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PubMed1995

Effect of the aminosteroid, U73122, on Ca2+ uptake and release properties of rat liver microsomes.

The putative phospholipase C inhibitor, U73122, transiently increases the cytosolic free Ca2+ concentration in rabbit pancreatic acinar cells by stimulating the release of Ca2+ from intracellular stores [Willems, Van de Put, Engbersen, Bosch, Van Hoof & De Pont (1994) Pflügers Arch. 427, 233-243]. In order to elucidate the exact mechanism of action of U73122 we studied its effects on both Ca(2+)-stimulated Mg(2+)-dependent ATPase activity and Ca(2+)-stimulated ATP-dependent Ca2+ uptake in rat liver microsomes. In addition, we studied its effects on Ca2+ release from steady-state loaded microsomes. The effects of U73122 were compared with those of thimerosal, described in the literature as inhibiting Ca(2+)-ATPases and sensitizing inositol 1,4,5-trisphosphate-operated Ca2+ release channels, and thapsigargin, a specific inhibitor of sarcoplasmic and endoplasmic reticulum Ca(2+)-ATPases. Both U73122 (IC50 = 9 microM) and thimerosal (IC50 = 11 microM) dose-dependently inhibited Ca(2+)-stimulated Mg(2+)-dependent ATPase activity, without significantly affecting Mg(2+)-stimulated ATPase activity. Similarly, both U73122 (IC50 = 9 microM) and thimerosal (IC50 = 14 microM) dose-dependently inhibited ATP-dependent Ca2+ uptake. At concentrations beyond 20 microM, U73122 stimulated Ca2+ release from steady-state loaded microsomes at a rate considerably higher than obtained with a maximally inhibitory concentration of thapsigargin (1 microM). This observation, which was not reached with equally inhibitory concentrations of thimerosal, demonstrates that higher U73122 concentrations cause an additional increase of passive Ca2+ leak. The data presented demonstrate that U73122 stimulates the release of actively stored Ca2+ primarily through inhibition of the internal Ca2+ pump.

Animals↗
PubMed2005

Mercury and autism: accelerating evidence?

The causes of autism and neurodevelopmental disorders are unknown. Genetic and environmental risk factors seem to be involved. Because of an observed increase in autism in the last decades, which parallels cumulative mercury exposure, it was proposed that autism may be in part caused by mercury. We review the evidence for this proposal. Several epidemiological studies failed to find a correlation between mercury exposure through thimerosal, a preservative used in vaccines, and the risk of autism. Recently, it was found that autistic children had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunoglobulin shots. It was hypothesized that children with autism have a decreased detoxification capacity due to genetic polymorphism. In vitro, mercury and thimerosal in levels found several days after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of MS is crucial in biochemical steps necessary for brain development, attention and production of glutathione, an important antioxidative and detoxifying agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations in autoimmune susceptible mice, increased oxidative stress and decreased intracellular levels of glutathione in vitro. Subsequently, autistic children have significantly decreased level of reduced glutathione. Promising treatments of autism involve detoxification of mercury, and supplementation of deficient metabolites.

Autistic Disorder↗
PubMed2006

[Contact allergy to preservatives contained in cosmetics].

