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PubMed1975

Polyploidization and endomitosis in giant cells of rabbit trophoblast.

Morphological and cytophotometric investigations have been performed on giant cells of the rabbit trophoblast to reveal a mechanism of nuclei polyploidization and define the level of polyploidy. The character of endomitotic chromosomes is found to differ and depend largely on the degree of nuclei polyploidy. Small chromosomes were found in nuclei with low levels of polyploidy. For highly polyploid nuclei, two stages are distinguished. In the first case condensed chromosomes join into bundles resembling Riesenchromosomen in plants, whereas in the second, decondensed chromosomal threads separate and disperse in the karyoplasm. The splitting does not involve nuclei-forming chromosomes in the region of the nucleolar organiser. The degree of polyploidy was determined on the 15th day of development. It was found that giant cell nuclei contain DNA in amounts corresponding to 32-512 chromosomal sets. Most of the nuclei have levels of 128c and 256c. Highly-polyploid nuclei disintegrate into small nuclei with the degree of polyploidy varying from 1c to 32c. Di- tri- and tetraploid nuclei predominate.

Animals↗
PubMed1998

Aneuploidy: a report of an ECETOC task force.

Aneuploidy plays a significant role in adverse human health conditions including birth defects, pregnancy wastage and cancer. Although there is clear evidence of chemically induced aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected aneugens are negative in the bacterial mutation assay. 3. The majority of definitive aneugens evaluated induce polyploidy in vitro. With few exception, they also induced structural chromosome aberrations in vitro. 4. All of the definitive aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ cells and not in somatic cells. Furthermore, an analysis of several databases indicates the proportion of chemicals which induce polyploidy and not chromosome aberrations in vitro is low. Based on these conclusions, the following recommendations are made: for screening purposes, a standard genotoxicity test battery (including an in vitro cytogenetic assay with an assessment of polyploidy and clastogenicity at the same harvest time) should be performed; in the absence of polyploidy induction in vitro no further evaluation of aneuploidy-inducing potential is needed; if polyploidy is observed, in vitro follow-up testing to investigate further the aneuploidy-inducing potential should be conducted; such follow-up testing will generally start with the conduct of a standard in vivo somatic cell micronucleus assay; if the in vivo somatic cell micronucleus assay is negative, with adequate evidence of exposure of the bone marrow to the test compound, no further testing of aneuploidy-inducing potential is needed; if the in vivo somatic cell micronucleus assay is positive, further information on mechanisms of micronucleus induction can be obtained by using kinetochore/centromeric staining in vitro and/or in vivo; an assessment of potential germ cell aneuploidy activity may then be considered; aneuploidy induction which does not involve the direct interaction of a chemical or its metabolite(s) with DNA is expected to have a threshold. This must be considered in the risk assessment of such chemicals; this is not addressed by current risk assessment guidelines.

Abnormalities, Drug-Induced↗
PubMed1995

Review: a major component of radiation action: interference with intracellular control of differentiation.

If genetic lesions were the sole reason of damage induced by ionizing radiation, an increase in the number of identical chromosome sets (polyploidy) may be expected to have a radioprotective effect. This effect is evident in terminally differentiated tissues when the reduction in remaining life span is used as the criterion. This effect is also evident in cells capable of proliferation if cytoplasmic growth during the period of mitotic delay is restricted and the criterion used is continuation of cell proliferation. Both instances demonstrate that polyploidy, in principle, can exert a radioprotective effect, although the genetic damage induced by a given dose increases in approximate proportion to ploidy. However, in mitotically active cells, without restrictions in cytoplasmic growth, differentiation enhancement dominates the effects of genetic lesions, and polyploidy does not protect. Enhancement of differentiation causes damage by eliminating amplification divisions normally passed through by cell progenies before terminal differentiation, thus reducing the number of differentiated cells produced. From its dependence on excess cytoplasmic growth it is concluded that the phenomenon is caused by the interference of ionizing radiation with a mechanism that provides intracellular signals needed to coordinate molecular interactions involved in the control of cell differentiation. This conclusion corresponds to experiments that suggest that intracellular control of differentiation depends on an increase in the ratio of essential cytoplasmic constituents, probably mitochondrial genomes, per nuclear genome. The action of chemical differentiation enhancing agents is similar and an outline of probable mechanisms is presented. Regarding late radiation damage it is concluded that non-specific genetic lesions can enhance differentiation by permanently prolonging the cell cycle, which causes an increased cytoplasmic growth rate per cycle. In this case polyploidy cannot protect because the induced genetic lesions are proportional to ploidy. Both the duration of mitotic delay, and the extent of genetic lesions increase with chromosome size, thus explaining the correlation between interphase chromosome volume and radio-sensitivity. Lack of substantial radioprotecting effect of polyploidy in neoplastically transformed mammalian cells indicates residual capabilities to cease cell proliferation by mechanisms related to terminal differentiation, thus offering clues to tumour therapy.

