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At least 19 recordsLinked to original sources
PubMed1991

A probable role for vaccines containing thimerosal in thimerosal hypersensitivity.

We patch tested 141 patients with 0.05% aq. thimerosal and 222 patients with 0.05% aq. mercuric chloride, including 63 children. The frequency of positive patch test reactions to thimerosal was 16.3%. There was a marked preponderance in the young age groups after vaccination, while none of 36 infants (aged 3-48 months) reacted to thimerosal. Positive reactions to mercuric chloride were found in 23 (10.4%) of 222 patients. We also sensitized guinea pigs with diphtheria-pertussis-tetanus (DPT) vaccine containing 0.01% thimerosal and succeeded in inducing hypersensitivity to thimerosal. From patch testing in humans and animal experiments, it is suggested that 0.01% thimerosal in vaccines can sensitize children, and that hypersensitivity to thimerosal is due to the thiosalicylic part of the molecule and correlates with photosensitivity to piroxicam.

Adolescent↗
PubMed1996

Redox modulation of calcium entry and release of intracellular calcium by thimerosal in GH4C1 pituitary cells.

In the present work we have investigated the actions of the oxidizing sulfhydryl reagent thimerosal on different mechanisms which regulate intracellular free Ca2+ concentration ([Ca2+]i) in GH4C1 pituitary cells. In intact Fura-2 loaded cells, low concentrations of thimerosal potentiated the spike phase of the TRH-induced (thyrotropin-releasing hormone) rise in [Ca2+]i, whereas high thimerosal concentrations inhibited it. The effect of thimerosal on the plateau phase was always inhibitory. The effect of thimerosal on the IP3-induced calcium release (IICR) was studied in permeabilized cells using the Ca2+ indicator Fluo-3. A low concentration of thimerosal (10 microM) stimulated IICR: the Ca2+ release induced by 300 nM inositol-1,4,5-trisphosphate (IP3) was enhanced in cells treated with thimerosal for 1 or 6 min (67 +/- 11 nM and 34 +/- 5 nM, respectively) as compared to control cells (17 +/- 2 nM). On the other hand, a high concentration of thimerosal (100 microM) inhibited IICR: when IP3 (10 microM) was added after a 5 min preincubation with thimerosal, the IP3-induced rise in [Ca2+]i (46 +/- 14 nM) was 57% smaller as compared with that seen in control cells (106 +/- 10 nM). The effect of thimerosal on the voltage-operated Ca2+ channels (VOCCs) was studied by depolarizing intact Fura-2 loaded cells by addition of 20 mM K+ to the cuvette. The depolarization-evoked increase in [Ca2+]i was inhibited in a dose-dependent manner by thimerosal. Direct evidence for an inhibitory effect of thimerosal on VOCCs was obtained by using the whole-cell configuration of the patch-clamp technique: thimerosal (100 microM) potently inhibited the Ba2+ currents through VOCCs. In addition, our results indicated that thimerosal inhibited the caffeine-induced increase in [Ca2+]i, and activated a capacitative Ca2+ entry pathway. The actions of thimerosal were apparently due to its oxidizing activity because the effects were mostly reversed by the thiol-reducing agent dithiothreitol (DTT). We conclude that, in GH4C1 pituitary cells, the mobilization of intracellular calcium and the different Ca2+ entry pathways are sensitive to redox modulation.

Animals↗
PubMed1999

Thimerosal: a versatile sulfhydryl reagent, calcium mobilizer, and cell function-modulating agent.

