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PubMed1993

Bell-shaped activation of inositol-1,4,5-trisphosphate-induced Ca2+ release by thimerosal in permeabilized A7r5 smooth-muscle cells.

There is no consensus about the different types of Ca2+ transport processes in the endoplasmic reticulum that are targeted by the sulphydryl reagent thimerosal. We have therefore investigated how thimerosal affects the various Ca2+ transport processes in permeabilized A7r5 smooth-muscle cells, using an unidirectional 45Ca2+ flux technique. Thimerosal up to a concentration of 32 microM did not have an effect on the passive 45Ca2+ leak from the stores, while higher concentrations increased this aspecific leak. Thimerosal inhibited the endoplasmic reticulum Ca2+ pump with an EC50 of 9 microM. Thimerosal exerted a biphasic effect on the Ca2+ release induced by inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] with a stimulation of the release at thimerosal concentrations below 10 microM, and an inhibitory effect at higher concentrations. Thimerosal (2.5-250 microM) did not exert an effect on the specific binding of [3H]Ins(1,4,5)P3 to its receptor, indicating that it probably did not act at the level of the binding site. This finding contrasts with the effect of the closely related sulphydryl reagent parachloromercuriphenylsulphonate, which, at high concentrations, inhibited [3H]Ins(1,4,5)P3 binding. The effects of thimerosal were largely prevented by the sulphydryl reducing agent dithiothreitol (3 mM). We conclude that thimerosal concentrations ranging from 0.32 to 1 microM can stimulate the Ins(1,4,5)P3-induced Ca2+ release without inhibiting the Ca2+ pumps or without increasing the passive Ca2+ permeability of the endoplasmic reticulum.

Animals↗
PubMed1992

Effect of the sulfhydryl reagent thimerosal on cytosolic free Ca2+ and membrane potential of thymocytes.

The sulfhydryl reagent thimerosal at concentrations 5-100 microM has been found to induce a variety of changes in ion transport in rat thymocytes. In particular, [Ca2+]i increases about 10-fold from the basal level. The [Ca2+]i response to thimerosal displays a two-stage time course, with the main [Ca2+]i rise during the second stage. Evidence has been obtained for the depletion of intracellular Ca2+ pools in thimerosal-treated cells, however, Ca2+ mobilization from intracellular stores does not contribute significantly into [Ca2+]i rise. Thimerosal elicits permeability not only for Ca2+, but also for Mn2+ and Ni2+, which is Ca(2+)-dependent. We failed to get any evidence on thimerosal-induced inhibition of the plasma membrane Ca(2+)-ATPase. The induction of Ca2+ influx, rather than inhibition of Ca(2+)-ATPase, accounts for the disturbance of [Ca2+]i homeostasis in thimerosal-treated cells. Thimerosal also elicits changes in monovalent ion fluxes resulting in marked depolarization. The latter seems unrelated to the changes in [Ca2+]i and is suggested to be mediated both by increased permeability for Na+ and a decreased one for K+. Thimerosal significantly stimulates AA release from thymocytes. Evidence has been presented that AA metabolite(s), probably, LO product(s), may mediate the changes in the transport of mono- and divalent cations elicited by the sulfhydryl reagent. Prolonged treatment of thymocytes with thimerosal resulted in cell death.

Animals↗
PubMed1993

Thimerosal induced changes of intracellular calcium in human endothelial cells.