Animals↗
PubMed1980

Changes in polyploidization of exocrine pancreas in db/db diabetic and normal mice.

Polyploidy in tele-insular and peri-insular exocrine pancreas of C57BL/KsJ-db/db diabetic mice and normal littermate controls was quantitated, because the diseased state has been shown to produce an increase in the percentage of polyploid islet B-cells. Three diabetic and 3 normal animals were sacrificed at 4.5, 7, 9.5, 12, 14.5, and 17 weeks of age. Semi-automatic nuclear size analysis on Feulgen stained sections separated the nuclei into polyploid classes, with the following results: 1) In both normal and diabetic mice, percentages of polyploid cells in peri-insular and tele-insular regions differed significantly from one another, and from that of the islet B-cells. Per-cent polyploidy was highest in the peri-insular regions, and lowest in the islets. 2) In the tele-insular regions, per cent polyploidy did not differ between normals and diabetics at 4.5 weeks. By 17 weeks, polyploidy in the diabetics was essentially unchanged, while that of the normal animals had risen and become significantly elevated over that of both the 4.5 week normal and the 17 week diabetic animals. 3) In peri-insular regions, per cent polyploidy did not differ significantly between normals and diabetics throughout the period studied.

Animals↗
PubMed2006

On the abundance of polyploids in flowering plants.

The wide distribution of polyploidy among plants has led to a variety of theories for the evolutionary advantages of polyploidy. Here we claim that the abundance of polyploidy may be the result of a simple ratcheting process that does not require evolutionary advantages due to the biological properties of organisms. The evolution of polyploidy is a one-way process in which chromosome number can increase but not decrease. Using a simple mathematical model, we show that average ploidal level within a plant lineage can continually increase to the levels observed today, even if there are ecological or physiological disadvantages to higher ploidy. The model allowed us to estimate the average net speciation and polyploidy rates for ten angiosperm genera. Based on these estimates, the model predicts distributions of ploidal levels statistically similar to those observed in nine of the 10 genera.

Biological Evolution↗
PubMed1997

Investigation of effects of pregnant mare serum gonadotropin (PMSG) on the chromosomal complement of CD-1 mouse embryos.

PURPOSE: The objective of this study was to examine the effect of superovulatory doses of gonadotropins on the frequency of chromosomal abnormalities of mouse embryos. METHODS: Chromosome analysis of 8- to 16-cell stage mouse embryos and zygotes was performed by a cytogenetic method. RESULTS: There was no significant effect of the pregnant mare serum gonadotropin (PMSG) dose on the level of aneuploidy and structural abnormalities from 8- to 16-cell-stage embryos among superovulated groups. However, a simple dose-response relationship between the PMSG dose and the incidence of polyploidy was observed, with the level of polyploidy rising from 2.9% with 10 i.u. PMSG to 10.5% with 15 i.u. PMSG. In zygote stage, the proportion of polyploid embryos also increased as the dose increased, from 1.9% in 5 i.u. to 6.7% in 15 i.u. PMSG. It was observed that the extra chromosomal set in polyploidy embryos originated by both fertilization of a diploid oocyte and dispermy. CONCLUSIONS: These results indicate a dose-response relationship between the PMSG dose and the incidence of polyploidy in the CD-1 mouse. Both a disturbance at maturation division and an error at fertilization were the cause of polyploidy.

