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Journal ArticleDOI

Cytotoxic effects of trimethyltin chloride on human peripheral blood lymphocytes in vitro.

01 Sep 1989-Human & Experimental Toxicology (SAGE Publications)-Vol. 8, Iss: 5, pp 349-353
TL;DR: Trimethyltin chloride was found to induce cytotoxic damage in vitro in human peripheral blood lymphocytes and endoreduplication, an extremely rare spontaneous event in human lymphocytes, was observed in a few cases at all dose levels.
Abstract: Trimethyltin chloride was found to induce cytotoxic damage in vitro in human peripheral blood lymphocytes. Two concentrations (0.5 μg and 1.0 μg) were added to lymphocytes from male and female subj...
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TL;DR: In this article, MeHg binds strongly to protein and soluble sulphydryl groups, which results in catastrophic depolymerization of immature tyrosinated microtubules.
Abstract: Neurotoxicants with similar structural features or common mechanisms of chemical action frequently produce widely divergent neuropathologic outcomes. Methylmercury (MeHg) produces marked cerebellar dysmorphogenesis during critical periods of development. The pathologic picture is characterized by complete architectural disruption of neuronal elements within the cerebellum. MeHg binds strongly to protein and soluble sulphydryl groups. Binding to microtubular -SH groups results in catastrophic depolymerization of immature tyrosinated microtubules. However, more mature acetylated microtubules are resistant to MeHg-induced depolymerization. In contrast to MeHg, the structurally similar organotin trimethyltin (TMT) elicits specific apoptotic destruction of pyramidal neurons in the CA3 region of the hippocampus and in other limbic structures. Expression of the phylogenetically conserved protein stannin is required for development of TMT-induced lesions. Inhibition of expression using antisense oligonucleotides ...

129 citations


Cites background from "Cytotoxic effects of trimethyltin c..."

  • ...Furthermore, TMT impairs immune function, causing splenic atrophy, and altered cell division and cell-cycle kinetics in lymphocytes, resulting in chromosomal alterations and formation of micronuclei (20, 61, 67, 119)....

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Journal ArticleDOI
TL;DR: The elevation of abnormalities and depression of mitotic index were linear to the increase of donor's age, with a higher frequency in males and females, and individuals with the smoking habit possessed higher frequencies of abnormalities than non-smokers.
Abstract: Spontaneous baseline frequencies of chromosome aberrations, micronucleus counts and cell division were analysed in peripheral lymphocytes of 127 normal healthy individuals in vitro. Cells were subjected to culture for 48 h in serum and PHA supplemented culture medium RPMI 1640. 100 metaphases were observed for chromosome aberrations and 1000 cells each for micronucleus counts and mitotic index. Regression analyses were carried out to see the effect of age on spontaneous abnormalities. The correlation of aberrations, micronucleus formation and mitotic index with donor's age is highly significant. The elevation of abnormalities and depression of mitotic index were linear to the increase of donor's age, with a higher frequency in males. Aged males and females from the age range of 40–70 years showed larger numbers of aberrations. Individuals with the smoking habit possessed higher frequencies of abnormalities than non-smokers.

97 citations

Journal ArticleDOI
TL;DR: Human peripheral blood lymphocytes of healthy male and female individuals of different age groups were treated with two aqueous doses of trimethyltin chloride and Chromatid and chromosome types of aberrations were observed to be increased in both treated sets in all age groups.
Abstract: Human peripheral blood lymphocytes of healthy male and female individuals of different age groups were treated with two aqueous doses (0.5 microgram and 1.0 microgram) of trimethyltin chloride in mitogen stimulated and serum supplemented culture medium for 72 h at 37 degrees C. Chromatid and chromosome types of aberrations were observed to be increased in both treated sets in all age groups. Significant variations were observed between age groups (P less than 0.001) and between experimental sets (P less than 0.001). Moreover, interaction of chemical and donors age was statistically highly significant (P less than 0.05-P less than 0.001). However, no linear correlation between the increase of donor's age and aberrations was observed.

