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PubMedDate not supplied

Thimerosal dependent agglutination, a newly described blood bank problem.

A number of ABO grouping, Rh typing, antibody screening, and antibody identification problems are associated with chemicals in blood bank reagents. We describe a newly discovered agglutination phenomenon due to a thimerosal (Merthiolate)-dependent agglutinin found in the serum of a normal blood donor. Thimerosal is used as a preservative in several low-ionic strength reagents. This agglutination phenomenon is detected only in test systems (low-ionic-strength, albumin, saline, ficin treated test cells) in which test cells are incubated in the presence of thimerosal. Agglutination does not occur in the absence of thimerosal. The thimerosal-dependent agglutinin behaves like an IgG IgG autoantibody. There is no evidence that the thimerosal-dependent agglutinin is responsible for increased red cell destruction.

Adult↗

PubMed1999

Modulation of type 1, 2 and 3 inositol 1,4,5-trisphosphate receptors by cyclic ADP-ribose and thimerosal.

The binding of inositol 1,4,5-trisphosphate (IP3) to the IP3 receptor (IP3R) is modulated by various compounds. Until now, limited progress has been made concerning the isoform-specific effects of these modulators. In this study, we examined how [3H]IP3 binding to the three IP3R isoforms is modulated by cyclic ADP-ribose (cADPR) and by the SH-reagent thimerosal. We used rabbit cerebellum, RBL-2H3 rat mucosal mast cells and 16HBE14o- human bronchial epithelial cells as model systems for IP3R-1, -2 and -3 respectively. [3H]IP3 binding was first characterized at various pH values. We showed that [3H]IP3 binding to RBL-2H3 microsomes was more enhanced by increasing the pH from 7.4 to 8.3 than that to rabbit cerebellar microsomes. In contrast, [3H]IP3 binding to 16HBE14o- microsomes was not stimulated at alkaline pH. At pH 7.4, cADPR (50 microM) increased [3H]IP3 binding to rabbit cerebellar microsomes, RBL-2H3 and 16HBE14o- microsomes 1.5-fold, 1.3-fold and 1.8-fold respectively. The effect of cADPR on IP3 binding was abolished at pH 8.3. Scatchard analysis indicated that cADPR induced in cerebellum a decrease in IP3 affinity (KD increases from 150 nM to 252 nM) of the IP3R and a parallel increase in Bmax (from 4.8 pmol/mg to 11.1 pmol/mg). Thimerosal dose-dependently increased [3H]IP3 binding to rabbit cerebellar microsomes. The stimulatory effects of cADPR and thimerosal were not additive. Binding to cerebellar microsomes returned to control level in the presence of 500 microM thimerosal. In contrast, thimerosal (up to 500 microM) had no stimulatory effect and only a very slight, if any, inhibitory effect on [3H]IP3 binding to RBL-2H3 and 16HBE14o- microsomes respectively. These results indicate that IP3 binding to the IP3R isoforms can be differentially modulated by cADPR and thimerosal.

Adenosine Diphosphate Ribose↗

PubMed2005

Thimerosal--is it really irrelevant?

Recently, several investigators claimed that thimerosal is one of the most irrelevant allergens existing in screening for contact dermatitis. 508 patients who were suspected to have allergic contact dermatitis were patch tested at our clinic. They completed a questionnaire including medical, demographic and occupational details. We used the standard tray of chemotechnique diagnostics (Malmö, Sweden) and additional series, which were case relevant. The relevance of the allergic reaction to thimerosal was scored from 1 to 6. 19 patients (3.7%) had an allergic reaction to thimerosal. 6 (31.5%) had a definite relevance and 8 (42.1%) had a probable relevance. Only 3 patients (15.8%) had an irrelevant reaction. SPIN value (significance-prevalence index number) was 2281. We found a high proportion of mechanics (42.1%) among the patients who had positive reaction to thimerosal (P < 0.0001). Although previous reports found thimerosal highly irrelevant, our daily experience being supported by the above data indicates that positive reactions to thimerosal could be relevant for many patients.

Allergens↗

PubMed2005

Effect of thimerosal on arrhythmia induced by coronary ligation: the involvement of ATP-dependent potassium channels.