Aneuploidy↗
PubMed1986

[Correlation between nuclear DNA content and cellular morphology in endometrial cancer--analysis by cell sorting with flow cytometry].

A comparative study of nuclear DNA content and morphological features of various endometrial lesions was carried out. The results were as follows: Similar nuclear DNA patterns were obtained by both FCM and fluorescence cytophotometry. On nuclear DNA histograms, a monopeak at 2C was shown in normal endometrium. In hyperplasia, a peak at 2C and a tapering pattern to 4C was shown. In endometrial cancer, 3C cells were characteristic of a well differentiated type, and polyploidy cells over 4C was specific for an anaplastic type. In a comparison of the nuclear area and nuclear DNA content, nuclear area correlates well with nuclear DNA content in 2C and 3C, and does not correlate well in polyploidy over 4C because of a chromatin conformation. In a comparison of nuclear DNA content with cellular morphology on endometrial cancer, 2C cells were 33.2 micron2, 3C were 55.8 micron2, and polyploidy were 78.1 micron2 in the nuclear area. It is easy to diagnose polyploidy as malignant, but very hard to recognize 2C and 3C cells as malignant. In a well differentiated type, the richness of 3C cells which are relatively hard to detect makes the diagnosis difficult. To make a correct diagnosis, not only polyploidy cells but 3C cells have to be detected precisely.

Cell Nucleus↗
PubMed1987

Cytogenetic evaluation of human endothelial cell cultures.

Cytogenetic evaluation of serially subcultivated human endothelial cells revealed significant differences between cultures derived from fetal umbilical cords and cultures derived from various vessel sites in adults. A rapid increase in the prevalence of polyploid cells, to levels of 100% in many cases, was detected in human umbilical vein endothelial cell cultures but not in endothelial cell cultures from adult vessels. Because the development of polyploidy has been viewed as one signpost of in vitro senescence, it may be that these in vitro observations of high levels of polyploidy are a reflection of the fact that umbilical tissue is at the end of its in vivo developmental lifespan when studied. Consistent karyotypic alterations also were observed in two clones from adult human abdominal aorta, even though these cultures exhibited low percentages of polyploid cells. Cultures of one clone exhibited a trisomy of chromosome 11, on which there are at least three onc gene loci, and a deletion of chromosome 13 through band q14. A loss of band 13q14 is a prezygotic chromosomal lesion known to predispose to retinoblastoma. In the other clone, two cell populations were observed, and each displayed a chromosomal abnormality. A trisomy of the long arm of chromosome 2 was noted in one cell population via a marker chromosome involving 2 and 14. The other cell population exhibited an abnormality of chromosome 2. Neither of these karyotypic alterations was detected in the parent culture from which the clones were derived. The results reported in this study have both practical and theoretical implications. The high incidence of polyploidy in serially cultivated umbilical cultures as well as the occurrence of chromosomal changes in umbilical and aortic cultures testify to the need for cytogenetic monitoring of cell cultures even though they are derived from presumably normal tissue. Cytogenetic changes in the endothelium may be important in atherogenesis and other pathologic states. The conversion of diploid endothelial cells into polyploid endothelial cells may provide a convenient model cell system for studying mechanisms of the development of polyploidy in cells and their relationship to in vitro senescence.

Adult↗
PubMed1997

Amplification of growth factor receptor genes and DNA ploidy pattern in the progression of gastric cancer.

