Mechanism of induction of polyploidy by colchicine. I. Biochemical studies on dehydrogenase activity in gram (Cicer arietinum) after induction of polyploidy by colchicine.
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Chromosomes↗
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Erythropoietic polyploidy II. Erythropoietic polyploidy in relation to thyroid function and treatment with thyrostatic compounds.
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Adult↗
Erythropoietic polyploidy 3. Erythropoietic polyploidy in relation to endemic goitre and endemic cretinism.
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Adolescent↗
Characterization of premature liver polyploidy in DNA repair (Ercc1)-deficient mice.
ERCC1-XPF is the endonuclease that cuts 5' of the damage in nucleotide excision repair (NER). Unlike other NER proteins, ERCC1-XPF is also involved in recombination and the repair of DNA interstrand cross-links. Unique among the NER gene knockouts, Ercc1 null mice are severely runted with high levels of hepatocyte polyploidy. To understand the link between DNA repair deficiency and polyploidy we have compared the premature polyploidy in Ercc1 null liver with the normal development of polyploidy in aging control mice. Polyploidy was accelerated dramatically in Ercc1 null hepatocytes, such that ploidy levels were equivalent in 3-week-old Ercc1 null and 1- to 2-year-old wild-type mouse liver. Levels of the cyclin-dependent kinase inhibitor, p21, were increased in the nuclei of Ercc1 null hepatocytes, and this increase was concentrated in, but not confined to, the polyploid hepatocytes. Much lower levels of p21 messenger RNA (mRNA) were found in old wild-type liver with equivalent levels of ploidy. We suggest that the more rapid accumulation of DNA damage in Ercc1 null liver leads to an increase in p21 levels, but that there is not a simple direct link between p21 levels and premature polyploidy. The failure to observe any link between p21 levels and polyploidy in aged wild-type liver may be attributable to the much lower levels of accumulated DNA damage, the much greater timescale involved, or the existence of a p21-independent mechanism for polyploidy. In conclusion, the premature polyploidy in Ercc1-deficient liver differs from the normal aging-related process.
Aging↗
Is polyploidy an important genotoxic lesion?
The importance of polyploidy as a genotoxic lesion is uncertain and there have been few publications and no reviews which have included data on spontaneous or induced polyploidy in routine genotoxicity screening. We have attempted to clarify some of the issues by reviewing the published literature and by reference to our historical data base for metaphase analysis of cultured human lymphocytes. In our studies on pharmaceutical compounds polyploidy was the lesion most often found, being induced by approximately 40% of the compounds tested. The mean spontaneous frequency was between 0.1 and 0.3%, and values for polyploidy induction were 5-fold to > 100-fold the spontaneous value. Spontaneous polyploids tended to be near-exact multiples of the haploid chromosome number whereas induced 'polyploids' were, in fact, very heteroploid with a wide range of chromosome numbers. Polyploidy induction often occurred at non-toxic concentrations, usually there were well defined no-effect (threshold) levels and it was unrelated to other genetic effects. Such observations would be expected for inducers of polyploidy because the target molecules are not DNA and for these non-DNA targets there is usually a degree of redundancy. Therefore, inducers of polyploidy are only likely to be a hazard for humans if they are positive at or below therapeutic concentrations. We conclude that polyploidy/near-polyploidy (shown as 'polyploidy' throughout) should be scored as accessory data which becomes important only when induction occurs at therapeutic levels.
Chromosome Aberrations↗
HB-EGF directs stromal cell polyploidy and decidualization via cyclin D3 during implantation.