We have measured the effects of the -SH oxidizing agent thimerosal on the intracellular calcium concentration in single endothelial cells from human umbilical cord vein. Application of 1 microM thimerosal after a 10 s prepulse of 10 microM evoked oscillations of intracellular calcium. Concentrations higher than 10 microM induced a few oscillations which were followed by a long lasting increase in intracellular calcium between 120 and 980 nM at 10 microM thimerosal, between 250 and 1290 nM at 100 microM. The plateau level of the thimerosal induced increase in intracellular calcium depended on the extracellular calcium concentration, and was clearly decreased in calcium free solution. It was also reduced if the extracellular potassium concentration was increased to 140 mM. Nickel (5 mM) did not block the elevation of intracellular calcium. Thimerosal induced quenching of the Fura-2 fluorescence in Ca2+ free solutions containing 1 mM Mn2+. These effects indicate that thimerosal opens a pathway for Ca2+ entry from the extracellular side. The amount of calcium which could be released by histamine was drastically reduced after initiation of the thimerosal response. If refilling of Ca2+ stores was prevented by incubation of the cells in Ca2+ free solution, histamine still induced a transient, but not maintained, increase in [Ca2+]i. After application of thimerosal in Ca2+ free solutions to prevent refilling of the stores, a transient increase in [Ca2+]i could still be recorded but the histamine response on [Ca2+]i almost disappeared indicating a discharge of Ca2+ stores by thimerosal.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMed1991

Thimerosal induces calcium mobilization, fructose 2,6-bisphosphate synthesis and cytoplasmic alkalinization in rat thymus lymphocytes.

The effect of thimerosal on intracellular calcium ([Ca2+]i), pH (pHi) and fructose 2,6-bisphosphate (Fru 2,6-P2) in thymus lymphocytes was investigated. The effect of thimerosal on cell growth was also examined. Thimerosal produced a dose-dependent increase in [Ca2+]i, pHi and in the level of fructose 2,6-bisphosphate. Thimerosal was, however, unable to produce cell proliferation and inhibited [3H]thymidine incorporation when cells were challenged with PHA and costimulator. In the absence of external calcium, thimerosal produced only a slight increase in [Ca2+]i. In Na(+)-containing buffer, thimerosal induced an initial acidification (0.05 +/- 0.01 pH units), followed by an alkalinization of 0.08 pH units/min, whereas in Na(+)-free media, pHi decreased 0.2 +/- 0.02 units and this acidification was maintained for more than 40 min. When external calcium was removed the initial acidification was unchanged and no further increase in pHi was observed. Polymyxin B, an inhibitor of protein kinase C, did not modify the initial thimerosal-induced acidification although pH returned to basal levels after 10 min. It was concluded that alkalinization induced by thimerosal is probably due to activation of the Na+/H+ exchanger and that changes in internal Ca2+, pH and metabolic rate are not sufficient to induce cellular proliferation. The mechanism by which thimerosal inhibits thymocyte proliferation remains to be clarified.

Animals↗
PubMed2004

Dose-response study of thimerosal-induced murine systemic autoimmunity.

The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury. A.SW mice were exposed to 1.25-40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 microg Hg/kg bw and a concentration of 21 and 1.9 microg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose-response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury.

Animals↗
PubMed2004

Property of thimerosal-induced decrease in cellular content of glutathione in rat thymocytes: a flow cytometric study with 5-chloromethylfluorescein diacetate.

There is a concern on the part of public health community that adverse health consequences by thimerosal, a preservative in vaccines for infants, may occur among infants during immunization schedule. Therefore, the effect of thimerosal on cellular content of glutathione was examined on thymocytes obtained from 4-week-old rats using a flow cytometer and 5-chloromethylfluorescein diacetate. Thimerosal at concentrations ranging from 1 to 10 microM reduced the cellular content of glutathione in a concentration-dependent manner, and the complete depletion of cellular glutathione was observed when the cells were treated with 30 microM thimerosal. L-Cysteine significantly attenuated the actions of thimerosal to reduce the glutathione content and to increase the intracellular Ca2+ concentration. Prolonged incubation (24 h) with 1-3 microM thimerosal induced the apoptosis. The cytotoxic action of thimerosal was greatly augmented when the cells suffered oxidative stress induced by H2O2. It may be unlikely that thimerosal exerts potent cytotoxic action under the in vivo condition because the blood concentration of thimerosal after receiving vaccines does not seem to reach micromolar range and nonprotein thiols at micromolar concentrations are present in the blood.