To study the background of oncogene amplification in gastric cancers, we examined the correlation between occurrence of oncogene amplification and DNA ploidy pattern. In 57 primary gastric cancers, amplifications of c-erbB, c-erbB-2, c-met and K-sam genes were investigated by Southern blot analysis, and the DNA ploidy pattern was determined by static cytofluorometry and by flow cytometry. Oncogene amplification was detected in 11 cancers, 10 of which were advanced gastric cancers and 1 was an early differentiated type. The amplification of c-erbB-2 and K-sam genes was found exclusively in differentiated- and undifferentiated-type cancers, respectively. Of the 11 cancers, 5 were DNA-diploid and 6 were DNA-aneuploid. All the 11 tumours with oncogene amplification contained polyploid cell populations (polyploidy), whereas none of the tumours without polyploidy showed oncogene amplification. In differentiated-type cancers the incidence of polyploidy was high in both early and advanced stages, while in undifferentiated-type cancers it was low in early stages but significantly higher in advanced stages. It was shown that amplification of growth factor receptor genes is closely related to the presence of polyploidy, irrespective of any different stemline DNA-ploidy mode. The time-course of oncogene amplification and kinds of genes amplified may differ between differentiated- and undifferentiated-type gastric cancers.

Adenocarcinoma↗
PubMed2006

Paleopolyploidy and gene duplication in soybean and other legumes.

Two of the most important observations from whole-genome sequences have been the high rate of gene birth and death and the prevalence of large-scale duplication events, including polyploidy. There is also a growing appreciation that polyploidy is more than the sum of the gene duplications it creates, in part because polyploidy duplicates the members of entire regulatory networks. Thus, it may be important to distinguish paralogs that are produced by individual gene duplications from the homoeologous sequences produced by (allo)polyploidy. This is not a simple task, for several reasons, including the chromosomally cryptic nature of many duplications and the variable rates of gene evolution. Recent progress has been made in understanding patterns of gene and genome duplication in the legume family, specifically in soybean.

Biological Evolution↗
PubMed2002

Relevance of chemical structure and cytotoxicity to the induction of chromosome aberrations based on the testing results of 98 high production volume industrial chemicals.

Over a 6-year period (1991-1996), the chromosomal aberration testing of high production volume (HPV) industrial chemicals had been conducted using Chinese hamster lung (CHL/IU) cells according to OECD HPV testing program and the national program in Japan. A total of 98 chemicals were tested for the induction of chromosome aberration (CA), consisting of structural CA and polyploidy. Of the 98 chemicals, structural CA and/or polyploidy were induced by 39 chemicals (40%). Anilines and phenols tended to induce only structural CA. p-tert-Butylphenol had a peculiar feature in inducing not only structural CA but also polyploidy at considerably high frequency (93.2%) after continuous treatment for 48 h, posing an aneugenic potential. Not all, but six of 11 carboxylic acids or esters also showed the simultaneous induction of structural CA and polyploidy. The majority of organic phosphates, alcohols or ethers, alkyl benzenes and non-cyclic alkanes had no CA induction activity. For chemicals which were negative in the bacterial reverse mutation assay (Ames test), the proportion of the chemicals that induced CA at a severely cytotoxic dose (doses manifesting more than 50% cytotoxicity) was similar to that of the CA-negative chemicals manifesting severe cytotoxicity, suggesting that severely cytotoxic chemicals do not always induce CA.

Alcohols↗
PubMed2005

Chromosomal instability induced by Pim-1 is passage-dependent and associated with dysregulation of cyclin B1.

Overexpression of the oncogenic serine/threonine kinase Pim-1 has been shown to induce chromosomal missegregation and polyploidy in prostate epithelial cell lines (1). Here we demonstrated that Pim-1-induced polyploidy develops in a passage-dependent manner in culture consistent with a stochastic mode of progression. Induction of chromosomal instability by Pim-1 was not restricted to prostate cells as it was also observed in telomerase-immortalized normal human mammary epithelial cells. Elevated levels of cyclin B1 protein, but not its messenger RNA, were evident in early passage Pim-1 overexpressing cells, suggesting that increased cyclin B1 levels contribute to the development of polyploidy. Furthermore, regulation of cyclin B1 protein and cyclin B1/CDK1 activity after treatment with anti-microtubule agents was impaired. Small interfering RNA targeting cyclin B1 reversed the cytokinesis delay but not the mitotic checkpoint defect in Pim-1 overexpressing cells. These results indicated that chronic Pim-1 overexpression dysregulates cyclin B1 protein expression, which contributes to the development of polyploidy by delaying cytokinesis.