BACKGROUND: The aim of this study was to assay the type of allergy to preservatives contained in cosmetics and to assess the usefulness of the composition of allergens included in a standard series for the diagnosis of occupational contact allergy used to date. MATERIALS AND METHODS: The frequency of contact allergy to the standard series of preservatives (thimerosal, Euxyl K 400, formaldehyde, Kathon CG, Quaternium 15, parabens) was assayed in a group of 1937 subsequent patients referred to the Nofer Institute of Occupational Medicine in L6di and examined in the years 2000-2005. The frequency and type of allergy to preservatives of a cosmetic series in a group of 113 patients with poor tolerance of cosmetics were also investigated. RESULTS: Allergy to thimerosal was found in 11.8% of patients tested with a standard series; to formaldehyde in 4.9%; and to Euxyl K 400 in 3.7%. Quaternium and parabens were less allergenic (0.8 and 0.3%, respectively). In the group of 113 patients subjected to patch test with a cosmetic series, allergy, i.e. at least one positive patch test, was observed in 49 (43.4%) patients. Of the 27 preservatives contained in cosmetics, 16 induced positive reaction to chemical compounds. Euxyl K 400 proved to be the basic allergenic preservative of this series, and induced allergy in 21 (18.6%) patients, whereas 17.7% of patients reacted to thimerosal. Only allergy to thimerosal applied to 8 persons, and 7 of them showed inflammatory lesions only on the face. Less allergic biocides were cocamidopropyl betaine (7.1%), Kathon CG (7.1%), Bronopol (5.3%), Germall II (4.4%), triethanolamine (3.5%), Germall 115 (2.6%), DMDM hydantoin (2.6%), Grotan BK (1.8%), sodium-2-pyridinethiol-1-oxide (1.8%), clioquinol (0.9%), Quaternium 15 (0.9%), and dimethylaminopropylamine (0.9%). CONCLUSIONS: The results of our study confirmed observations of other authors that allergy to preservatives present in numerous industrial products, especially Euxyl K 400, is still a growing problem. Like many other researchers, we are of the opinion that this allergen should be included in a standard series for the diagnosis of all patients with suspected allergic dermatitis, including that of occupational origin.

Adult↗
PubMed1999

Spontaneous calcium transients are required for neuronal differentiation of murine neural crest.

We have shown that cultured mouse neural crest (NC) cells exhibit transient increases in intracellular calcium. Up to 50% of the cultured NC-derived cells exhibited calcium transients during the period of neuronal differentiation. As neurogenic activity declined, so did the percentage of active NC-derived cells and their calcium spiking frequency. The decrease in calcium transient activity correlated with a decreased sensitivity to thimerosal, which sensitizes inositol 1,4,5-triphosphate receptors. Thimerosal increased the frequency of oscillations in active NC-derived cells and induced them in a subpopulation of quiescent cells. As neurogenesis ended, NC-derived cells became nonresponsive to thimerosal. Using the expression of time-dependent neuronal traits, we determined that neurons exhibited spontaneous calcium transients as early as a neuronal phenotype could be detected and continued through the acquisition of caffeine sensitivity, soon after which calcium transient activity stopped. A subpopulation of nonneuronal NC-derived cells exhibited calcium transient activity within the same time frame as neurogenesis in culture. Exposing NC-derived cells to 20 mM Mg(2+) blocked calcium transient activity and reduced neuronal number without affecting the survival of differentiated neurons. Using lineage-tracing analysis, we found that 50% of active NC-derived cells gave rise to clones containing neurons, while inactive cells did not. We hypothesize that calcium transient activity establishes a neuronal competence for undifferentiated NC cells.

Animals↗
PubMed1990

Calcium influx into endothelial cells and formation of endothelium-derived relaxing factor is controlled by the membrane potential.