Stromal cell polyploidy is a unique phenomenon that occurs during uterine decidualization following embryo implantation, although the developmental mechanism still remains elusive. The general consensus is that the aberrant expression and altered functional activity of cell cycle regulatory molecules at two particular checkpoints G1 to S and G2 to M in the cell cycle play an important role in the development of cellular polyploidy. Despite the compelling evidence of intrinsic cell cycle alteration, it has been implicated that the development of cellular polyploidy may be controlled by specific actions of extracellular growth regulators. Here we show a novel role for heparin-binding EGF-like growth factor (HB-EGF) in the developmental process of stromal cell polyploidy in mice. HB-EGF, which is one of the earliest known molecular mediators of implantation in mice and humans, promotes stromal cell polyploidy via upregulation of cyclin D3. Adenoviral delivery of antisense cyclin D3 attenuates cyclin D3 expression and abrogates HB-EGF-induced stromal cell polyploidy in vitro and in vivo. Collectively, the results demonstrate that the regulation of stromal cell polyploidy and decidualization induced by HB-EGF depend on cyclin D3 induction.
Adenoviridae↗
Alterations in beta-adrenoceptors and polyploidy in cultured aortic smooth muscle cells from different age groups of spontaneously hypertensive rats and Wistar-Kyoto rats.
OBJECTIVE: The relationship between the number of beta-adrenoceptors and polyploidy in cultured aortic smooth muscle cells derived from different age groups of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were examined. DESIGN: The number of beta-adrenoceptors, the percentage of multinucleated cells and the incidence of polyploidy from cultured smooth muscle cells derived from SHR and WKY rats aged 3-4, 10-12 and 28-30 weeks were measured. The effect of passaging of the cells on the expression of beta-adrenoceptors and polyploidy on cultured smooth muscle cells from both SHR and WKY rats was also investigated. METHODS: Receptor binding experiments were carried out using [125]-monoiodocyanopindolol with osmotically lysed cultured aortic smooth muscle cells to investigate the properties of vascular beta-adrenoceptors in SHR and WKY rats. The proportion of polyploid smooth muscle cells was determined by frequency distribution analyses of Feulgen DNA microdensitometric measurements. RESULTS: The incidence of polyploid smooth muscle cells was consistently higher in cells cultured from SHR than in those from WKY rats in all three age groups, with a positive correlation between polyploidy and age in SHR. Furthermore, in all three age groups the number of beta-adrenoceptor binding sites was also higher in cultured smooth muscle cells from SHR than in those from WKY rats. There was no significant difference in the receptor affinity. The increase in beta-adrenoceptor number was associated with an increase in polyploidy, and both of these changes were positively correlated both with the age of the rats from which these cells were derived and with the number of passages. CONCLUSIONS: Under cell culture conditions the expression of beta-adrenoceptor density increases with the number of passages in both SHR and WKY rats. Smooth muscle cells derived from older SHR and WKY rats have a greater propensity to develop polyploidy. This trend is significantly accelerated in cultured smooth muscle cells derived from SHR compared with those from WKY rats, suggesting a premature ageing process. These findings suggest that, in cultured smooth muscle cells from SHR and WKY rats, beta-adrenoceptors may influence the expression of polyploidy.
Animals↗
Distribution of diploidy, polyploidy, and endoreduplication in fra(X) positive and negative lymphocytes, amniocytes, and chorionic villi.
Expression of fragile X [fra(X)] (q27.3) and endoreduplicated metaphases have been reported in methotrexate-treated (MTX) fra(X) cultures (Kerem B, Biotein R, Schaap T [1988]: Chromosoma 97: 6-10). Further, new data (Kimchi-Sarfaty C, Goitein R, Kerem B, Werner M, Medan B, Schaap T [1991]: Am J Med Genet, this issue) indicate that MTX may specifically induce polyploidy and endoreduplication in cells with the fra(X) mutation. To confirm and extend these results, we have studied short-term lymphocyte cultures incubated in M199, a folate deficient system, and RPMI-1640 in the presence and absence of 5-fluorodeoxyuridine (FUdR) exposure during the last day of a 4 day culture. No endoreduplicated cells were seen under these conditions and there was no change in the level of polyploidy. We also studied the distribution of polyploid and endoreduplicated cells in amniotic fluid and chorionic villus sample cultures from one fra(X) positive and 4 at-risk specimens. No increase in the incidence of polyploidy or endoreduplication was observed in cultures exposed to MTX for both 24 and 48 hours from a fra(X) positive amniotic fluid case. Cytogenetic results were fra(X) negative for the remaining 4 cases tested. There was significant discordance between our findings and those expected based on MTX-induced increased frequencies of polyploidy and endoreduplication. Thus, our studies do not confirm the reported correlation between the presence of FRAXA and increased frequencies of polyploidy and endoreduplication in MTX-exposed amniocyte cultures and there was no evidence for increased levels of polyploidy and endoreduplication in short-term fra(X) lymphocyte cultures exposed to non-MTX fra(X) induction.