33 citations

Journal ArticleDOI
TL;DR: The clastogenicity of trimethyltin chloride was evaluated in human peripheral blood lymphocytes with micronucleus counts (MNC) as the endpoint and higher frequencies of MNC enhancement were observed in male individuals than in females.
Abstract: The clastogenicity of trimethyltin chloride was evaluated in human peripheral blood lymphocytes with micronucleus counts (MNC) as the endpoint. Two concentrations (0.5 micrograms and 1.0 microgram) of trimethyltin chloride were added to lymphocytes of healthy male and female subjects of different age groups, in mitogen-stimulated and serum-supplemented culture medium (RPMI 1640, Gibco) for 48 h at 37 degrees C. A significant increase in micronucleus counts was observed with both doses, which was more pronounced with the lower dose. ANOVA in male and female donors revealed significant differences between age groups (P less than 0.001), chemical concentrations (P less than 0.001) and for the interaction of these 2 factors (P less than 0.05 in females only). However, no regular increase or decrease in MNC frequencies was observed with the donor's age. Higher frequencies of MNC enhancement were observed in male individuals than in females.

32 citations

Journal ArticleDOI
TL;DR: The results presented here indicate a considerable toxicological potential of some organotin species but demonstrate clearly that the toxicity is modulated by the cellular uptake capability.
Abstract: Organotin compounds have been widely used as stabilizers and anti-fouling agents with the result that they are ubiquitously distributed in the environment. Organotins accumulate in the food chain and potential effects on human health are disquieting. It is not known as yet whether cell surface adsorption or accumulation within the cell, or indeed both is a prerequisite for the toxicity of organotin compounds. In this study, the alkylated tin derivatives monomethyltin trichloride (MMT), dimethyltin dichloride (DMT), trimethyltin chloride (TMT) and tetramethyltin (TetraMT) were investigated for cyto- and genotoxic effects in CHO-9 cells in relation to the cellular uptake. To identify genotoxic effects, induction of micronuclei (MN), chromosome aberrations (CA) and sister chromatid exchanges (SCE) were analyzed and the nuclear division index (NDI) was calculated. The cellular uptake was assessed using ICP-MS analysis. The toxicity of the tin compounds was also evaluated after forced uptake by electroporation. Our results show that uptake of the organotin compounds was generally low but dose-dependent. Only weak genotoxic effects were observed after exposure of cells to DMT and TMT. MMT and TetraMT were negative in the test systems. After forced uptake by electroporation MMT, DMT and TMT induced significant DNA damage at non-cytotoxic concentrations. The results presented here indicate a considerable toxicological potential of some organotin species but demonstrate clearly that the toxicity is modulated by the cellular uptake capability.

30 citations

References
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Journal ArticleDOI
13 Sep 1974-Nature
TL;DR: If human lymphocytes1 or Chinese hamster2 cells are treated with the base analogue 5-bromodeoxyuridine in the latter part of the S period, Giemsa stained chromosomes exhibit a pattern of condensed and extended segments along their length, allowing the identification of the two chromatids, and the observation of sister chromatid exchanges (SCEs) without recourse to autoradiography.
Abstract: IF human lymphocytes1 or Chinese hamster2 cells are treated with the base analogue 5-bromodeoxyuridine (BrdU) in the latter part of the S period, Giemsa stained chromosomes exhibit a pattern of condensed and extended segments along their length. This phenomenon has been attributed to a delay in the spiralisation pattern of the late replicating regions along the chromosomes. Other experiments3 with Chinese hamster ovary (CHO) cells have shown that after two rounds of replication in the presence of BrdU or IdU, sister chromatids stain differentially with Giemsa, allowing the identification of the two chromatids, and the observation of sister chromatid exchanges (SCEs) without recourse to autoradiography. The chromatid with the bifilarly substituted DNA (BrdU substituted in both strands of DNA) is less condensed and stains more weakly with Giemsa than the unifilarly substituted sister chromatid. The yield of SCEs is approximately that observed by autoradiography.