We studied the role of the membrane potential in the control of the intracellular free calcium concentration ([Ca2+]i) and release of the two autacoids endothelium-derived relaxing factor (EDRF = nitric oxide) and prostaglandin I2 in endothelial cells. ATP (3 mumol/l) and bradykinin (1 nmol/l) evoked rapid increases (sixfold) in [Ca2+]i in cultured endothelial cells. [Ca2+]i remained elevated over several minutes. When the cells were depolarized, either by K+ (70-90 mmol/l) or by preincubation with the blocker of K+ channels tetraethylammonium (3 mmol/l), the initial peak of [Ca2+]i remained unaffected but [Ca2+]i returned significantly faster to resting levels, indicating a reduction in Ca2+ influx. In native, freshly isolated endothelial cells, K+ abolished increases in [Ca2+]i induced by acetylcholine (3 mumol/l). Release of EDRF in response to bradykinin (cultured cells) and acetylcholine (native cells) was inhibited by K+ (by 70%), whereas release of prostaglandin I2 was not significantly reduced. Preincubation of cultured endothelial cells with the receptor-independent stimulus thimerosal (5 mumol/l, 40 min) evoked a long-lasting release of EDRF and small elevations of [Ca2+]i (twofold) after washout of the drug. Depolarization with K+ decreased thimerosal-induced EDRF release and [Ca2+]i in a reversible manner. In patch-clamped endothelial cells, bradykinin (1 nmol/l) induced transient hyperpolarizations that were significantly prolonged by BRL 34915 (1 mumol/l), an activator of K+ channels. BRL 34915 also elicited increases in [Ca2+]i, particularly in thimerosal-stimulated endothelial cells. These effects were abolished by K+. We conclude that the initial rise in [Ca2+]i in response to receptor-binding agonists, caused by mobilization of Ca2+ from intracellular stores, activates K+ channels, thereby inducing hyperpolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1999

Cardiac ryanodine receptor activity is altered by oxidizing reagents in either the luminal or cytoplasmic solution.

The location of reactive cysteine residues on the ryanodine receptor (RyR) calcium release channel was assessed from the changes in channel activity when oxidizing or reducing reagents were added to the luminal or cytoplasmic solution. Single sheep cardiac RyRs were incorporated into lipid bilayers with 10(-7) m cytoplasmic Ca2+. The thiol specific-lipophilic-4,4'-dithiodipyridine (4,4'-DTDP, 1 mm), as well as the hydrophilic thimerosal (1 mm), activated and then inhibited RyRs from either the cis (cytoplasmic) or trans (luminal) solutions. Activation was associated with an increase in the (a) mean channel open time and (b) number of exponential components in the open time distribution from one ( approximately 2 msec) to three (approximately 1 msec; approximately 7 msec; approximately 15 msec) in channels activated by trans 4,4'-DTDP or cis or trans thimerosal. A longer component (approximately 75 msec) appeared with cis 4, 4'-DTDP. Activation by either oxidant was reversed by the thiol reducing agent, dithiothreitol. The results suggest that three classes of cysteines are available to 4,4'-DTDP or thimerosal, SHa or SHa* activating the channel and SHi closing the channel. SHa is either distributed over luminal and cytoplasmic RyR domains, or is located within the channel pore. SHi is also located within the transmembrane domain. SHa* is located on the cytoplasmic domain of the protein.

Animals↗
PubMed1992

Ca(2+)-induced Ca2+ release in insulin-secreting cells.

The sulphydryl reagent thimerosal (50 microM) released Ca2+ from a non-mitochondrial intracellular Ca2+ pool in a dose-dependent manner in permeabilized insulin-secreting RINm5F cells. This release was reversed after addition of the reducing agent dithiothreitol. Ca2+ was released from an Ins(1,4,5)P3-insensitive pool, since release was observed even after depletion of the Ins(1,4,5)P3-sensitive pool by a supramaximal dose of Ins(2,4,5)P3 or thapsigargin. The Ins(1,4,5)P3-sensitive pool remained essentially unaltered by thimerosal. Thimerosal-induced Ca2+ release was potentiated by caffeine. These findings suggest the existence of Ca(2+)-induced Ca2+ release also in insulin-secreting cells.

Caffeine↗
PubMed1988

Multiple effects of ethylmercurithiosalicylate on the metabolization of arachidonic acid by human neutrophils.

The effects of ethylmercurithiosalicylate (thimerosal) on the transformation of arachidonic acid via the 5-lipoxygenase pathway in human leukocytes stimulated with the Ca-ionophore A23187 were studied. Thimerosal inhibited acyltransferase, 5-lipoxygenase and the omega-oxidation system of LTB4 in a concentration-dependent fashion which was characteristic for the individual metabolites. LTA4 hydrolase activity was not affected. The inhibitory effects of thimerosal occurred instantaneously. The effects of the drug were not influenced by the concentration of the stimulus Ca-ionophore A23187.