Animals↗
PubMed2000

Inhibitory action of thimerosal, a sulfhydryl oxidant, on sodium channels in rat sensory neurons.

The effects of thimerosal, a sulfhydryl oxidizing agent, on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp technique. Thimerosal blocked the two types of sodium channels in a dose-dependent manner. The inhibitory effect of thimerosal was much more pronounced in TTX-R sodium channels than TTX-S sodium channels. The effect of thimerosal was irreversible upon wash-out with thimerosal-free external solution. However, dithiothreitol, a reducing agent, partially reversed it. Thimerosal shifted the steady-state inactivation curves for both types of sodium channels in the hyperpolarizing direction. The voltage dependence of activation of both types of sodium channels was shifted in the depolarizing direction by thimerosal. The inactivation rate in both types of sodium channels increased after thimerosal treatment. All these effects of thimerosal would add up to cause a depression of sodium channel function leading to a diminished neuronal excitability.

Animals↗
PubMed2002

Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway.

The major source of thimerosal (ethyl mercury thiosalicylate) exposure is childhood vaccines. It is believed that the children are exposed to significant accumulative dosage of thimerosal during the first 2 years of life via immunization. Because of health-related concerns for exposure to mercury, we examined the effects of thimerosal on the biochemical and molecular steps of mitochondrial pathway of apoptosis in Jurkat T cells. Thimerosal and not thiosalcylic acid (non-mercury component of thimerosal), in a concentration-dependent manner, induced apoptosis in T cells as determined by TUNEL and propidium iodide assays, suggesting a role of mercury in T cell apoptosis. Apoptosis was associated with depolarization of mitochondrial membrane, release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria, and activation of caspase-9 and caspase-3, but not of caspase-8. In addition, thimerosal in a concentration-dependent manner inhibited the expression of XIAP, cIAP-1 but did not influence cIAP-2 expression. Furthermore, thimerosal enhanced intracellular reactive oxygen species and reduced intracellular glutathione (GSH). Finally, exogenous glutathione protected T cells from thimerosal-induced apoptosis by upregulation of XIAP and cIAP1 and by inhibiting activation of both caspase-9 and caspase-3. These data suggest that thimerosal induces apoptosis in T cells via mitochondrial pathway by inducing oxidative stress and depletion of GSH.

Apoptosis↗
PubMed2004

Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor type 1, but not type 3, via modulation of an isoform-specific Ca2+-dependent intramolecular interaction.

Thiol-reactive agents such as thimerosal have been shown to modulate the Ca2+-flux properties of IP3 (inositol 1,4,5-trisphosphate) receptor (IP3R) via an as yet unidentified mechanism [Parys, Missiaen, De Smedt, Droogmans and Casteels (1993) Pflügers Arch. 424, 516-522; Kaplin, Ferris, Voglmaier and Snyder (1994) J. Biol. Chem. 269, 28972-28978; Missiaen, Taylor and Berridge (1992) J. Physiol. (Cambridge, U.K.) 455, 623-640; Missiaen, Parys, Sienaert, Maes, Kunzelmann, Takahashi, Tanzawa and De Smedt (1998) J. Biol. Chem. 273, 8983-8986]. In the present study, we show that thimerosal potentiated IICR (IP3-induced Ca2+ release) and IP3-binding activity of IP3R1, expressed in triple IP3R-knockout R23-11 cells derived from DT40 chicken B lymphoma cells, but not of IP3R3 or [D1-225]-IP3R1, which lacks the N-terminal suppressor domain. Using a 45Ca2+-flux technique in permeabilized A7r5 smooth-muscle cells, we have shown that Ca2+ shifted the stimulatory effect of thimerosal on IICR to lower concentrations of thimerosal and thereby increased the extent of Ca2+ release. This suggests that Ca2+ and thimerosal synergetically regulate IP3R1. Glutathione S-transferase pull-down experiments elucidated an interaction between amino acids 1-225 (suppressor domain) and amino acids 226-604 (IP3-binding core) of IP3R1, and this interaction was strengthened by both Ca2+ and thimerosal. In contrast, calmodulin and sCaBP-1 (short Ca2+-binding protein-1), both having binding sites in the 1-225 region, weakened the interaction. This interaction was not found for IP3R3, in agreement with the lack of functional stimulation of this isoform by thimerosal. The interaction between the IP3-binding and transmembrane domains (amino acids 1-604 and 2170-2749 respectively) was not affected by thimerosal and Ca2+, but it was significantly inhibited by IP3 and adenophostin A. Our results demonstrate that thimerosal and Ca2+ induce isoform-specific conformational changes in the N-terminal part of IP3R1, leading to the formation of a highly IP3-sensitive Ca2+-release channel.

