per doubling, is made less steep by stimulators of megakaryocyte colony formation and is less steep in mixed erythroid-megakaryocyte than in pure megakaryocyte colonies. Therefore, megakaryocytopoiesis provides a unique model for the study of clonal heterogeneity in a hemopoietic lineage, which is the subject of this review. DATA SOURCES: Articles relevant to the interpretation of these data were selected from the authors' and public databases. DATA SYNTHESIS: Exponential NbD distributions were first explained by postulating that following the assembly of thrombopoiesis-specific regulators, megakaryocyte progenitors require only a single random event to arrest proliferation and commit to polyploidization. However, this stochastic model was refuted by data indicating that intrinsic properties of individual progenitors affect the NbD they achieve. We suggest that the unequal repartition of critical compounds (including receptors, signaling molecules, and gene regulators) inherent in the stem cell-progenitor transition causes a heritable heterogeneity in megakaryocyte progenitor responsiveness to polyploidization inducers. This model would be compatible with 1) the evidence for intraclonal synchronization in megakaryocyte and other hemopoietic clones generated by committed progenitors; 2) the low probability of polyploidization of the relatively insensitive bipotent megakaryocyte progenitors; and 3) the thesis that stimulators act in part by recruiting megakaryocyte progenitor cells endowed with lesser responsiveness to polyploidization inducers and higher proliferative potential. CONCLUSION: The responsiveness of individual megakaryocyte progenitors to polyploidization inducers may be a major determinant of the exponential shape of NbD distributions.

Animals↗
PubMed2003

Formation of stable epialleles and their paramutation-like interaction in tetraploid Arabidopsis thaliana.

Polyploidization is found frequently in plants, and species previously considered to be diploid may show remnants of earlier polyploidization events on closer inspection of their genomes. The success of polyploids may lie in increased genetic redundancy supporting subsequent genetic diversification. Although doubling the genome does not generate diversity per se, recent studies show that rapid genomic rearrangements and changes in DNA modification and gene expression patterns are associated with polyploid formation. But recessive modifications will not become phenotypically apparent in early polyploid generations. Here we show that epialleles in tetraploid plants (but not in diploids) interact in trans and lead to heritable gene silencing persisting after segregation from the inactivating allele. This mechanism, resembling paramutation, leads to the establishment of functional epigenetic homozygosity and, thus, to conversion of new recessive alleles into traits expressed in early polyploid generations. Such interactions probably contribute to rapid adaptation and evolution of polyploid plant species.

Alleles↗
PubMed1975

[Morphological and cytofluorometric study of the giant cells of the trophoblast of the common vole].

The primary and secondary giant cells of trophoblast in placenta Microtus arvalis were studied. The giant polyploid nuclei are formed in result of series of successively proceeding endomitotic polyploidization of chromosomes. Two stages of endomitosis are described: endointerphase with the uniform net of thin chromatin threads and the stage when small round or rod-shaped paired chromosomes gather mostly under the nuclear membrane. Great number of round, oval, and complex-shaped nucleoli may be seen in nuclei during both stages of endomitosis, the number growing during polyploidization. The morphology of the chromosome-nucleolar apparatus involves peculiarities of the polyploidization mechanism in placenta Microtus arvalis trophoblast. Endomitosis occurs both in low and high-polyploid nuclei. Cytofluorometric determination of the DNA amount in nuclei polyploid nature. The degree of polyploidy of the trophoblast giant cells nuclei during terminal differentiation of placenta corresponds to 128c-512c, and some nuclei contain the DNA amount corresponding to 1024 and 2048 chromosomal sets. The cause of origin of the polyploid cells in trophoblast of rodents placenta is discussed.

Animals↗
PubMed1987

Significance of polyploidy in megakaryocytes and other cells in health and tumor disease.

Polyploidy--the doubling of chromosome sets of cells caused by a stop of mitosis at different levels of the mitotic cycle--is a phenomenon widely observed in plants, protozoa, metazoa, and animals. In man obligate polyploid tissues are found in liver parenchyma, heart muscle cells, and bone marrow megakaryocytes. Polyploidy occurs mostly in stable and highly differentiated cells and tissues. Besides age, stimulation of proliferation and increased metabolic function lead to polyploidization in these organs. Aneuploidy, however, is exclusively found in tumor cells. Megakaryocyte differentiation and polyploidy are controlled by thrombopoietin-like activities, of which the loci of production are still unknown. Megakaryocytes are unique among polyploid mammal cells. On the precursor level they maintain their proliferative activity independently of the mammal's age. Once having entered the incomplete mitotic cycle they stop cytokinesis and develop into highly polyploid cells. Polyploidization of megakaryocytes is the basic requirement for establishing highly effective hemostasis in mammals, which exhibit blood circulation based on high blood pressures. Every polyploidization results in increased production of membrane materials with which the platelet becomes endowed. By shedding cytoplasmic fragments approximately 3000 platelets are set free from a 32c megakaryocyte, compared with only 16 nucleated thrombocytes by mitotic division. There is further evidence that the heterogeneity of platelets mostly depends on the different polyploidy classes of the megakaryocytes from which they are derived. Changes in the polyploidy pattern of megakaryocytes could therefore have consequences for hemostatic disorders in several human diseases, particularly in malignancy.

Humans↗