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PubMed2004

[Polyploidy: significance for cardiomyocyte function and heart aerobic capacity].

Somatic polyploidy, defined as genome multiplication, was found in all differentiated mammalian tissues. The highest level of such a polyploidy was found in the myocardium. This phenomenon was shown to be associated with changes in the pattern of gene expression. Hence, polyploidization may create cells with new physiology. The effect of polyploidy on the heart function has never been studied. The aim of the present study was to investigate the effect of polyploidy on cardiomyocyte functioning and heart aerobic capacity. DNA and the total protein content, nucleolar activity reflecting the rate of rRNA synthesis and, consequently, ribosome biogenesis, were measured in ventricular myocytes isolated from the human and from 21 mammalian species by image cytometry and microscopic morphometry. The total protein content was estimated after staining slides with naphtol-yellow dye. For measurement of DNA and nucleolar area, staining with Hoechst and AgNO3 was applied. Cardiac aerobic capacity was evaluated by the heart mass to body mass ratio. A negative correlation between the heart index and the average cell ploidy was revealed (r = -0.79; P < 0.0001). The average genome number per myocyte was registered to be higher by approximately 35% in the sedentary mammals, with the heart index about 0.4% from body mass, than in the athletes with heart index about 0.6% of body mass. Polyploidization was shown to be associated with a sharp decrease in the protein/DNA ratio in cardiomyocytes. As a result, cardiomyocytes in the athletic mammals with poorly polyploid hearts have much higher protein content per genome than do cells in the sedentary species with highly polyploid hearts. Surprisingly, despite decreased protein/DNA ratio, the nucleolar area per genome significantly increased with polyploidization, indicating the imbalance between the cellular protein content and the rate of ribosome biogenesis. Such an imbalance should obviously impair cardiac function, because the additional genomes take some valuable space and biological resources from the cell, which could have been otherwise directed to the maintenance of cardiomyocyte contractile machinery. It is generally accepted that somatic polyploidy is associated with oxidative stress and energetic starvation. Thus, we suppose that additional genomes may serve for cardiomyocyte protection from oxidative damage in the hearts.

Animals↗

PubMed1976

[Somatic polyploidy in animal embryogenesis].

The evidence provided in our laboratory on somatic polyploidy is reviewed. The development of some embryonal cell populations being taken as an example, the main problems of somatic polyploidy are discussed: somatic polyploidy and proliferation, growth, cell differentiation and specialization, the significance of polyploidy in the development of embryonal populations, in the realization of development programs etc. The term "somatic polyploidy" is not thought to involve the complex of phenomena it designates. A new, more precise and general concept is proposed--"hyperreplication of DNA", which seems to cover indeed the whole complex of phenomena characterizing the increase of DNA content in the nuclei of somatic cells including the polyploid ones.

Animals↗

PubMed2005

Molecular evidence for asymmetric evolution of sister duplicated blocks after cereal polyploidy.

Polyploidy (genome duplication) is thought to have contributed to the evolution of the eukaryotic genome, but complex genome structures and massive gene loss during evolution has complicated detection of these ancestral duplication events. The major factors determining the fate of duplicated genes are currently unclear, as are the processes by which duplicated genes evolve after polyploidy. Fine-scale analysis between homologous regions may allow us to better understand post-polyploidy evolution. Here, using gene-by-gene and gene-by-genome strategies, we identified the S5 region and four homologous regions within the japonica genome. Additional phylogenomic analyses of the comparable duplicated blocks indicate that four successive duplication events gave rise to these five regions, allowing us to propose a model for this local chromosomal evolution. According to this model, gene loss may play a major role in post-duplication genetic evolution at the segmental level. Moreover, we found molecular evidence that one of the sister duplicated blocks experienced more gene loss and a more rapid evolution subsequent to two recent duplication events. Given that these two recent duplication events were likely involved in polyploidy, this asymmetric evolution (gene loss and gene divergence) may be one possible mechanism accounting for the diploidization at the segmental level.

