Effect of 'Pan Masala' on the germ cells of male mice.
TL;DR: Pan Masala is a potent clastogen, reaches the testes and affects the germinal cells, and indicates that sperm head abnormalities were significantly high for all the doses tested.
About: This article is published in Cancer Letters.The article was published on 1991-07-04. It has received 23 citations till now. The article focuses on the topics: Meiotic metaphase I.
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TL;DR: Evidence that strongly supports causative mechanisms for genotoxicity and carcinogenicity of these substitute products, including gutkha and pan masala, are strongly implicated in the recent increase in the incidence of oral submucous fibrosis is reviewed.
Abstract: In south-east Asia, Taiwan and Papua New Guinea, smoking, alcohol consumption and chewing of betel quid with or without tobacco or areca nut with or without tobacco are the predominant causes of oral cancer. In most areas, betel quid consists of a mixture of areca nut, slaked lime, catechu and several condiments according to taste, wrapped in a betel leaf. Almost all habitual chewers use tobacco with or without the betel quid. In the last few decades, small, attractive and inexpensive sachets of betel quid substitutes have become widely available. Aggressively advertised and marketed, often claimed to be safer products, they are consumed by the very young and old alike, particularly in India, but also among migrant populations from these areas world wide. The product is basically a flavoured and sweetened dry mixture of areca nut, catechu and slaked lime with tobacco (gutkha) or without tobacco (pan masala). These products have been strongly implicated in the recent increase in the incidence of oral submucous fibrosis, especially in the very young, even after a short period of use. This precancerous lesion, which has a high rate of malignant transformation, is extremely debilitating and has no known cure. The use of tobacco with lime, betel quid with tobacco, betel quid without tobacco and areca nut have been classified as carcinogenic to humans. As gutkha and pan masala are mixtures of several of these ingredients, their carcinogenic affect can be surmised. We review evidence that strongly supports causative mechanisms for genotoxicity and carcinogenicity of these substitute products. Although some recent curbs have been put on the manufacture and sale of these products, urgent action is needed to permanently ban gutkha and pan masala, together with the other established oral cancer-causing tobacco products. Further, education to reduce or eliminate home-made preparations needs to be accelerated.
421 citations
TL;DR: There is a maximum dose and an optimum time for the detection of genetic effects because the toxicity associated with high doses of CP will affect cell division and increases in chromosome damage and gene mutations have been found in the peripheral blood lymphocytes of nurses, pharmacists and female workers occupationally exposured to CP.
Abstract: Cyclophosphamide (CP) is used to treat a wide range of neoplastic diseases as well as some non-malignant ones such as rheumatoid arthritis It is also used as an immunosuppressive agent prior to organ transplantation CP is, however, a known carcinogen in humans and produces secondary tumors There is little absorption either orally or intravenously and 10% of the drug is excreted unchanged CP is activated by hepatic mixed function oxidases and metabolites are delivered to neoplastic cells via the bloodstream Phosphoramide mustard is thought to be the major anti-neoplastic metabolite of CP while acrolein, which is highly toxic and is produced in equimolar amounts, is thought to be responsible for most of the toxic side effects DNA adducts have been formed after CP treatment in a variety of in vitro systems as well as in rats and mice using 3H-labeled CP 32P-postlabeling techniques have also been used in mice However, monitoring of adducts in humans has not yet been carried out CP has also been shown to induce unscheduled DNA synthesis in a human cell line CP has produced mutations in base-pair substituting strains of Salmonella tryphimurium in the presence of metabolic activation, but it has been shown to be negative in the E coli chromotest It has also been shown to be positive in Saccharomyces cerevisiae in D7 strain for many endpoints but negative in D62M for aneuploidy/malsegregation It has produced positive responses in Drosophila melanogaster for various endpoints and in Anopheles stephensi In somatic cells, CP has been shown to produce gene mutations, chromosome aberrations, micronuclei and sister chromatid exchanges in a variety of cultured cells in the presence of metabolic activation as well as sister chromatid exchanges without metabolic activation It has also produced chromosome damage and micronuclei in rats, mice and Chinese hamsters, and gene mutations in the mouse spot test and in the transgenic lacZ construct of Muta Mouse Increases in chromosome damage and gene mutations have been found in the peripheral blood lymphocytes of nurses, pharmacists and female workers occupationally exposured to CP during its production or distribution Chromosome aberrations, sister chromatid exchanges and gene mutations have been observed in somatic cells of patients treated therapeutically with CP In general, there is a maximum dose and an optimum time for the detection of genetic effects because the toxicity associated with high doses of CP will affect cell division In germ cells, CP has been shown to induce genetic damage in mice, rats and hamsters although the vast majority of such studies have used male mice(ABSTRACT TRUNCATED AT 400 WORDS)
295 citations
TL;DR: Nitrosated derivatives of arecal alkaloids, proven carcinogens inducing tumours throughout the upper gut and foregut derivatives in animals, are also associated with increased tumour risks in man.