Animals↗
PubMed2006

Analysis of polyploid cells in mouse embryonic cells cultured under diabetic conditions.

To clarify the cytogenetic effects of glucose and ketone bodies on the pathogenesis of diabetes-associated congenital anomalies, we cultured cells from gestation-day-8 ICR mouse embryos under the diabetic condition. Cells were cultured in the medium with glucose (300 mg/dL) plus DL-2-hydroxybutyric acid (32 mM) (G + B group), glucose alone (G group), or neither of them (C group) for 5 days. At the end of the culture, cells were analyzed for the chromosomes. After 3-4 days culture, when the living cells grew into a mono-layered sheet, cells floating in the medium were observed and showed morphological features of apoptosis. Ratio of the floating cells was significantly higher in the G + B group than in the G or C group (P < 0.05), suggesting the deleterious effect of glucose and ketone body. Polyploidy was observed in the cultured cells more frequently in the G + B group (64.1%) than in the G group (49.0%), which was higher than the C group (20.5%) (G + B vs G: P < 0.05, G vs C: P < 0.001). The higher ratio of the polyploidy, but not of the aneuploidy, in the G + B and G groups suggested the specific effect of glucose and ketone body for inducing polyploidy. These results suggest that diabetic condition causes polyploidy in cultured embryonic cells.

Animals↗
PubMed2000

Polyploid incidence and evolution.

Changes in ploidy occurred early in the diversification of some animal and plant lineages and represent an ongoing phenomenon in others. While the prevalence of polyploid lineages indicates that this phenomenon is a common and successful evolutionary transition, whether polyploidization itself has a significant effect on patterns and rates of diversification remains an open question. Here we review evidence for the creative role of polyploidy in evolution. We present new estimates for the incidence of polyploidy in ferns and flowering plants based on a simple model describing transitions between odd and even base chromosome numbers. These new estimates indicate that ploidy changes may represent from 2 to 4% of speciation events in flowering plants and 7% in ferns. Speciation via polyploidy is likely to be one of the more predominant modes of sympatric speciation in plants, owing to its potentially broad-scale effects on gene regulation and developmental processes, effects that can produce immediate shifts in morphology, breeding system, and ecological tolerances. Theoretical models support the potential for increased adaptability in polyploid lineages. The evidence suggests that polyploidization can produce shifts in genetic systems and phenotypes that have the potential to result in increased evolutionary diversification, yet conclusive evidence that polyploidy has changed rates and patterns of diversification remains elusive.

Animals↗
PubMed2000

Genome evolution in polyploids.

Polyploidy is a prominent process in plants and has been significant in the evolutionary history of vertebrates and other eukaryotes. In plants, interdisciplinary approaches combining phylogenetic and molecular genetic perspectives have enhanced our awareness of the myriad genetic interactions made possible by polyploidy. Here, processes and mechanisms of gene and genome evolution in polyploids are reviewed. Genes duplicated by polyploidy may retain their original or similar function, undergo diversification in protein function or regulation, or one copy may become silenced through mutational or epigenetic means. Duplicated genes also may interact through inter-locus recombination, gene conversion, or concerted evolution. Recent experiments have illuminated important processes in polyploids that operate above the organizational level of duplicated genes. These include inter-genomic chromosomal exchanges, saltational, non-Mendelian genomic evolution in nascent polyploids, inter-genomic invasion, and cytonuclear stabilization. Notwithstanding many recent insights, much remains to be learned about many aspects of polyploid evolution, including: the role of transposable elements in structural and regulatory gene evolution; processes and significance of epigenetic silencing; underlying controls of chromosome pairing; mechanisms and functional significance of rapid genome changes; cytonuclear accommodation; and coordination of regulatory factors contributed by two, sometimes divergent progenitor genomes. Continued application of molecular genetic approaches to questions of polyploid genome evolution holds promise for producing lasting insight into processes by which novel genotypes are generated and ultimately into how polyploidy facilitates evolution and adaptation.