An overview of the literature concerning the effects of thimerosal is presented. Because of its antibacterial effect, thimerosal is used for a variety of practical purposes such as antiseptic and preservative. In biomedical studies, thimerosal is used as a sulfhydryl reagent, and as a calcium-mobilizing agent. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Relatively little study has been devoted to the mechanism of the reaction of thimerosal with the sulfhydryl group; the sulfhydryl reactive capacity is mostly concluded on the basis of inactivation of the effect by dithiothreitol (DTT). Thimersal causes a release of calcium from intracellular stores in many cells types; this is followed by an influx of extracellular calcium. Both InsP3- and ryanodine-sensitive calcium stores may be affected. Studies with permeabilized cells or organelles show that the effect of thimerosal on calcium is dependent on the concentration: low concentrations of thimerosal stimulate calcium release, high concentrations are inhibitory. This dependence is not found in intact cells. Thimerosal may activate or inhibit a number of cell functions. These are often related to the ability to release calcium or with the sulfhydryl reactivity. In platelets, thimerosal causes aggregation, increase of arachidonic acid metabolism, and exocytotic release of serotonin. In neutrophils, thimerosal causes, besides an increase of cytosolic free calcium, an increase of formyl-methionyl-leucyl-phenylalanine (fMLP)-activated leukotriene release, and a modulation of chemotactic migration and exocytosis. At low concentrations, thimerosal induces chemotactic migration of neutrophils, in the absence of other chemoattractants. The effect is also observed with thiosalicylic acid, indicating that the stimulation of migration was due to the thiosalicylic acid moiety of the thimerosal molecule. At higher concentrations, thimerosal causes inhibition of fMLP-activated migration. Low concentrations of thimerosal, but not of thiosalicylic acid, induced exocytotic enzyme release from neutrophils. High concentrations of thimerosal inhibited fMLP-activated exocytosis. The results point to an involvement of calcium mobilization and calcium influx of activation, and reaction with sulfhydryl groups for inhibition.

Animals↗
PubMed1992

The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor.

The thiol reagent, thimerosal, has been shown to cause an increase in intracellular Ca2+ concentration ([Ca2+]i) in several cell types, and to cause Ca2+ spikes in unfertilized hamster eggs. Using single cell video-imaging we have shown that thimerosal evokes repetitive Ca2+ spikes in intact Fura-2-loaded HeLa cells that were similar in shape to those stimulated by histamine. Both thimerosal- and histamine-stimulated Ca2+ spikes occurred in the absence of extracellular (Ca2+ o), suggesting that they result from mobilization of Ca2+ from intracellular stores. Whereas histamine stimulated formation of inositol phosphates, thimerosal, at concentrations that caused sustained Ca2+ spiking, inhibited basal and histamine-stimulated formation of inositol phosphates. Thimerosal-evoked Ca2+ spikes are therefore not due to the stimulated production of inositol 1,4,5-trisphosphate (InsP3). The effects of thimerosal on Ca2+ spiking were probably due to alkylation of thiol groups on intracellular proteins because the spiking was reversed by the thiol-reducing compound dithiothreitol, and the latency between addition of thimerosal and a rise in [Ca2+]i was greatly shortened in cells where the intracellular reduced glutathione concentration had been decreased by preincubation with DL-buthionine (S,R)-sulfoximine. In permeabilized cells, thimerosal caused a concentration-dependent inhibition of Ca2+ accumulation, which was entirely due to inhibition of Ca2+ uptake into stores because thimerosal did not affect unidirectional 45Ca2+ efflux from stores preloaded with 45Ca2+. Thimerosal also caused a concentration-dependent sensitization of InsP3-induced Ca2+ mobilization: half-maximal mobilization of Ca2+ stores occurred with 161 +/- 20 nM InsP3 in control cells and with 62 +/- 5 nM InsP3 after treatment with 10 microM thimerosal. We conclude that thimerosal can mimic the effects of histamine on intracellular Ca2+ spiking without stimulating the formation of InsP3 and, in light of our results with permeabilized cells, suggest that thimerosal stimulates spiking by sensitizing cells to basal InsP3 levels.

Calcium↗
PubMed1992

Cytosolic Ca2+ spikes evoked by the thiol reagent thimerosal in both intact and internally perfused single pancreatic acinar cells.