Animals↗
PubMed2002

Allergic contact dermatitis from mercury antiseptics and derivatives: study protocol of tolerance to intramuscular injections of thimerosal.

BACKGROUND: Mercury derivatives are frequent contact allergens and their cross-reactivity is not constant. Thimerosal is an organic mercurial used as an antiseptic and as a preservative in most vaccines. OBJECTIVE: To evaluate cross-reactivity, exposure factors, and tolerance to vaccines containing thimerosal in patients sensitized to mercury derivatives. METHODS DESIGN: Observational study (cross-sectional); PATIENTS: 125 patients were recruited for the study, 72 women and girls and 53 boys and men, average age 18.7 years old, range 3 to 65, with positive patch tests to mercury derivatives and/or thimerosal; INTERVENTIONS: All patients were studied by means of enquiry, patch tests, intradermal tests, and intramuscular challenge with thimerosal. RESULTS: A sensitization to thimerosal was observed in 57 patients. Twenty-four of these 125 patients presented a positive intradermal reaction. Ammoniated mercury seems to be a good marker of mercury sensitization eliciting positive reaction in 78% of all patients and merbromin in 66%. In most cases, (100/125) cross-reactivity was found among mercury derivatives. The intramuscular injection of thimerosal induced a mild local reaction in only 5 patients (4% of the total, 9% of thimerosal positive reactions). Childhood vaccinations, merbromin used as an antiseptic, broken thermometers, and the use of drops were the main sources of exposure. CONCLUSIONS: The majority of the patients showed positive tests to both organic and inorganic mercury derivatives. Vaccination with thimerosal is relatively safe, even for individuals with delayed type hypersensitivity to this chemical, since more than 90% of allergic patients tolerated intramuscular challenge tests with thimerosal. A simplified protocol of patch tests to study mercury derivatives is proposed. It would be advisable to restrict the use of mercurial antiseptics and mercury thermometers.

Adolescent↗
PubMed1992

Thimerosal blocks stimulated but not basal release of endothelium-derived relaxing factor (EDRF) in dog isolated coronary artery.