Evolution, Molecular↗
PubMed1995

[Evolution of aneuploidy from diploid colorectal carcinoma as revealed by the analyses of ploidy heterogeneity and Ras mutation patterns].

UNLABELLED: To analyze ploidy alterations during progression of colorectal tumors, we mapped the ploidy constitutions by cytofluorometry using (measurements of metaphase cells in) tissue sections as well as cell suspensions isolated from the tissue sections. Clonality of the tumor with heterogeneous ploidy constitution was checked by mutation pattern of K-ras codon 12. To assess the significance of polyploidy detected in the diploid tumor component, the present materials were confined to 23 tumors that contained diploid tumor cells. RESULTS: 1) Eight diploid tumors without polyploidy that invaded the submucosa or deeper were greater than 2 cm in diameter. 2) Aneuploidy was detected in tissue sections from 9 out of 15 tumors that had diploid component with polyploidy, and was occasionally predominant in the extramucosal invasive parts. 3) Near-diploid aneuploidy was detected in the cells isolated from diploid (+ polyploid) regions of 2 tumors with aneuploidy. 4) Three of the 6 tumors with heterogeneous ploidy constituents had ras mutation with the mutation patterns common to diploid and aneuploid parts. These findings suggest that aneuploid cells evolve preferentially from the diploid tumor cell population with polyploidy, which often include near-diploid aneuploidy.

Aneuploidy↗
PubMed2006

Mechanisms of genomic rearrangements and gene expression changes in plant polyploids.

Polyploidy is produced by multiplication of a single genome (autopolyploid) or combination of two or more divergent genomes (allopolyploid). The available data obtained from the study of synthetic (newly created or human-made) plant allopolyploids have documented dynamic and stochastic changes in genomic organization and gene expression, including sequence elimination, inter-chromosomal exchanges, cytosine methylation, gene repression, novel activation, genetic dominance, subfunctionalization and transposon activation. The underlying mechanisms for these alterations are poorly understood. To promote a better understanding of genomic and gene expression changes in polyploidy, we briefly review origins and forms of polyploidy and summarize what has been learned from genome-wide gene expression analyses in newly synthesized auto-and allopolyploids. We show transcriptome divergence between the progenitors and in the newly formed allopolyploids. We propose models for transcriptional regulation, chromatin modification and RNA-mediated pathways in establishing locus-specific expression of orthologous and homoeologous genes during allopolyploid formation and evolution.

Chromosomes, Plant↗
PubMed2002

Functional analysis of mouse hepatocytes differing in DNA content: volume, receptor expression, and effect of IFNgamma.

Polyploidy and binuclearity are characteristics of the mammalian liver. Increasing polyploidisation occurs with age and after administration of various drugs and chemicals. This study was designed to examine the function of ploidy by addressing several questions: (1) Does the increase in size of polyploid hepatocytes have any physiological function by altering surface receptor expression such as intercellular adhesion molecule-1 (ICAM-1, CD54) or IFNgammaR? and (2) Do polyploid cells respond differently to inflammatory cytokines such as interferon gamma (IFNgamma)? We have developed a method to accurately measure the volume of live isolated hepatocytes using confocal microscopy and image analysis. Using flow cytometry, we have shown that the expression of ICAM-1 increases with increasing DNA content and IFNgammaR is not detectable on isolated mouse hepatocytes. Diploid (2n), tetraploid (4n) and octoploid (8n) hepatocytes were found to be equally susceptible to IFNgamma-induced apoptosis in vitro. Although the function of polyploidy remains unanswered, we have described some of the characteristics of polyploidy in isolated hepatocytes and in vitro.

Animals↗