Amniotic Fluid↗
Plant polyploidy and non-uniform effects on insect herbivores.
Genomic duplication through polyploidy has played a central role in generating the biodiversity of flowering plants. Nonetheless, how polyploidy shapes species interactions or the ecological dynamics of communities remains largely unknown. Here we provide evidence from a 4 year study demonstrating that the evolution of polyploidy has reshaped the interactions between a widespread plant and three species of phytophagous moths. Our results show that polyploidy has produced non-uniform effects, with polyploids less attacked by one insect species, but significantly more attacked by two other species. These results suggest that the evolution of plant polyploidy may not generally confer uniform resistance to multiple species of insect herbivores. In the absence of such a uniform release, the extreme evolutionary success of polyploid plants is probably due to factors other than escape from herbivory. Together, these results suggest that a primary consequence of plant polyploidy may be to shape the ecological structure of plant-insect interactions, thereby providing opportunities for diversification in both plant and insect taxa.
Animals↗
The effects of perindopril on vascular smooth muscle polyploidy in stroke-prone spontaneously hypertensive rats.
OBJECTIVE: To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters. DESIGN: The following experimental groups were used: young (age < 20 weeks) and old (age > 20 weeks) untreated WKY rats and untreated SHRSP; SHRSP treated with perindopril, and age- and sex-matched control SHRSP; and SHRSP treated with hydralazine and hydrochlorothiazide and age- and sex-matched control SHRSP. The effects of treatment of the SHRSP with perindopril for 30 days on vascular smooth muscle polyploidy and growth kinetics were measured and compared with the effects of equivalent antihypertensive doses of hydralazine and hydrochlorothiazide. METHODS: Vascular smooth muscle polyploidy was measured using flow-cytometry DNA analysis of freshly harvested cells. Growth curves were performed on cultured aortic cells. Plasma renin activity was measured by an antibody-trapping method, plasma angiotensin II (Ang II) by radioimmunoassay and plasma ACE activity by a colorimetric method. Cardiac hypertrophy was evaluated by measuring the heart weight:body weight and left ventricle + septum weight:body weight ratios. RESULTS: The SHRSP had markedly and significantly elevated G2 + M phase of the cell cycle. Treatment with perindopril resulted in a significant reduction in polyploidy in the SHRSP, whereas treatment with hydralazine and hydrochlorothiazide had no effect on the percentage of cells in the G2 + M phase of the cell cycle. The regression of polyploidy after treatment with perindopril was associated with a significant reduction in the concentration of Ang II and ACE activity, and with a significant regression of cardiac hypertrophy. Increased mitogenesis of cultured vascular smooth muscle cells from the SHRSP was not altered by treatment with perindopril. CONCLUSIONS: ACE inhibition reduces vascular smooth muscle polyploidy in large conduit arteries. This type of vascular protection is mediated by the reduced Ang II and possibly by increased kinins level, rather than by the hypotensive effect alone.
Angiotensin-Converting Enzyme Inhibitors↗
Polyploidy of myocyte nuclei in pressure overloaded human hearts: a flow cytometric study in left and right ventricular myocardium.