Thiol-modifying agents induce the release of nitric oxide (NO) from endothelial epithelium and the release of reactive oxygen free radicals in the vascular system. Moreover, thiol groups are essential for the functioning of the ATP dependent potassium channel (K-ATP). The effects of thiol-modifying agents and their molecular mechanisms on arrhythmia have not been widely studied. In this study, we investigated the effect of the hydrophilic SH-group-oxidizing substance thimerosal on the arrhythmia induced by reperfusion/ischemia after coronary artery ligation in rats. We studied the possible involvement of the K-ATP and NOS on the effect of thimerosal. Thimerosal pretreatment (3, 30 mg/kg dose iv. 10 minutes before coronary occlusion) significantly decreased the length of total arrhythmia, ventricular tachycardia, and the arrhythmia score. This effect of thimerosal was reversed by the K-ATP opener pinacidil but not by the K-ATP blocker glibenclamide. The inhibition of iNOS by L-NAME did not alter the antiarrhythmic effect of thimerosal. These data clearly suggest that the antiarrhythmic effect of thimerosal is dependent upon the blockage of K-ATP.

Adenosine Triphosphate↗

PubMedDate not supplied

Interference of thimerosal in the bicinchoninic acid protein microassay.

In this investigation the total amount of protein present in the three influenza vaccine formulations Fluvirin, Fluzone and Flushield have been tested where thimerosal is present as a preservative. Interaction of thimerosal with protein has been confirmed by analysing ovalbumin as a control against ovalbumin-thimerosal solution. The results indicate that interference of thimerosal can be overcame for the quantitative assay of proteins by BCA technique with the good reproducibility. The present study identified also the degree of interference of thimerosal in the protein formulations and development of a method to nullify the interference by removing thimerosal.

Drug Contamination↗

PubMed2004

A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism.

BACKGROUND: The purpose of the study was to evaluate the effects of MMR immunization and mercury from thimerosal-containing childhood vaccines on the prevalence of autism. MATERIAL/METHODS: Evaluations of the Biological Surveillance Summaries of the Centers for Disease Control and Prevention (CDC), the U.S. Department of Education datasets, and the CDC's yearly live birth estimates were undertaken RESULTS: It was determined that there was a close correlation between mercury doses from thimerosal--containing childhood vaccines and the prevalence of autism from the late 1980s through the mid-1990s. In contrast, there was a potential correlation between the number of primary pediatric measles-containing vaccines administered and the prevalence of autism during the 1980s. In addition, it was found that there were statistically significant odds ratios for the development of autism following increasing doses of mercury from thimerosal-containing vaccines (birth cohorts: 1985 and 1990-1995) in comparison to a baseline measurement (birth cohort: 1984). The contribution of thimerosal from childhood vaccines (>50% effect) was greater than MMR vaccine on the prevalence of autism observed in this study. CONCLUSIONS: The results of this study agree with a number of previously published studies. These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile.

Adolescent↗

PubMed2005

Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria.

There is a worldwide increasing concern over the neurological risks of thimerosal (ethylmercury thiosalicylate) which is an organic mercury compound that is commonly used as an antimicrobial preservative. In this study, we show that thimerosal, at nanomolar concentrations, induces neuronal cell death through the mitochondrial pathway. Thimerosal, in a concentration- and time-dependent manner, decreased cell viability as assessed by calcein-ethidium staining and caused apoptosis detected by Hoechst 33258 dye. Thimerosal-induced apoptosis was associated with depolarization of mitochondrial membrane, generation of reactive oxygen species, and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol. Although thimerosal did not affect cellular expression of Bax at the protein level, we observed translocation of Bax from cytosol to mitochondria. Finally, caspase-9 and caspase-3 were activated in the absence of caspase-8 activation. Our data suggest that thimerosal causes apoptosis in neuroblastoma cells by changing the mitochondrial microenvironment.

Animals↗

PubMedDate not supplied

Effect of thimerosal concentration on the efficacy of inactivated Newcastle disease oil-emulsion vaccines.

Different quantities of the preservative thimerosal in inactivated Newcastle disease oil-emulsion vaccines were tested to determine the influence on the hemagglutination-inhibition (HI) response of broilers. The effect of thimerosal was measured in vaccines that had been stored for 1, 21, and 52 weeks; HI serology was conducted at 2, 4, and 6 weeks after vaccination. Mean HI titers 4 weeks after vaccination decreased at a significant rate (P less than or equal to 0.001) with increasing concentrations of thimerosal. HI titers 4 weeks after vaccination with 1-week-old vaccine were significantly (P less than or equal to 0.05) higher than those after vaccination with 52-week-old vaccine at all thimerosal concentrations tested. Titers were also significantly higher (P less than or equal to 0.05) after vaccination with 1-week-old vaccine than after vaccination with 21-week-old vaccine at all thimerosal concentrations below about 8.25 mg/ml of antigen. Thimerosal at the levels recommended in commercial vaccines does not significantly decrease vaccine efficacy.