Abstract: Betel nut (Areca catechu) is chewed regularly by at least 10% of the world population, imported by immigrant users wherever they settle, and is the fourth most widely used addictive substance. It is thought, by users, to soothe the digestion and to be a stimulant and its use has a major role in social situations. Specific arecal alkaloids act as competitive inhibitors of GABA receptors and have widespread effects in the body, including actions on the brain, cardiovascular system, lungs, gut and pancreas. Nitrosated derivatives of arecal alkaloids, proven carcinogens inducing tumours throughout the upper gut and foregut derivatives in animals, are also associated with increased tumour risks in man. These nitrosated compounds are also diabetogenic in CD1 mice, producing a type 2 diabetes with obesity. Increased central obesity is found in association with betel usage in man as well as increases in circulating markers of inflammatory and cardiovascular damage. The effects of chronic betel usage in man are at least as diverse as those of smoking and the habit increases the risks of ill health.
242 citations
Cites methods from "Effect of 'Pan Masala' on the germ ..."
...light microscopy at the same interval of time after completion of 5 days’ betel feeding as the interval before mating in our betel feeding studies.(44)...
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TL;DR: This review focuses on the consumption of smokeless tobacco and its components, such as paan and gutkha, and the role of these substances in the induction of OSMF and ultimately oral cancer.
Abstract: Smokeless tobacco consumption, which is widespread throughout the world, leads to oral submucous fibrosis (OSMF), which is a long-lasting and devastating condition of the oral cavity with the potential for malignancy In this review, we mainly focus on the consumption of smokeless tobacco, such as paan and gutkha, and the role of these substances in the induction of OSMF and ultimately oral cancer The list of articles to be examined was established using citation discovery tools provided by PubMed, Scopus, and Google Scholar The continuous chewing of paan and swallowing of gutkha trigger progressive fibrosis in submucosal tissue Generally, OSMF occurs due to multiple risk factors, especially smokeless tobacco and its components, such as betel quid, areca nuts, and slaked lime, which are used in paan and gutkha The incidence of oral cancer is higher in women than in men in South Asian countries Human oral epithelium cells experience carcinogenic and genotoxic effects from the slaked lime present in the betel quid, with or without areca nut Products such as 3-(methylnitrosamino)-proprionitrile, nitrosamines, and nicotine initiate the production of reactive oxygen species in smokeless tobacco, eventually leading to fibroblast, DNA, and RNA damage with carcinogenic effects in the mouth of tobacco consumers The metabolic activation of nitrosamine in tobacco by cytochrome P450 enzymes may lead to the formation of N-nitrosonornicotine, a major carcinogen, and micronuclei, which are an indicator of genotoxicity These effects lead to further DNA damage and, eventually, oral cancer
138 citations
TL;DR: The findings suggest that betelnut (Areca) consumption may be diabetogenic and induce an inheritable abnormality in mice with an increased incidence of foregut cancers related to betel-nut nitrosamines.