Chromosomes, Artificial, Bacterial↗

PubMed1978

The development of polyploidy in two classes of rat liver nuclei.

Two classes of nuclei from livers of Sprague-Dawley rats were isolated, one pelleting in 2.3 M sucrose (H nuclei) and the second class sedimenting through 1.6 and 1.8 M sucrose and banding at the 1.8/2.3 M sucrose interface (L nuclei) of a three-step discontinuous gradient. In younger animals, the L nuclear fraction was the major fraction, but the percentage of nuclei found in the L fraction decreased as the animals grew. Nuclear ploidy was determined by flow microfluorometry using propidium iodide as a DNA stain. Both the H and L nuclear fractions contained diploid, tetraploid and octaploid nuclei; but the degree of polyploidy was greater in the H fraction. Concomitant with the change in distribution of nuclei between the H and L fractions with increasing age was a progressive increase in the degree of polyploidy in the H fraction. Polyploidy did not increase linearly with age in the H nuclear fraction but increased in cycles marked by large changes in the numbers of nuclei found in H and L nuclear fractions. By 12 weeks of age, 4n-H nuclei were the largest single population of nuclei in rat liver. These observations suggested that the shift of liver nuclei from the L fraction to the H fraction was associated with the development of polyploidy and with the differentiation of hepatocytes.

Aging↗

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↗

PubMed2005

Polyploidy and genome evolution in plants.

Genome doubling (polyploidy) has been and continues to be a pervasive force in plant evolution. Modern plant genomes harbor evidence of multiple rounds of past polyploidization events, often followed by massive silencing and elimination of duplicated genes. Recent studies have refined our inferences of the number and timing of polyploidy events and the impact of these events on genome structure. Many polyploids experience extensive and rapid genomic alterations, some arising with the onset of polyploidy. Survivorship of duplicated genes are differential across gene classes, with some duplicate genes more prone to retention than others. Recent theory is now supported by evidence showing that genes that are retained in duplicate typically diversify in function or undergo subfunctionalization. Polyploidy has extensive effects on gene expression, with gene silencing accompanying polyploid formation and continuing over evolutionary time.

Evolution, Molecular↗

PubMed1997

Needle crystals of vitamin B2 induce polyploidy in Chinese hamster lung (CHL/IU) cells.

Induction of polyploidy by vitamin B2 (VB2) was investigated in cultured Chinese hamster lung (CHL/IU) cells. We report that VB2 in the form of needle crystals induces polyploidy via the formation of CHL/IU cells with more than one nucleus. The incidence of polyploid cells depended on the amount of needle crystals. No induction of polyploidy was observed when VB2 was used in solution. Electron-microscopic examination revealed that needle crystals adhered to the cell surface, and were enclosed by viscous cellular materials. These results indicate that needle crystals of VB2 have the ability to induce polyploidy in cultured CHL/IU cells, probably by physically fixing the shape of the cells and by this preventing normal mitosis.

Animals↗

PubMed2006

Independent ancient polyploidy events in the sister families Brassicaceae and Cleomaceae.

Recent studies have elucidated the ancient polyploid history of the Arabidopsis thaliana (Brassicaceae) genome. The studies concur that there was at least one polyploidy event occurring some 14.5 to 86 million years ago (Mya), possibly near the divergence of the Brassicaceae from its sister family, Cleomaceae. Using a comparative genomics approach, we asked whether this polyploidy event was unique to members of the Brassicaceae, shared with the Cleomaceae, or an independent polyploidy event in each lineage. We isolated and sequenced three genomic regions from diploid Cleome spinosa (Cleomaceae) that are each homoeologous to a duplicated region shared between At3 and At5, centered on the paralogs of SEPALLATA (SEP) and CONSTANS (CO). Phylogenetic reconstructions and analysis of synonymous substitution rates support the hypothesis that a genomic triplication in Cleome occurred independently of and more recently than the duplication event in the Brassicaceae. There is a strong correlation in the copy number (single versus duplicate) of individual genes, suggesting functionally consistent influences operating on gene copy number in these two independently evolving lineages. However, the amount of gene loss in Cleome is greater than in Arabidopsis. The genome of C. spinosa is only 1.9 times the size of A. thaliana, enabling comparative genome analysis of separate but related polyploidy events.