Cytosolic calcium signals evoked by the sulphydryl-group-oxidising agent, thimerosal, have been investigated in acutely isolated pancreatic acinar cells. Two techniques were employed for the assessment of the cytosolic free-calcium concentration ([Ca2+]i): measurement of calcium-dependent chloride and non-specific cation currents (whole-cell patch-clamp recording) and microfluorimetry (fura-2). Thimerosal (0.5-100 microM) evoked repetitive spikes in both chloride and cation currents as seen by patch-clamp recording, and in [Ca2+]i as seen by microfluorimetry, with a latency of 1-3 min. The response increased in magnitude over time and was not reversed on removal of thimerosal. The thimerosal-induced spikes were reversibly blocked by 2 mM dithiothreitol and by 20 mM caffeine. Inclusion of heparin (200 micrograms/ml) in the pipette solution blocked the thimerosal-induced spikes. The calcium spikes continued after the removal of extracellular calcium; however, low concentrations of thimerosal (0.5-5 microM) were unable to initiate a current response in the absence of external calcium. High concentrations of thimerosal (50-100 microM) could initiate spikes without extracellular calcium. Thimerosal, at concentrations that failed to produce an independent effect, potentiated the acetylcholine-evoked oscillations in [Ca2+]i. We conclude that thimerosal is able to mobilise calcium from an intracellular store; the blockade by heparin may indicate that thimerosal exerts an action on the inositol trisphosphate pathway. The dependence on extracellular calcium for initiation, but not for continuation of the thimerosal-induced calcium spikes suggests that thimerosal may have the additional effect of inhibiting the plasma membrane calcium ATPase.

Action Potentials↗
PubMed2006

Thimerosal induces apoptosis and G2/M phase arrest in human leukemia cells.

Thimerosal is an organomercury compound with sulfhydryl-reactive properties. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Due to its antibacterial effect, thimerosal is widely used as preservatives and has been reported to cause chemically mediated side effects. In the present study, we showed that the molecular mechanism of thimerosal induced apoptosis in U937 cells. Thimerosal was shown to be responsible for the inhibition of U937 cells growth by inducing apoptosis. Treatment with 2.5-5 microM thimerosal but not thiosalicylic acid (structural analog of thimerosal devoid of mercury) for 12 h produced apoptosis, G(2)/M phase arrest, and DNA fragmentation in a dose-dependent manner. Treatment with caspase inhibitor significantly reduced thimerosal-induced caspase 3 activation. In addition, thimerosal-induced apoptosis was attenuated by antioxidant Mn (III) meso-tetrakis (4-benzoic acid) porphyrin (Mn-TBAP). These data indicate that the cytotoxic effect of thimerosal on U937 cells is attributable to the induced apoptosis and that thimerosal-induced apoptosis is mediated by reactive oxygen species generation and caspase-3 activation.

Apoptosis↗
PubMed2005

Comparison of blood and brain mercury levels in infant monkeys exposed to methylmercury or vaccines containing thimerosal.

Thimerosal is a preservative that has been used in manufacturing vaccines since the 1930s. Reports have indicated that infants can receive ethylmercury (in the form of thimerosal) at or above the U.S. Environmental Protection Agency guidelines for methylmercury exposure, depending on the exact vaccinations, schedule, and size of the infant. In this study we compared the systemic disposition and brain distribution of total and inorganic mercury in infant monkeys after thimerosal exposure with those exposed to MeHg. Monkeys were exposed to MeHg (via oral gavage) or vaccines containing thimerosal (via intramuscular injection) at birth and 1, 2, and 3 weeks of age. Total blood Hg levels were determined 2, 4, and 7 days after each exposure. Total and inorganic brain Hg levels were assessed 2, 4, 7, or 28 days after the last exposure. The initial and terminal half-life of Hg in blood after thimerosal exposure was 2.1 and 8.6 days, respectively, which are significantly shorter than the elimination half-life of Hg after MeHg exposure at 21.5 days. Brain concentrations of total Hg were significantly lower by approximately 3-fold for the thimerosal-exposed monkeys when compared with the MeHg infants, whereas the average brain-to-blood concentration ratio was slightly higher for the thimerosal-exposed monkeys (3.5 +/- 0.5 vs. 2.5 +/- 0.3). A higher percentage of the total Hg in the brain was in the form of inorganic Hg for the thimerosal-exposed monkeys (34% vs. 7%). The results indicate that MeHg is not a suitable reference for risk assessment from exposure to thimerosal-derived Hg. Knowledge of the toxicokinetics and developmental toxicity of thimerosal is needed to afford a meaningful assessment of the developmental effects of thimerosal-containing vaccines.