Animals↗

PubMed1984

Evidence for thimerosal induced cytoprotection on rat stomach.

Intragastrically administered thimerosal protects against ethanol induced ulceration with an ID50 of 1.6 mg/kg body weight. In contrast, intravenously administered thimerosal exhibits an ID50 of greater than 30 mg/kg. The antiulcerogenic effect of thimerosal persists for at least 20 hours before allowing gastric ulcers to be induced by ethanol. Intragastric application of thimerosal protects against acetyl salicylic acid induced with an ID50 of 6.8 mg/kg. Stress ulceration is inhibited by thimerosal with an ID50 of 9.2 mg/kg body weight. Investigations on the structure-activity relationship show that it is the mercury moiety and not the thiosalicylic acid moiety which is responsible for the inhibition by thimerosal.

Animals↗

PubMed1995

Thimerosal triggers meiosis reinitiation in oocytes of the Japanese clam Ruditapes philippinarum by eliciting an intracellular Ca2+ surge.

Ovarian oocytes of the bivalve mollusc Ruditapes philippinarum are arrested during first meiotic prophase. Release from this blockade is triggered by the neurohormone serotonin (5HT or 5-hydroxytryptamine), which promotes germinal vesicle breakdown and drives these oocytes to a second arrest in metaphase I. 5HT action involves binding to a specific G protein-coupled receptor which results in a transient rise in IP3 and in the intracellular free Ca2+ concentration. Here we analyze the cytological effects and mode of action of the sulphydryl reagent thimerosal which could also trigger meiosis reinitiation in Ruditapes. No metaphase I spindle formed under these conditions since thimerosal was found to be able to preclude or reverse tubulin polymerization when applied to prophase- or to metaphase-arrested oocytes, respectively. Our results strongly suggest that the common final target for 5HT and thimerosal actions consists in a transient rise in internal free Ca2+ level that we could follow using Fluo3/AM as a probe. The effect of thimerosal in promoting oocyte maturation and increasing intracellular free Ca2+ concentration was improved by excess KCI. In addition, thimerosal, but not KCI, was found to facilitate 5HT-induced maturation at subthreshold hormone concentrations which, by themselves, did not produce an intracellular Ca2+ surge. These data suggest that thimerosal may inhibit Ca2+ pumps of the endoplasmic reticulum and unmask the plasma membrane voltage-sensitive Ca2+ channels which also appear after 5HT-induced GVBD.

Aniline Compounds↗

PubMed1976

Platelet aggregation by thimerosal: role of ADP and SH groups.

Thimerosal, a sulphydryl inhibitor, induces aggregation of normal platelet rich plasma over a wide range of concentrations. Low doses induce a monophasic response preceded by a lag phase, high doses produce an immediate biphasic response. Thimerosal induces platelet aggregation through its binding by sulphydryl groups. Thimerosal induced aggregation is not mediated by ADP, it is not influenced by fibrinogen, von Willebrand factor, calcium, and magnesium ions of the medium. Thimerosal induced platelet aggregation is normal in patients affected by thrombocytopathia (defect of ADP release) but not in patients affected by Glanzmann's thrombasthenia. Mercaptopropionglycine, a substance which tends to preserve SH groups, inhibits platelet aggregation induced by thimerosal, thrombin, collagen, and ADP. A mechanism is proposed for thimerosal induced aggregation and the role of SH groups also in ADP, thrombin and collagen induced aggregation is indicated.

Adenosine Diphosphate↗

PubMed1993

Sperm, inositol trisphosphate, and thimerosal-induced intracellular Ca2+ elevations in rabbit eggs.