Arabidopsis↗

PubMed1994

Differential effect of renal wrap hypertension on aortic smooth muscle polyploidy in the rat and rabbit.

1. The incidence of aortic smooth muscle cell polyploidy was investigated in rabbits and rats with renal wrap induced (cellophane perinephritic) chronic hypertension. 2. Bilateral renal cellophane wrapping was performed in young adult animals. Blood pressure was measured intra-arterially in the rabbits twice during the experimental period and tail-cuff blood pressure measured twice weekly in the rats. At 8 weeks post-surgery the incidence of aortic smooth muscle cell polyploidy was determined in enzymatically isolated cells by flow cytometric DNA analysis. 3. Systolic blood pressure was significantly increased in the bilateral renal wrapped rabbits and rats compared to the shams, such that at 8 weeks post-surgery, systolic blood pressure was 139 +/- 2 mmHg and 84 +/- 2 mmHg, respectively, in the rabbits and 188 +/- 6 mmHg and 155 +/- 4 mmHg, respectively, in the rats. 4. The incidence of polyploid smooth muscle cells was significantly higher in the hypertensive renal wrapped rat compared to the sham (20.9 +/- 1.5% and 8.1 +/- 0.5%, respectively). However, the incidence of polyploid cells was low in the rabbit aortae with no significant difference in the incidence of aortic smooth muscle polyploidy in the hypertensive rabbit compared to the sham (2.6 +/- 0.6% and 2.7 +/- 0.6%, respectively). 5. This study demonstrates a species difference in the induction of polyploidy during the same model of experimental hypertension in aortic smooth muscle derived from the rabbit and rat.

Animals↗

PubMed2005

Induction of polyploidy by histone deacetylase inhibitor: a pathway for antitumor effects.

Histone deacetylase (HDAC) inhibitors can induce various transformed cells to undergo growth arrest and/or death. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor which is in phase I/II clinical trials and has shown antitumor activity in hematologic and solid tumors at doses well tolerated by patients. HDAC is the target for SAHA, but the mechanisms of the consequent induced death of transformed cells are not completely understood. In this study, we report that SAHA induced polyploidy in human colon cancer cell line HCT116 and human breast cancer cell lines, MCF-7, MDA-MB-231, and MBA-MD-468, but not in normal human embryonic fibroblast SW-38 and normal mouse embryonic fibroblasts. The polyploid cells lost the capacity for proliferation and committed to senescence. The induction of polyploidy was more marked in HCT116 p21WAF1-/- or HCT116 p53-/- cells than in wild-type HCT116. The development of senescence of SAHA-induced polyploidy cells was similar in all colon cell lines. The present findings indicate that the HDAC inhibitor could exert antitumor effects by inducing polyploidy, and this effect is more marked in transformed cells with nonfunctioning p21WAF1 or p53 genes.

Antineoplastic Agents↗

PubMed1996

Vascular smooth muscle polyploidy and cardiac hypertrophy in genetic hypertension.