Animals↗
PubMed1996

Effects of thimerosal, an organic sulfhydryl modifying agent, on serotonin transport activity into rabbit blood platelets.

The effects of the sulfhydryl group inhibitor thimerosal on serotonin (5-HT) transport activity into rabbit blood platelets were investigated, along with its effects on the intracellular concentration of Ca2+ ([Ca2+]i). 3H-5-HT transport activity into rabbit blood platelets was inhibited by treatment with 10(-5) M thimerosal for 30 min, which did not cause 5-HT release from platelets. The thimerosal-induced inhibition of 5-HT transport was antagonized by dithiotheritol. It was suggested that the thimerosal acts as a sulfhydryl inhibitor and inhibits 5-HT transport activity independently of the 5-HT release reaction in our experiment using rabbit blood platelets. As aspirin did not affect thimerosal-induced 5-HT transport inhibition, it was suggested that the thromboxane A2-generating system does not operate in the effect of thimerosal on 5-HT transport into blood platelets. Furthermore, thimerosal induced a transient elevation of [Ca2+]i, which was followed by a sustained increase. In the absence of extracellular Ca2+, thimerosal caused only a transient increase in [Ca2+]i. It was suggested that the elevation of [Ca2+]i consisted of two phases, e.g. a transient phase induced by Ca2+ mobilization from the intracellular store sites and a sustained phase which might be explained by Ca2+ influx from the extracellular environment. In conclusion, thimerosal inhibited 5-HT transport into blood platelets at a concentration which did not induce 5-HT release, and intracellular Ca2+ mobilization might mediate the inhibitory effect of thimerosal on 5-HT transport.

Animals↗
PubMed2005

Thimerosal-induced cytosolic Ca2+ elevation and subsequent cell death in human osteosarcoma cells.

The effect of the oxidizing agent thimerosal on cytosolic free Ca(2+) concentration ([Ca(2+)]i) and proliferation has not been explored in human osteoblast-like cells. This study examined whether thimerosal alters Ca(2+) levels and causes cell death in MG63 human osteosarcoma cells. [Ca(2+)]i and cell death were measured using the fluorescent dyes fura-2 and WST-1, respectively. Thimerosal at concentrations above 5 microM increased [Ca(2+)]i in a concentration-dependent manner. The Ca(2+) signal was reduced by 80% by removing extracellular Ca(2+). The thimerosal-induced Ca(2+) influx was sensitive to blockade of La(3+), and dithiothreitol (50 microM) but was insensitive to nickel and several L-type Ca(2+) channel blockers. After pretreatment with 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor), thimerosal failed to induce [Ca(2+)]i rises. Inhibition of phospholipase C with 2 microM U73122 did not change thimerosal-induced [Ca(2+)]i rises. At concentrations of 5, 10 and 20 microM thimerosal killed 33, 55 and 100% cells, respectively. The cytotoxic effect of 5 microM thimerosal was reversed by 54% by prechelating cytosolic Ca(2+) with BAPTA. Collectively, in MG63 cells, thimerosal induced a [Ca(2+)]i rise by causing Ca(2+) release from endoplasmic reticulum stores and Ca(2+) influx from extracellular space. Furthermore, thimerosal can cause Ca(2+)-related cytotoxicity in a concentration-dependent manner.

Bone Neoplasms↗
PubMed2001

Stimulation by thimerosal of histamine-induced Ca(2+) release in intact HeLa cells seen with aequorin targeted to the endoplasmic reticulum.