Increased heart weight is known to be associated with polyploidy of myocardial nuclei. However, the relation between polyploidy and myocardial hypertrophy at a cellular level, i.e. myocyte hypertrophy, has not yet been investigated. The present study was conducted to reveal this relation in different regions in the heart using two recently developed techniques, i.e. flow cytometry to measure polyploidy and microscopic morphometry to measure myocyte dimensions in fixed tissue sections. We investigated the effect of pressure overload induced hypertrophy in subendocardial and subepicardial regions of 43 human left ventricles and transmural samples from 47 human right ventricles. In all regions the degree of polyploidy correlated well with myocyte volume indexed for body surface area. At equal extent of myocyte hypertrophy, the degree of polyploidy was higher in left ventricular samples than in right ventricular samples. In conclusion, pressure overload induced myocyte hypertrophy is associated with polyploidy, which is more pronounced in the left ventricle than in the right ventricle.
Cell Nucleus↗
Dose-response studies of the induction of hyperdiploidy and polyploidy by diethylstilbestrol and 17beta-estradiol in cultured human lymphocytes using multicolor fluorescence in situ hybridization.
Diethylstilbestrol (DES) and 17beta-estradiol (E2) are known inducers of aneuploidy and polyploidy in vivo and in vitro. Isolated human lymphocytes were treated with the stilbene estrogen DES (0.05-50 microM) and the steroid estrogen E2 (0.05-75 microM) in culture. Multicolor fluorescence in situ hybridization (FISH) with DNA probes for the centromere and adjacent heterochromatin regions of chromosomes 1, 9, and 16 was used to detect hyperdiploidy, polyploidy, and chromosomal breakage affecting these chromosomes. Using this FISH technique, significant nonlinear increases in hyperdiploidy were observed with both compounds, whereas no induction of chromosomal breakage affecting the pericentric heterochromatin regions of chromosomes 1, 9, and 16 could be detected. DES induced a maximum of approximately 13% hyperdiploid cells at 30 microM, whereas E2 showed its highest induction at 75 microM with 7% hyperdiploid cells. To distinguish hyperdiploidy from polyploidy, a FISH labeling strategy to detect multiple chromosomes simultaneously was established. Using this approach, we could show that most of the cells showing multiple hybridization regions after treatment with both chemicals were most likely the result of polyploidy rather than true hyperdiploidy. These results indicate that the induction of hyperdiploidy/polyploidy with DES and E2 show sublinear dose-response relationships with likely threshold concentrations in human lymphocytes and that FISH with multiple probes targeting different chromosomes can be used to estimate hyperdiploidy and polyploidy frequencies.
Benzimidazoles↗
Hepatocyte polyploidy and metabolism/life-history traits: hypotheses testing.
Two alternate hypotheses explaining the causes of mammalian liver polyploidy have been tested by means of statistical analysis of more than 30 placental species. According to the first (general) hypothesis, the omission of mitosis is beneficial in rapidly growing and differentiating tissues that should early perform their specialized functions (economy on mitosis). In this case it is to be expected that the level of polyploidy is positively correlated to the rate of development. The second hypothesis suggests that hepatocyte polyploidy provides additional gene copies necessary under heavy chemical damage to metabolically active hepatocytes, which have to detoxicate noxious substances. In this case it is reasonable to expect that the level of liver ploidy is positively correlated with the rate of metabolism while inversely with the species lifespan (since it is usually assumed that DNA repair systems are more effective in more long-lived species). It is found that, if taken separately, the developmental rate, the rate of basal metabolism, the body weight (inversely), and the maximum lifespan (inversely) are all correlated with the level of hepatocyte polyploidy. However, all these parameters are intercorrelated. When the other parameters are fixed (in partial correlation analysis), only the developmental rate and the rate of basal metabolism remain significant predictors of the hepatocyte ploidy level, with only the former being a predictor of the nuclear ploidy level, while only the latter being positively correlated with the frequency of binucleated cells. These results suggest that relative importance of the two above explanations can differ for the different modes of liver cell polyploidy.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hepatic polyploidy and liver growth control.