We studied the mechanisms responsible for vascular and cardiac hypertrophy in hypertension (pressure load and humoral and genetic factors) in two experimental approaches: (1) We carried out a cosegregation analysis to correlate cardiac and vascular hypertrophy with subphenotypes of blood pressure in an F2 generation of a cross between stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats; (2) we treated 8-week-old SHRSP with perindopril, an angiotensin-converting enzyme inhibitor; losartan, an angiotensin type 1 receptor antagonist; or perindopril combined with a nitric oxide synthase inhibitor to investigate the relative contributions of blood pressure and angiotensin II to the pathogenesis of cardiac hypertrophy and vascular smooth muscle polyploidy. Vascular smooth muscle polyploidy was measured with flow cytometry DNA analysis. Cardiac hypertrophy was assessed by measuring the ratios of heart weight to body weight and left ventricle + septum weight to body weight. Blood pressure was measured with radiotelemetry in the F2 cosegregation experiment and with tail-cuff plethysmography in the pharmacological study. In the F2 rats, the best predictor of smooth muscle polyploidy by ANCOVA was systolic pressure (F=29.28, P < .0001). The ratio of left ventricle + septum weight to body weight had four major predictors: the male progenitor of the cross, sex, pulse pressure, and change in systolic pressure during salt (F=43.67, P < .0001; F=16.37, P < .0001; F=8.41, P=.0022; and F=12.39, P= .0003, respectively). The ratio of heart weight to body weight had similar predictors. In the pharmacological study, treatment with losartan alone, perindopril alone, or perindopril in combination with N(G)-nitro-L-arginine methyl ester prevented the development of smooth muscle polyploidy and cardiac hypertrophy. The prevention of cardiac hypertrophy was most marked in the SHRSP treated with perindopril plus N(G)-nitro-L-arginine methyl ester, despite blood pressure being higher in this group than in the two other treatment groups. We conclude that vascular and cardiac hypertrophy in this form of hypertension are regulated by different variables. However, suppression of the action of angiotensin II lessens hypertrophy of both types of muscle.

Angiotensin II↗

PubMed2004

Evolution by polyploidy and gene regulation in Anura.

The evolution of the metazoa has been characterized by gene redundancy, generated by polyploidy, tandem duplication and retrotransposition. Polyploidy can be detected by looking for duplicated chromosomes or segments of orthologous chromosomes in post-polyploid animals. It has been proposed that the evolutionary role of polyploidy is to provide extra-copies of genes, whose subsequent alteration leads to new functions, increased biological complexity, and, ultimately, speciation. We review the theory of evolution by genome duplication, basing our arguments on findings from autopolyploid anurans and fish, undergoing post-polyploidy diploidization. We conclude that: 1) the high genetic variability of autotetraploid anurans is a result of tetrasomic expression, based on studies of isozymes and other proteins. 2) Epigenetic mechanisms mediate the reduced expression or silencing of redundant copies of genes in the regulation of gene expression of these tetraploids. This conclusion is based on data concerning ribosomal and hemoglobin gene activity. 3) Duplication of the genome may have occurred more than once in the phylogeny of the anurans, as exemplified by 4n and 8n Leptodactylidae species.

Animals↗

PubMedDate not supplied

The effect of 13-cis-retinoic acid on dibutylnitrosamine induced polyploidy changes in mouse urothelium.

The epithelium in the normal urinary bladder contains cells with diploid to octoploid DNA-content. The carcinogen dibutylnitrosamine (DBN), given subcutaneously in repeated doses causes a loss of polyploidy prior to cancer development. In this study the changes in polyploidy caused by DBN was followed by use of flow cytometry. 13-cis-retinoic acid did not prevent this loss of polyploidy, and did not affect the polyploidy in the normal urothelium.

Animals↗

PubMed2005

In vitro induction of polyploidy and chromatid exchanges by culture medium extracts of natural rubbers compounded with 2-mercaptobenzothiazole as a positive control candidate for genotoxicity tests.

We tested extracts of custom-made natural rubber samples for cytotoxicity using V79 cells and for chromosome aberration (CA) induction using CHL cells in compliance with the Japanese guidelines for basic biological tests of medical materials and devices. The samples were formulated with a high level of 2-mercaptobenzothiazole (MBT) (A); a low level of MBT (B); or zinc dibutyldithiocarbamate (ZDBC) (C). In the CA test, MBT induced mainly polyploidy, including endoreduplication, and ZDBC induced structural CAs. In the cytotoxicity test, culture medium extracts of A, B, and C suppressed colony formation to 50% of the control value at 53.1%, 94.3%, and >100%, respectively. Culture medium extracts of sample A induced polyploidy and structural CAs in the absence of an exogenous metabolic activation system (S9 mix), but at lower concentrations in its presence, indicating the existence of other leachable promutagens. The extracts of sample B induced structural CAs at the highest concentration and only with S9 mix. Sample C was negative. The facts suggest that sample A may be a candidate for a positive control for genotoxicity tests. The high frequency of polyploidy induced by sample A was not predicted by MBT, suggesting the usefulness of the test for safety evaluation of medical devices. Numerical CAs induced by MBT and sample A are discussed.