Abstract: Many mutagenic nitroso compounds are also diabetogenic. Betel-nut (Areca catechu) chewing populations have an increased incidence of foregut cancers related to betel-nut nitrosamines which suggests that betel consumption could be diabetogenic. Young adult CD1 mice with a low spontaneous incidence of diabetes were fed betel nut in standard feed for 2–6 days. Single point (90 min) intra-peritoneal glucose tolerance tests were used to follow glucose tolerance up to 6 months of age. Glucose intolerance was defined as over 3 SD above mean control values. Glucose intolerance was found in 3 of 51 male and 4 of 33 female adult mice which were fed the betel diet (p<0.01). Studies on the progeny of these mice are presented separately for animals studied in Aberdeen (Group 1) and London (Group 2). In matings of Group 1 betel-fed parents glucose intolerance was found in 4 of 25 male and 1 of 22 female F1 offspring, with significant hyperglycaemia in F1 males born to hyperglycaemic but not to normoglycaemic mothers (p<0.01). In the F2 generation 4 of 23 males and 1 of 16 females and in the F3 generation 1 of 16 males and 0 of 20 females were glucose intolerant. In the Group 2 studies where betel-fed parents were mated to normal controls glucose intolerance was found in 10 of 35 male and 10 of 33 female Fl progeny (p<0.005), and mean islet areas were increased in offspring of betel-fed parents (p<0.001). The total incidence of glucose intolerance in Fl progeny from studies in Groups 1 and 2 was 14 of 60 males and 11 of 55 females (p<0.005). Insulin dependence did not develop in the glucose-intolerant betel-fed animals or their descendants; affected animals appearing well built and active. The development of glucose intolerance in F1 offspring was not dependent on maternal glucose intolerance or on maternal betel-feeding, and 90-min glucose levels of F1 offspring were directly related to paternal but not to maternal glycaemia (p<0.01). Our findings suggest that betelnut (Areca) consumption may be diabetogenic and induce an inheritable abnormality. The hypothesis is of interest in view of the widespread habit of betel consumption and of the strategies known to inhibit the induction of experimental diabetes by diabetogenic nitroso compounds.
95 citations
References
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Book•
31 Jan 2014
TL;DR: This book discusses the development and validation of short-term assays designed to detect the mutagenic effects of environmental chemicals, and the detection of mutagens in human feces as an approach to the discovery of causes of colon cancer.
Abstract: This book discusses the development and validation of short-term assays designed to detect the mutagenic effects of environmental chemicals. Topics considered include the grasshopper neuroblast short-term assay for evaluating the effects of environmental chemicals on chromosomes and cell kinetics, a comparison of the mutagenic responses of lung-derived and skin-derived human diploid fibroblast populations, the L-arabinose resistance test with Salmonella typhimurium, the Bacillus subtilis multigene sporulation test for the detection of environmental mutagens, the L5178Y/TK gene mutation assay system, the induction of bacteriophage lambda by DNA-interacting chemicals, the granuloma pouch assay, the use of multiply marked Escherichia coli K12 strains in the host-mediated assay, and the detection of mutagens in human feces as an approach to the discovery of causes of colon cancer.
1,480 citations
TL;DR: The air-drying method gives improved spreading of the chromosomes and less cell breakage compared with squash techniques, suitable for stages of male meiosis in which the chromosomes are condensed.
Abstract: A suspension is made in isotonic (2.2%) sodium citrate solution from the contents of the tubules from a whole testis or a testicular biopsy specimen. The germinal cells are sedimented by centrifuging, leaving most of the sperm in the supernatant fluid, which is discarded. The cells are resuspended in hypo-tonic (1%) sodium citrate solution and left to stand at room temperature for 12 minutes, after which they are sedimented again and fixed as a concentrated suspension in a mixture of 3 parts absolute ethyl alcohol to 1 part glacial acetic acid plus a trace of chloroform. Two quick changes into fresh fixative follow. Air-dried preparations are made from the final fixed suspension and stained in lactic-acetic-orcein. The method is suitable for stages of male meiosis in which the chromosomes are condensed. Its principle advantage is the separation of the clumps of spermatogonia and spermatocytes into individual cells which are randomly dispersed over the preparations. Compared with squash techniques, the air-drying method gives improved spreading of the chromosomes and less cell breakage.
1,032 citations
TL;DR: Salmonella/microsome tests (Ames tests) and chromosomal aberration tests in vitro using a Chinese hamster fibroblast cell line were carried out on 190 synthetic food additives and 52 food additives derived from natural sources, all of which are currently used in Japan.