The onset of cellular polyploidy is recognized in all differentiated mammalian tissues. Polyploidy has been noted frequently in the normal liver, as well as in pathophysiological states of the liver. As insights into the significance of polyploidy accumulate gradually, it is becoming clear that cells belonging to high ploidy classes exhibit advancement toward terminal differentiation and cellular senescence with greater probabilities of apoptosis. Involvement of specific genetic abnormalities, such as impaired DNA repair, may lead to hepatocellular polyploidy. Working models indicate that extensive polyploidy could lead to organ failure, as well as to oncogenesis with activation of precancerous cell clones.
Animals↗
Polyploidy in cardiac myocytes of normal and hypertrophic human hearts; range of values.
Two-wavelength scanning DNA cytophotometry was used for DNA and protein estimation in human ventricular myocytes. In many hypertrophic hearts weighing more than 500 g the DNA content assessed by ploidy of myocytes, was within the range of normal adult variation (4-10c, where c is the haploid DNA content). A correlation was found between the protein content of myocytes and the weight of the hypertrophic ventricle. In congenital heart disease, the excessive polyploidy (up to 15-20c) developed through the normal route of myocyte polyploidization in childhood. Excessive polyploidization was revealed only in overloaded hypertrophied ventricles. A correlation was identified between the ploidy level, the ventricular weight and age of the child. Excessive polyploidy was also detected in adults with congenital or acquired in childhood diseases. There was no correlation between the myocyte ploidy and age. We propose that childhood polyploidy excess persists in these adults. The ranges of polyploidy are compared with the recent data on genome: protein ratio in cardiac myocytes and the interrelationships allow us to discuss the significance of childhood heart polyploidy as a reserve utilised under pathological conditions in adults.
Adolescent↗
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↗
Noscapine-induced polyploidy in vitro.
The conditions under which noscapine causes high levels of polyploidy in vitro in human lymphocytes were investigated to try to determine its mode of action and to assess whether it was likely to be a genotoxic hazard when used as an antitussive agent. Irrespective of duration of treatment or type of medium, there seemed to be a threshold for polyploidy induction between 15.0 and 30.0 micrograms/ml and a maximum between 100.0 and 150.0 micrograms/ml noscapine. High levels (10.0-20.0%) of noscapine-induced polyploidy were never found with 4 h treatments or with RPMI 1640 medium plus 15% (v/v) foetal calf serum; the use of Iscove's modified Dulbecco's medium and 24 h treatments were needed. The reasons for these observations seemed to be the faster cell division and greater sensitivity of cells grown in Iscove's medium. There was conflicting evidence about the mechanism of polyploidy induction by noscapine; either spindle damage or cell fusion remain as possibilities. The need for prolonged exposure and the precise nutritional requirements suggest that a short exposure, albeit at high concentration, in the upper gastro-intestinal tract is unlikely to be a hazard for humans. Furthermore, evidence of a threshold at approximately 20 micrograms/ml plus the virtual elimination of noscapine-induced polyploidy by microsomal metabolism (S9 mix) together with published metabolic data imply that the low-level systemic exposure after absorption may well not be hazardous. We conclude that the use of noscapine in cough mixtures does not pose a significant potential hazard for humans.
Bromodeoxyuridine↗
Polyploidy associated with oxidative injury attenuates proliferative potential of cells.
Polyploid cells are encountered ubiquitously but the biological significance of polyploidy is unclear. In view of their extensive capacity for regeneration, hepatocytes offer excellent systems for analyzing growth control mechanisms. We isolated hepatocytes from adult rats with and without two-third partial hepatectomy, which induces hepatic polyploidy. Polyploid hepatocytes showed evidence for oxidative injury with antioxidant depletion, lipid peroxidation and 8-hydroxy-adducts of guanine in nuclear DNA. Liver repopulation assays in intact animals showed markedly decreased replication capacity in polyploid hepatocytes. Recapitulation of polyploidy in cultured hepatocytes established that mitogenic stimulation in the presence of oxidative DNA injury was capable of inducing polyploidy. The findings provide novel frameworks in the context of polyploidy for understanding tissue development, regeneration and oncogenesis.
Animals↗