The oxidizing thiol reagent, thimerosal, has been shown to activate reversibly the inositol 1,4,5-trisphosphate (InsP(3)) receptor in several cell types. We have studied here the effects of thimerosal by monitoring the [Ca(2+)] inside the endoplasmic reticulum (ER) of intact HeLa cells with targeted aequorin. We show that thimerosal produced little effects on the ER-Ca(2+)-pump and only slightly increased the ER-Ca(2+)-leak in intact cells. Instead, thimerosal increased the sensitivity to histamine of ER-Ca(2+)-release by about two orders of magnitude, made the response much more prolonged at saturating histamine concentrations and enhanced both cytosolic and mitochondrial [Ca(2+)] responses to histamine. Moreover, inhibition of ER-Ca(2+)release by cytosolic [Ca(2+)] microdomains was fully preserved and sensitive to BAPTA-loading, and histamine-induced Ca(2+) release remained quantal in the presence of both thimerosal and intracellular BAPTA. The effects of thimerosal were reversible in the presence of dithiotreitol, suggesting the possible presence of a physiological redox regulatory mechanism. However, in permeabilized cells thimerosal potentiated InsP(3)-induced Ca(2+) release but oxidized glutathione had no effect. In addition, thimerosal increased the [Ca(2+)](ER) steady-state level in permeabilized cells. Thimerosal partially inhibited also plasma membrane Ca(2+)extrusion and increased Ca(2+)(Mn(2+)) entry through the plasma membrane, both phenomena contributing to increase the steady-state cytosolic [Ca(2+)]. Thimerosal-induced Ca(2+) entry was additive to that induced by emptying of the ER, suggesting that store-operated Ca(2+) channels may not be involved. These results provide new insights on the mechanisms of activation and inactivation of InsP(3) receptors.

Aequorin↗
PubMedDate not supplied

Neurodevelopmental disorders following thimerosal-containing childhood immunizations: a follow-up analysis.

The authors previously published the first epidemiological study from the United States associating thimerosal from childhood vaccines with neurodevelopmental disorders (NDs) based upon assessment of the Vaccine Adverse Event Reporting System (VAERS). A number of years have gone by since their previous analysis of the VAERS. The present study was undertaken to determine whether the previously observed effect between thimerosal-containing childhood vaccines and NDs are still apparent in the VAERS as children have had a chance to further mature and potentially be diagnosed with additional NDs. In the present study, a cohort of children receiving thimerosal-containing diphtheria-tetanus-acellular pertussis (DTaP) vaccines in comparison to a cohort of children receiving thimerosal-free DTaP vaccines administered from 1997 through 2000 based upon an assessment of adverse events reported to the VAERS were evaluated. It was determined that there were significantly increased odds ratios (ORs) for autism (OR = 1.8, p < .05), mental retardation (OR = 2.6, p < .002), speech disorder (OR = 2.1, p < .02), personality disorders (OR = 2.6, p < .01), and thinking abnormality (OR = 8.2, p < .01) adverse events reported to the VAERS following thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines. Potential confounders and reporting biases were found to be minimal in this assessment of the VAERS. It was observed, even though the media has reported a potential association between autism and thimerosal exposure, that the other NDs analyzed in this assessment of the VAERS had significantly higher ORs than autism following thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines. The present study provides additional epidemiological evidence supporting previous epidemiological, clinical and experimental evidence that administration of thimerosal-containing vaccines in the United States resulted in a significant number of children developing NDs.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts.