1. The effect of an acetly-coA lysolecithin acyltransferase inhibitor, thimerosal, on the release of endothelium-derived relaxing factor (EDRF) was examined in the greyhound isolated coronary artery. 2. Thimerosal (1-10 microM) relaxed fully, ring segments of coronary artery which were contracted with the thromboxane A2-mimetic, U46619 (30 nM). The response was endothelium-dependent, slow in both onset and time to reach maximum. The maximum relaxation to the highest concentration of thimerosal (10 microM) was maintained for 10-20 min before the tissue slowly regained active force (1-2 h) to the same or higher level as that prior to the addition of thimerosal. At this time the endothelium-dependent relaxation responses to acetylcholine (ACh), substance P (SP), bradykinin (BK) and the calcium ionophores, ionomycin and A23187 were abolished. The endothelium-dependent contractions to the nitric oxide synthase inhibitors, NG-nitro-L-arginine (L-NNA; 10-100 microM) and NG-monomethyl-L-arginine (L-NMMA: 10-100 microM), however, were unaffected. 3. Thimerosal (10 microM) did not affect the relaxation curve to sodium nitroprusside (SNP) nor the contraction curve to the thromboxane A2-mimetic, U46619. 4. Both the relaxation response to thimerosal and the selective block of the relaxation responses to stimulated EDRF release were unaffected by either indomethacin (10 microM) or superoxide dismutase (150 u ml-1). 5. L-NNA (100 microM) significantly blocked the relaxation curves to thimerosal and A23187 but not that to SNP.6. Abolition of stimulated EDRF-mediated responses with thimerosal was unlikely to result from maximal and maintained stimulation of EDRF release even when active U46619-induced force had returned to pre-thimerosal levels, since the relaxation curves to glyceryl trinitrate (GTN) and SNP were markedly attenuated in the presence of SNP and GTN respectively when active force was restored with endothelin-1 (ET-1).7. Melittin (1 microM), ionomycin (1 microM) and A23187 (1 microM) each had selective effects on stimulated but not basal EDRF responses, similar to those of thimerosal.8. We propose that stimulated but not 'basal' release of EDRF is dependent on the release of arachidonic acid or one of its non-cyclo-oxygenase metabolites, possibly by Ca2'-dependent activation of phospholipase A2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Ethylmercuric chloride: the responsible agent in thimerosal hypersensitivity.

The causative agent of thimerosal allergy (sodium ethylmercury thiosalicylate) has not previously been thoroughly investigated. To evaluate whether the organic mercury component or the thiosalicylic acid molecule induces thimerosal sensitization, 23 patients positive to thimerosal were patch tested with ethylmercuric chloride, thiosalicylic acid and 8 different derivatives of mercury. To date, ethylmercuric chloride has not been tested in thimerosal allergy. 19/23 patients (82%) showed positive patch test reactions to ethylmercuric chloride. 4/23 patients negative to ethylmercuric chloride reacted positively to thimerosal 0.1% but not to thimerosal 0.05%. 8/23 patients (35%) also reacted to other mercurials. 20 controls negative to thimerosal showed negative patch test reactions to ethylmercuric chloride. Neither patients nor controls reacted to thiosalicylic acid. These results indicate that testing with thimerosal 0.1% leads to false-positive reactions and that the ethyl mercury component is the responsible agent in thimerosal allergy.

Adult↗
PubMed2003

Association between thimerosal-containing vaccine and autism.

CONTEXT: Mercuric compounds are nephrotoxic and neurotoxic at high doses. Thimerosal, a preservative used widely in vaccine formulations, contains ethylmercury. Thus it has been suggested that childhood vaccination with thimerosal-containing vaccine could be causally related to neurodevelopmental disorders such as autism. OBJECTIVE: To determine whether vaccination with a thimerosal-containing vaccine is associated with development of autism. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of all children born in Denmark from January 1, 1990, until December 31, 1996 (N = 467 450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of the same vaccine. MAIN OUTCOME MEASURES: Rate ratio (RR) for autism and other autistic-spectrum disorders, including trend with dose of ethylmercury. RESULTS: During 2 986 654 person-years, we identified 440 autism cases and 787 cases of other autistic-spectrum disorders. The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval [CI], 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 microg of ethylmercury, 0.98 [95% CI, 0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders). CONCLUSION: The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders.

Autistic Disorder↗
PubMed2002

Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with human lymphocytes.