634 citations
TL;DR: The mouse sperm morphology test has potential use for identifying chemicals that induce spermatogenic dysfunction and perhaps heritable mutations, and is found to be highly sensitive to germ-cell mutagens.
Abstract: The literature on the mouse sperm morphology test and on other sperm tests in nonhuman mammals was reviewed (a) to evaluate the relationship of these tests to chemically induced spermatogenic dysfunction, germ-cell mutagenicity, and carcinogenicity, and (b) to make an interspecies comparison to chemicals. A total of 71 papers were reviewed. The mouse sperm morphology test was used to assess the effects of 154 of the 182 chemical agents covered. 4 other murine sperm tests were also used: the induction of acrosomal abnormalities (4 agents), reduction in sperm counts, (6 agents), motility (5 agents), and F1 sperm morphology (7 agents)). In addition, sperm tests for the spermatogenic effects of 35 agents were done in 9 nonmurine mammalian species; these included analyses for sperm count, motility, and morphology, using a large variety of study designs. For the mouse sperm morphology test, 41 agents were judged by the reviewing committee to be positive inducers of sperm-head shape abnormalities, 103 were negative, and 10 were inconclusive. To evaluate the relationship between changes in sperm morphology and germ cell mutagenicity, the effects of 41 agents on mouse sperm shape were compared to available data from 3 different mammalian germ-cell mutational tests (specific locus, heritable translocation, and dominant lethal). The mouse sperm morphology test was found to be highly sensitive to germ-cell mutagens; 100% of the known mutagens were correctly identified as positives in the sperm morphology test. Data are insufficient at present to access the rate of false positives. Although it is biologically unclear why one might expect changes in sperm morphology to be related to carcinogenesis, we found that (a) a positive response in the mouse sperm morphology test is highly specific for carcinogenic potential (100% for the agents surveyed), and (b) overall, only 50% of carcinogens were positive in the test (i.e., sensitivity approximately equal to 50%). Since many carcinogens do not produce abnormally shaped sperm even at lethal doses, negative findings with the sperm test cannot be used to classify agents as noncarcinogens. We conclude that the mouse sperm morphology test has potential use for identifying chemicals that induce spermatogenic dysfunction and perhaps heritable mutations. Insufficient numbers of chemicals agents have been studied by the other sperm tests to permit similar comparisons. A comparison of 25 chemicals tested with sperm counts, motility, and morphology in at least 2 species (including man, mouse and 9 other mammals) demonstrated good agreement in response among species. With further study, interspecies comparisons of chemically induced sperm changes may be useful for predicting and evaluating human effects.
396 citations
TL;DR: In this paper, a trend test for evidence of a dose response is proposed for such SCE data, where the percent of cells with chromosome aberrations is the response of interest, and Monte Carlo methods are used to show that the trend test is more sensitive than four other statistical procedures considered for the analysis of Poisson-distributed SCE.
Abstract: It is a widely held view that objective statistical criteria are needed for the evaluation of genetic toxicity assays. This paper presents statistical methods for the analysis of data from in vitro sister chromatid exchange (SCE) and chromosome aberration tests that use Chinese hamster ovary cells. For SCEs, an extensive study of solvent control results demonstrated that there is a substantial interday component of variability in the data, and that a Poisson sampling model is applicable to data generated via the protocol of Galloway et al [1985]. Consequently, a trend test for evidence of a dose response is proposed for such SCE data. As an illustration of this statistical method, analysis of data previously considered to be negative [Gulati et al, 1985] indicates that di(2-ethyl-hexyl) phthalate induces a weak, but reproducible, SCE dose response in CHO cells. Monte Carlo methods are used to show that the trend test is more sensitive than four other statistical procedures considered for the analysis of Poisson-distributed SCEs. A similar trend test for dose response in proportions is proposed for chromosome aberration data, where the percent of cells with chromosome aberrations is the response of interest. Sensitivity (or power) studies indicate that three doses and a control with 50 cells/dose point is a reasonable design for an in vitro SCE study that uses the Galloway et al protocol. For in vitro chromosome aberrations, however, three doses and a control with 100 cells/dose point appears to produce too insensitive an assay; an increase to 200 cells/dose point in the Galloway et al protocol seems worthy of serious consideration.
157 citations