3,159 citations

Journal ArticleDOI
TL;DR: Failure of the pale stained chromatids to restore Giemsa affinity with urea and trypsin and the diminished Feulgen reaction after light exposure suggest that not masking proteins but photolysis of the BrdU-incorporated chromatid components in the presence of photosensitive dyes play a role in the differential staining.
Abstract: The essential steps of the 33258 Hoechst-Giemsa method for differential chromatid staining consist of (1) 33258 Hoechst treatment, (2) exposure to light, and (3) Giemsa staining. The staining was shown to be a function of the concentration of 33258 Hoechst and the light exposure. The dye was successfully replaced by various metachromatic dyes such as thionine. Two simple methods are proposed. Failure of the pale stained chromatids to restore Giemsa affinity with urea and trypsin and the diminished Feulgen reaction after light exposure suggest that not masking proteins but photolysis of the BrdU-incorporation chromatid components in the present of photosensitive dyes play a role in the differential staining.

280 citations

Journal ArticleDOI
TL;DR: Male and female Wistar rats were fed bis(tri-n-butyltin)oxide (TBTO) at 0, 5, 20, 80, or 320 mg/kg diet for 4 weeks, and a dose-related reduction was found in the number and staining intensity of TSH-producing cells in the pituitary, correlating with histopathologically decreased activity of the thyroid.
Abstract: Male and female Wistar rats were fed bis(tri-n-butyltin)oxide (TBTO) at 0, 5, 20, 80, or 320 mg/kg diet for 4 weeks. Clinical signs and decreases in feed and water consumption were observed in the 80 and 320 mg/kg groups. The serum transferase activities (alanine amino transferase and aspartate amino transferase were increased at 20 (males only), 80, and 320 mg/kg. The serum glucose and liver glycogen concentrations were lowered in the 320 mg/kg group. At 80 and 320 mg/kg the serum IgG level was reduced and IgM level was increased. Compared to controls the mean relative weight of the thymus was decreased at 20 (males), 80, and 320 mg/kg. In the groups receiving 80 or 320 mg/kg microcytic anemia was found. The white blood cell counts were decreased, due to the reduction in the number of lymphocytes in the 80 (males) and 320 mg/kg groups. The concentration of neutrophilic granulocytes was increased in the highest dose group. Histopathologic effects included a dose-related lymphocyte depletion of thymic cortex and of T lymphocytes in spleen and mesenteric lymph nodes. In the spleen also depletion of iron stores was found, and in the medullary sinuses of mesenteric lymph nodes, rosettes of erythrocytes were found around mononuclear cells; the occurrence of rosettes increased with dose from 5 to 80 mg/kg, and appeared to be the most sensitive parameter. A low incidence of areas of liver necrosis with inflammatory reaction and bile duct hyperplasia was found in the 320 mg/kg group. A viral or bacterial etiology could not be demonstrated for these liver lesions, but they appeared associated with TBTO-induced ulcerative inflammation of the common bile duct as shown in an additional study. In 6-week studies exposure of male weanlings to the 0, 20, and 80 mg/kg diets, the serum insulin concentration in the treated groups was decreased, although the response to glucose challenge was unaffected. The serum thyroxin and thyrotropin (TSH) concentrations were reduced, whereas the luteinizing hormone (LH) concentration was increased in the 80 mg/kg group. The concentrations of follicle-stimulating hormone (FSH) and corticosterone were not changed. The release of LH and FSH was enhanced in the 80 mg/kg group and a tendency toward reduced release was found for TSH. Using immunocytochemistry a dose-related reduction was found in the number and staining intensity of TSH-producing cells in the pituitary, correlating with histopathologically decreased activity of the thyroid. On the other hand, a dose-related increase was seen in the number of cells staining strongly for luteinizing hormone. No effect was observed on FSH, growth hormone and adrenocorticotropin-producing cells, nor on the pancreatic insulin and glucagon-producing cells. In tissues, a dose-dependent increase of the total tin concentration was found, with the highest residues in liver and kidney. Residues in adipose tissue and brain were 5–10 times lower. From these studies it is concluded that low-dose dietary TBTO exposure induces atrophy of the thymus and peripheral lymphoid organs, depletion of splenic iron stores, erythrocyte rosettes in mesenteric lymph nodes, decreased activity of the pituitary-thyroid axis, and increased LH immunoreactivity and secretion.

178 citations

Journal Article

161 citations