Thimerosal is an organic mercurial compound used as a preservative in biomedical preparations. Little is known about the reactions of human neuronal and skin cells to its micro- and nanomolar concentrations, which can occur after using thimerosal-containing products. A useful combination of fluorescent techniques for the assessment of thimerosal toxicity is introduced. Short-term thimerosal toxicity was investigated in cultured human cerebral cortical neurons and in normal human fibroblasts. Cells were incubated with 125-nM to 250-microM concentrations of thimerosal for 45 min to 24 h. A 4', 6-diamidino-2-phenylindole dihydrochloride (DAPI) dye exclusion test was used to identify nonviable cells and terminal transferase-based nick-end labeling (TUNEL) to label DNA damage. Detection of active caspase-3 was performed in live cell cultures using a cell-permeable fluorescent caspase inhibitor. The morphology of fluorescently labeled nuclei was analyzed. After 6 h of incubation, the thimerosal toxicity was observed at 2 microM based on the manual detection of the fluorescent attached cells and at a 1-microM level with the more sensitive GENios Plus Multi-Detection Microplate Reader with Enhanced Fluorescence. The lower limit did not change after 24 h of incubation. Cortical neurons demonstrated higher sensitivity to thimerosal compared to fibroblasts. The first sign of toxicity was an increase in membrane permeability to DAPI after 2 h of incubation with 250 microM thimerosal. A 6-h incubation resulted in failure to exclude DAPI, generation of DNA breaks, caspase-3 activation, and development of morphological signs of apoptosis. We demonstrate that thimerosal in micromolar concentrations rapidly induce membrane and DNA damage and initiate caspase-3-dependent apoptosis in human neurons and fibroblasts. We conclude that a proposed combination of fluorescent techniques can be useful in analyzing the toxicity of thimerosal.

Apoptosis↗
PubMed2003

Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication.

We were initially highly skeptical that differences in the concentrations of thimerosal in vaccines would have any effect on the incidence rate of neurodevelopmental disorders after childhood immunization. This study presents the first epidemiologic evidence, based upon tens of millions of doses of vaccine administered in the United States, that associates increasing thimerosal from vaccines with neurodevelopmental disorders. Specifically, an analysis of the Vaccine Adverse Events Reporting System (VAERS) database showed statistical increases in the incidence rate of autism (relative risk [RR] = 6.0), mental retardation (RR = 6.1), and speech disorders (RR = 2.2) after thimerosal-containing diphtheria, tetanus, and acellular pertussis (DTaP) vaccines in comparison with thimerosal-free DTaP vaccines. The male/female ratio indicated that autism (17) and speech disorders (2.3) were reported more in males than females after thimerosal-containing DTaP vaccines, whereas mental retardation (1.2) was more evenly reported among male and female vaccine recipients. Controls were employed to determine if biases were present in the data, but none were found. It was determined that overall adverse reactions were reported in similar-aged populations after thimerosal-containing DTaP (2.4 +/- 3.2 years old) and thimerosal-free DTaP (2.1 +/- 2.8 years old) vaccinations. Acute control adverse reactions such as deaths (RR = 1.0), vasculitis (RR = 1.2), seizures (RR = 1.6), ED visits (RR = 1.4), total adverse reactions (RR = 1.4), and gastroenteritis (RR = 1.1) were reported similarly after thimerosal-containing and thimerosal-free DTaP vaccines. An association between neurodevelopmental disorders and thimerosal-containing DTaP vaccines was found, but additional studies should be conducted to confirm and extend this study.

Adverse Drug Reaction Reporting Systems↗
PubMed1988

Thimerosal: an ophthalmic preservative which acts as a hapten to elicit specific antibodies and cell mediated immunity.

A rabbit model for the study of hypersensitivity to thimerosal was established in order to develop better techniques for screening patient sera and tears for specific antibodies to lens care re-agents. Thimerosal (sodium ethylmercury thiosalicylatelate) was successfully coupled to several protein carriers using a water soluble carbodiimide which linked the carboxyl group of thimerosal to free amino groups of the carrier proteins. Thimerosal was also shown to spontaneously react with proteins as detected by the irreversible binding of mercury to the protein carrier. Immunization of rabbits with the chemically coupled thimerosal resulted in the production of antibodies which specifically reacted with thimerosal. The rabbits also manifested delayed and immediate forms of hypersensitivity to the thimerosal conjugates. The ELISA assay for specific serum antibodies was found to be a sensitive, reliable and specific screening tool However, there was no immunological cross reactivity between the chemically coupled thimerosal and the spontaneously coupled thimerosal. Therefore, the epitopes produced by these two reaction mechanisms were probably immunochemically different even though both contained detectable thimerosal derived mercury.

Animals↗