Thimerosal is a widely used preservative in health care products, especially in vaccines. Due to possible adverse health effects, investigations on its metabolism and toxicity are urgently needed. An in vivo study on chronic toxicity of thimerosal in rats was inconclusive and reports on genotoxic effects in various in vitro systems were contradictory. Therefore, we reinvestigated thimerosal in the cytochalasin B block micronucleus test. Glutathione S-transferases were proposed to be involved in the detoxification of thimerosal or its decomposition products. Since the outcome of genotoxicity studies can be dependent on the metabolic competence of the cells used, we were additionally interested whether polymorphisms of glutathione S-transferases (GSTM1, GSTT1, or GSTP1) may influence the results of the micronucleus test with primary human lymphocytes. Blood samples of six healthy donors of different glutathione S-transferase genotypes were included in the study. At least two independent experiments were performed for each blood donor. Significant induction of micronuclei was seen at concentrations between 0.05-0.5 micro g/ml in 14 out of 16 experiments. Thus, genotoxic effects were seen even at concentrations which can occur at the injection site. Toxicity and toxicity-related elevation of micronuclei was seen at and above 0.6 micro g/ml thimerosal. Marked individual and intraindividual variations in the in vitro response to thimerosal among the different blood donors occurred. However, there was no association observed with any of the glutathione S-transferase polymorphism investigated. In conclusion, thimerosal is genotoxic in the cytochalasin B block micronucleus test with human lymphocytes. These data raise some concern on the widespread use of thimerosal.

Actin Cytoskeleton↗
PubMed2000

Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization.

OBJECTIVE: Thimerosal is an important preservative in vaccines and ophthalmologic preparations. The substance is known to be a type IV sensitizing agent. High sensitization rates were observed in contact-allergic patients and in health care workers who had been exposed to thimerosal-preserved vaccines. There is evidence for the involvement of the glutathione system in the metabolism of thimerosal or its decomposition products (organomercury alkyl compounds). Thus detoxification by polymorphically expressed glutathione S-transferases such as GSTT1 and GSTM1 might have a protective effect against sensitization by these substances. METHODS: To address this question, a case control study was conducted, including 91 Central European individuals with a positive patch-test reaction to thimerosal. This population was compared with 169 healthy controls and additionally with 114 individuals affected by an allergy against para-substituted aryl compounds. The latter population was included in order to test whether possible associations were due to substance-specific effects, or were a general feature connected with type IV immunological diseases. Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase chain reaction. RESULTS: Glutathione S-transferase M1 deficiency was significantly more frequent among patients sensitized to thimerosal (65.9%, P = 0.013) compared with the healthy control group (49.1%) and the "para-compound" group (48%, P = 0.034). Glutathione S-transferase T1 deficiency in the thimerosal/mercury group (19.8%) was barely elevated versus healthy controls (16.0%) and the "para-compound" group (14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more frequent among thimerosal-sensitized patients than in healthy controls (17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6% vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme deficiencies (healthy controls vs. thimerosal GSTM1 negative individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1], GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]). CONCLUSIONS: Since the glutathione-dependent system was repeatedly shown to be involved in the metabolism of thimerosal decomposition products, the observed association may be of functional relevance.

Adolescent↗
PubMed1994

Deleterious effect of thimerosal on the potency of inactivated poliovirus vaccine.

High-potency inactivated poliovirus vaccine (eIPV) was combined with diphtheria-tetanus-pertussis (DTP) vaccine containing thimerosal as a preservative to simulate the performance of a potential tetravalent vaccine. Neither type 1 nor type 3 poliovirus antigens appeared to be affected by thimerosal after exposure for 1 h at 37 degrees C as measured by enzyme-linked immunosorbent assay (ELISA). One epitope on the type 2 antigen was damaged within 5 min of exposure; however, the overall potency was unchanged when measured using a polyclonal antibody preparation. Exposure to thimerosal at 37 degrees C decreased the potency of all three poliovirus types to well below the level caused by heat deterioration alone in 1-2 days and to 0% after 16-17 days. At 25 degrees C, the potency of type 1 poliovirus decreased by 46% in 1 day, whereas poliovirus types 2 and 3 were stable for 1 week. Storage of eIPV at 4 degrees C in the presence of thimerosal reduced the potency of type 1 poliovirus antigen to undetectable levels after 4-6 months. Type 2 and 3 antigens were less markedly affected by 8 months of exposure to thimerosal at 4 degrees C. The loss of potency of type 1 as measured by ELISA was paralleled by a reduced level of neutralizing antibodies in mice injected with these preparations. The results obtained from testing eIPV in combination with DTP and thimerosal were generally similar to those obtained using eIPV with thimerosal. It remains to be seen to what extent thimerosal will affect the immunogenicity of eIPV in humans when injected as combined eIPV-DTP vaccine.