Fertilization-induced calcium (Ca2+) changes were examined in in vivo fertilized rabbit eggs, using the fluorescent Ca2+ inducer fura-2 dextran. Twenty-four of 48 fertilized eggs exhibited repetitive Ca2+ rises with intervals of 13 +/- 1 min (mean +/- SEM) during the recording period of 45 min. None of the unfertilized eggs showed Ca2+ rises (6/6). The mean peak Ca2+ concentration ([Ca2+]i) was 466 +/- 30 nM and the average duration was 100 +/- 3 sec. The amplitude of the Ca2+ rises decreased and the duration increased as the stage of fertilization progressed from recently fertilized to pronuclear apposition (P < 0.05). In unfertilized eggs, Ca2+ release was elicited by injection of inositol 1,4,5 trisphosphate (InsP3; 5 microM in the injection pipette) with a mean peak [Ca2+]i of 764 +/- 88 nM and a duration of 28 +/- 1 sec (n = 9). Injection of InsP3S3 (500 microM), a nonmetabolizable analogue of InsP3, induced repetitive Ca2+ rises different from sperm-induced rises in periodicity and duration. Exposure to 400 microM thimerosal caused spontaneous Ca2+ rises (1.4 +/- 0.1 Ca2+ rises in 45 min of measurements) with an amplitude of 1200 +/- 54 nM and duration of 114 +/- 8 sec. Heparin injection (100 mg/ml), an InsP3 receptor antagonist, blocked both InsP3 and thimerosal-induced spontaneous Ca2+ rises. Successive application of InsP3 and thimerosal in Ca(2+)-free medium showed that either InsP3 or thimerosal produced smaller Ca2+ rise(s) when preceded by Ca2+ rise(s) induced by the other agonist. The results of this study indicate that rabbit eggs, like other mammalian eggs, exhibit repetitive Ca2+ rises during fertilization. InsP3 and thimerosal stimulate intracellular Ca2+ release most likely from a common large intracellular pool by activating the InsP3 receptor.

Animals↗

PubMed1990

Thimerosal hyperpolarizes arterial smooth muscles in an endothelium-dependent manner.

Thimerosal activates the production of endothelium-derived relaxing factor (EDRF). I examined whether thimerosal also causes the release of an endothelium-dependent hyperpolarizing factor (EDHF). Thimerosal caused an endothelium-dependent hyperpolarization of smooth muscle. This effect is unlikely to be caused by the property of thimerosal to inhibit the acyl-coenzyme A: lysolecithin acyltransferase (LAT) since neither arachidonic acid nor lysolecithin hyperpolarized the muscles. I conclude that thimerosal is not a pure activator of EDRF (nitric oxide) production, but that it also releases a distinct EDHF.

1-Acylglycerophosphocholine O-Acyltransferase↗

PubMed1988

Enhancement of eicosanoid synthesis in mouse peritoneal macrophages by the organic mercury compound thimerosal.

Availability of the common precursor arachidonic acid represents the fundamental prerequisite of the cellular eicosanoid synthesis. The amount of free arachidonic acid is regulated not only by phospholipases, which liberate this polyunsaturated fatty acid from lipid pools, but also by the reacylating enzyme acylCoA:lysophosphatide acyltransferase. We have previously shown (Goppelt-Strübe, G., C.-F. Körner, G. Hausmann, D. Gemsa, and K. Resch. Control of Prostanoid Synthesis: Role of Reincorporation of Released Precursor Fatty Acids. Prostaglandins 32:373. 1986.) that the organic mercury compound thimerosal in murine peritoneal macrophages inhibits arachidonic acid reincorporation into cellular lipids, thereby leading to an enhanced prostanoid synthesis. In this report we show that the production of leukotriene C4 was also increased after the addition of thimerosal to mouse peritoneal macrophages in a time and dose dependent manner. Concomitantly, thimerosal led to a significant rise of the intracellular calcium concentration as measured by fura-2 fluorescence. Simultaneous addition of thimerosal and indomethacin or exogeneous arachidonic acid to the cells resulted in a synergistic enhancement of leukotriene C4 synthesis. On the other hand, another sulfhydryl group blocking agent, ethacrynic acid, was found to be ineffective in increasing leukotriene C4 levels even in combination with exogeneous arachidonic acid. Thimerosal therefore provides a helpful tool in studying the basic regulatory mechanisms of the cellular leukotriene synthesis.

Animals↗

PubMed2006

Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury).