Animals↗

PubMed2002

Roads to polyploidy: the megakaryocyte example.

Polyploidy, recognized by multiple copies of the haploid chromosome number, has been described in plants, insects, and in mammalian cells such as, the platelet precursors, the megakaryocytes. Several of these cell types reach high ploidy via a different cell cycle. Megakaryocytes undergo an endomitotic cell cycle, which consists of an S phase interrupted by a gap, during which the cells enter mitosis but skip anaphase B and cytokinesis. Here, we review the mechanisms that lead to this cell cycle and to polyploidy in megakaryocytes, while also comparing them to those described for other systems in which high ploidy is achieved. Overall, polyploidy is associated with an orchestrated change in expression of several genes, of which, some may be a result of high ploidy and hence a determinant of a new cell physiology, while others are inducers of polyploidization. Future studies will aim to further explore these two groups of genes.

Animals↗

PubMed1984

Occurrence of polyploidy and multinuclearity in the differentiating liver of chick embryo.

Increase in nuclear size in liver has been used as an index of polyploidy. It has long been considered that the occurrence of polyploidy and multinuclearity are characteristics of mammalian liver. The present study shows the occurrence of these phenomena in the liver of birds, so these features are not confined to mammals. 3 classes of nuclear size groups have been identified. The simultaneous occurrence of polyploidy and binuclearity indicates some sort of interrelationship between them.

Animals↗

PubMed2005

Polyploidy, evolutionary opportunity, and crop adaptation.

The finding that even the smallest of plant genomes has incurred multiple genome-wide chromatin duplication events, some of which may predate the origins of the angiosperms and therefore shape all of flowering plant biology, adds new importance to the molecular analysis of polyploidization/diploidization cycles and their phenotypic consequences. Early clues as to the possible phenotypic consequences of polyploidy derive from recent QTL mapping efforts in a number of diverse crop plants of recent and well-defined polyploid origins. A small sampling examples of the role(s) of polyploidy in conferring crop adaptation from human needs include examples of (1) dosage effects of multiple alleles in autopolyploids, and (2) 'intergenomic heterosis' conferring novel traits or transgressive levels of existing traits, associated with merging divergent genomes in a common allopolyploid nucleus. A particularly interesting manifestation of #2 is the evolution of complementary alleles at corresponding ('homoeologous') loci in divergent polyploid taxa derived from a common ancestor. Burgeoning genomic data for both botanical models and major crops offer new avenues for investigation of the molecular and phenotypic consequences of polyploidy, promising new insights into the role of this important process in the evolution of botanical diversity.

Adaptation, Biological↗

PubMed1983

Liver polyploidy: influence of age and of dietary restriction.

Polyploidy increases with age in mammalian liver. Since dietary restriction increases lifespan, the question posed in this study was whether liver polyploidy would be influenced by dietary protein restriction. Restricted mice were fed a 4% protein diet, while control mice received a 26% protein diet. Polyploidy was determined from measurements of nuclear diameter on liver of 3 week, 1 1/2, 3, 10, 20 and 24-1/2 month old Swiss albino mice. The percentage of polyploid cells increased steadily with age. The rate of increase, expressed as the polyploidization index, was greater in the fully fed control animals as compared to the animals on protein restriction. Protein restriction thus retards the age associated process of polyploidization of liver nuclei. Nuclear diameter increased slightly with age, but was not influenced by protein restriction.

Aging↗