Animals↗
PubMed2005

Immunosuppressive and autoimmune effects of thimerosal in mice.

The possible health effects of the organic mercury compound thimerosal (ethylmercurithiosalicylate), which is rapidly metabolized to ethylmercury (EtHg), have recently been much debated and the effect of this compound on the immune system is largely unknown. We therefore studied the effect of thimerosal by treating A.SW (H-2s) mice, susceptible to induction of autoimmunity by heavy metals, with 10 mg thimerosal/L drinking water (internal dose ca 590 microg Hg/kg body weight/day) for up to 30 days. The lymph node expression of IL-2 and IL-15 mRNA was increased after 2 days, and of IL-4 and IFN-gamma mRNA after 6 and 14 days. During the first 14 days treatment, the number of splenocytes, including T and B cells as well as Ig-secreting cells decreased. A strong immunostimulation superseded after 30 days treatment with increase in splenic weight, number of splenocytes including T and B cells and Ig-secreting cells, and Th2- as well as Th-1-dependent serum immunoglobulins. Antinucleolar antibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin, and systemic immune-complex deposits developed. The H-2s strains SJL and B10.S also responded to thimerosal treatment with ANoA. The A.TL and B10.TL strain, sharing background genes with the A.SW and B10.S strain, respectively, but with a different H-2 haplotype (t1), did not develop ANoA, linking the susceptibility to H-2. Thimerosal-treated H-2s mice homozygous for the nu mutation (SJL-nu/nu), or lacking the T-cell co-stimulatory molecule CD28 (B10.S-CD28-/-), did not develop ANoA, which showed that the autoimmune response is T-cell dependent. Using H-2s strains with targeted mutations, we found that IFN-gamma and IL-6, but not IL-4, is important for induction of ANoA by thimerosal. The maximum added renal concentration of thimerosal (EtHg) and inorganic mercury occurred after 14 days treatment and was 81 microg Hg/g. EtHg made up 59% and inorganic mercury 41% of the renal mercury. In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury.

Administration, Oral↗
PubMed1993

The effects of thimerosal on calcium uptake and inositol 1,4,5-trisphosphate-induced calcium release in cerebellar microsomes.

Thimerosal inhibits calcium uptake in skeletal muscle sarcoplasmic reticulum and rat cerebellar microsomes by inhibiting the Ca(2+)-ATPase. In the presence of 5 mM dithiothreitol (DTT), Ca2+ uptake and ATPase activity were not inhibited by thimerosal, indicating that thimerosal modifies cysteine residues of the Ca(2+)-ATPase. Low thimerosal concentrations (2 microM) sensitize the inositol 1,4,5-trisphosphate (InsP3)-sensitive Ca2+ channel, making it open at lower InsP3 concentrations. Higher concentrations of thimerosal, however, cause inhibition of InsP3-induced Ca2+ release. Both sensitization and inhibition of the InsP3 receptor by thimerosal can be prevented by DTT. The binding and metabolism of InsP3 by cerebellar microsomes is not affected by thimerosal. The amount of InsP3-induced Ca2+ release is co-operatively linked to the InsP3 concentration with a Hill coefficient of 2.0 +/- 0.3. This is decreased to 1.0 +/- 0.2 at inhibitory concentrations of thimerosal. Under our experimental conditions, we observed no dependence of quantal Ca2+ release on intraluminal Ca2+ concentration.

Adenosine Triphosphate↗