Inorganic mercury may aggravate murine systemic autoimmune diseases which are either spontaneous (genetically determined) or induced by non-genetic mechanisms. Organic mercury species, the dominating form of mercury exposure in the human population, have not been examined in this respect. Therefore, ethyl mercury in the form of thimerosal, a preservative recently debated as a possible health hazard when present in vaccines, was administered in a dose of 0.156-5 mg/L drinking water to female (NZB x NZW)F1 (ZBWF1) mice. These mice develop an age-dependent spontaneous systemic autoimmune disease with high mortality primarily due to immune-complex (IC) glomerulonephritis. Five mg thimerosal/L drinking water (295 microg Hg/kg body weight (bw)/day) for 7 weeks induced glomerular, mesangial and systemic vessel wall IC deposits and antinuclear antibodies (ANA) which were not present in the untreated controls. After 22-25 weeks, the higher doses of thimerosal had shifted the localization of the spontaneously developing renal glomerular IC deposits from the capillary wall position seen in controls to the mesangium. The altered localization was associated with less severe histological kidney damage, less proteinuria, and reduced mortality. The effect was dose-dependent, lower doses having no effect compared with the untreated controls. A different effect of thimerosal treatment was induction of renal and splenic vessel walls IC deposits. Renal vessel wall deposits occurred at a dose of 0.313-5 mg thimerosal/L (18-295 microg Hg/kg bw/day), while splenic vessel wall deposits developed also in mice given the lowest dose of thimerosal, 0.156 mg/L (9 microg Hg/kg bw/day). The latter dose is 3- and 15-fold lower than the dose of Hg required to induce vessel wall IC deposits in genetically susceptible H-2s mice by HgCl2 and thimerosal, respectively. Further studies on the exact conditions needed for induction of systemic IC deposits by low-dose organic mercurials in autoimmune-prone individuals, as well as the potential effect of these deposits on the vessel walls, are warranted.

Animals↗

PubMed1993

Thimerosal reveals calcium-induced calcium release in unfertilised sea urchin eggs.

The fertilisation calcium wave in sea urchin eggs triggers the onset of development. The wave is an explosive increase in intracellular free calcium concentration ([Ca2+i]) that begins at the point of sperm entry and crosses the egg in about 20 s. Thimerosal is a sulphydryl reagent that sensitises calcium release from intracellular stores in a variety of cell types. Treatment of unfertilised eggs with thimerosal causes a slow increase [Ca2+i] that results eventually in a large, spontaneous calcium transient and egg activation. At shorter times after thimerosal treatment, egg activation and the calcium transient can be triggered by calcium influx through voltage-gated calcium channels, a form of calcium-induced/calcium release (CICR). Thimerosal treatment also reduces the latency of the fertilisation calcium response and increases the velocity of the fertilisation wave. These results indicate that thimerosal can unmask CICR in sea urchin eggs and suggest that the ryanodine receptor channel based CICR may contribute to explosive calcium release during the fertilisation wave.

Action Potentials↗

PubMed2003

Oxidation by thimerosal increases calcium levelsin renal tubular cells.

The effect of thimerosal, a reactive oxidant, on cytoplasmic free Ca2+ concentrations ([Ca2+]i) in Madin Darby canine kidney (MDCK) cells was explored by using the Ca2+-sensitive dye fura-2. Thimerosal acted in a concentration-dependent manner with an EC50 of 0.5 microM. The Ca2+ signal comprised a gradual rise and a sustained elevation. Removal of extracellular Ca2+ reduced 80% of the signal. In Ca2+-free medium, the [Ca2+]i rise induced by 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) was completely inhibited by pretreatment with 5 microM thimerosal. The thimerosal (5 microM)-induced Ca2+ release was not changed by inhibition of phospholipase C with 2 microM U73122. Collectively, this study shows that thimerosal induced [Ca2+]i rises in renal tubular cells via releasing store Ca2+ from the endoplasmic reticulum Ca2+ stores in a manner independent of phospholipase C activity.

Animals↗

PubMed2001

Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal.

We have investigated the interaction of thimerosal, a widely used antiseptic and preservative, with the human erythrocytic GST T1 (glutathione-S-transferase T1). This detoxifying enzyme is expressed in the erythrocytes of solely the human species and it displays a genetic polymorphism. Due to this polymorphism about 25% of the individuals of the caucasian population lack this activity ("non-conjugators"), while 75% show it ("conjugators") (Hallier, E., et al., 1993). Using our newly developed HPLC-fluorescence detection assay (Müller, M., et al., 2001) we have profiled the kinetics of enzyme inhibition in erythrocyte lysates of two individuals previously identified as "normal conjugator" (medium enzyme activity) and "super-conjugator" (very high activity). For the normal conjugator we have determined a 2.77 mM thimerosal concentration to inhibit 50% of the GST T1 activity. In the case of the super-conjugator a 2.3 mM thimerosal concentration causes a 50% inhibition of the enzyme activity. For both phenotypes a 14.8 mM thimerosal concentration results in residual enzyme activities equal to those typically detected in non-conjugator lysates. Thus, sufficiently high doses of thimerosal may be able to change the phenotypic status of an individual--at least in vitro--by inhibition of the GST T1 enzyme.

Anti-Infective Agents, Local↗