Acyltransferases↗
PubMed1983

Superior limbic keratoconjunctivitis in contact lens wearers.

Forty patients with daily wear, cosmetic contact lenses (CL) presented with symptoms of ocular irritation and a keratoconjunctivitis clinically resembling superior limbic keratoconjunctivitis (SLK). Typically the patients were either successful hard CL wearers who changed to soft lenses and used a chemical aseptisizing solution or preserved saline solution, or successful soft CL wearers using salt tablets who switched to a preservative-containing system. In all cases, exposure to thimerosal-preserved solutions was documented. Upon discontinuation of lens wear, all signs and symptoms slowly resolved without permanent sequelae. Positive skin and ocular sensitivity reactions to thimerosal were present in one-third (5/15) of patients tested. Light and transmission electron microscopic examination of conjunctival specimens disclosed intercellular epithelial edema, pseudoepitheliomatous hyperplasia, acute and chronic inflammation, and decreased numbers of goblet cells. Exposure to thimerosal is implicated in the etiology of contact lens-superior limbic keratoconjunctivitis (CL-SLK).

Adolescent↗
PubMedDate not supplied

Piroxicam-induced photodermatitis. Cross-reactivity among oxicams. A case report.

BACKGROUND: there is a group of patients with contact allergy to thimerosal (thiosalicylic acid and ethylmercuric chloride), thiosalicylic acid sensitized, who develop photodermatitis to piroxicam. We present a case which we have investigated cross-reactivity among different oxicams. METHODS AND RESULTS: a 44-year-old man with contact allergy to thimerosal. A few hours after the intake of Feldene (piroxicam) while running outside, developed a papuloerithematosus exanthema in the neck, knees and forearms, and microvesicles on the finger webs, that became descamative a few days later. Oclusive patch tests with thiosalicylic acid, mercury, piroxicam, tenoxicam, droxicam and meloxicam and photopatch test with the oxicams were performed. Patch tests with thiosalicylic acid and piroxicam were positive and negative with the others. All the oxicams photopatch tests were positive. CONCLUSIONS: we present a case of photodermatitis and dermatitis to piroxicam, in a patient with contact allergy to the thiosalicylic moiety of thimerosal, in which cross-reactivity with the other oxicams have been demonstrated. In cases of oxicams-induced photodermatitis, all oxicams should be avoided, to elude posible cross-reactions.

Adult↗
PubMed1994

Inhibition of Plasmodium falciparum lysophospholipase by anti-malarial drugs and sulphydryl reagents.

The activity of lysophospholipase of human erythrocytes increased by about 3 orders of magnitude upon infection with Plasmodium falciparum. The apparent Km for hydrolysis of lysophosphatidylcholine by this enzyme was 50 +/- 7 microM and the apparent Vmax 6.8 +/- 0.6 nmol/h x 10(6) cells. The activity was Ca2+ independent and had a broad pH maximum at pH 8. The enzyme was insensitive to such anti-malarials as mefloquine and arteether and was only weakly inhibited by chloroquine, with a 50% inhibition concentration (IC50) of 70 mM. The anti-malarials quinine and quinacrine were more efficient inhibitors, with IC50s of 2.6 mM and 0.7 mM, respectively. The sulphydryl agents p-hydroxymercuribenzoate (pHMB) and thimerosal were considerably more potent, inhibiting the plasmodial lysophospholipase with IC50s of 18 microM and 10 microM, respectively. When present at 10 microM prior to invasion, both pHMB and thimerosal arrested the growth and reinvasion capacity of P. falciparum in culture. In a synchronized P. falciparum culture the continuous presence of 5 microM thimerosal dramatically decreased total parasitaemia and, within 4 days, totally abolished the capacity of the surviving parasites to reinvade. Thus the plasmodial lysophospholipase may represent a potential new target for anti-malarial chemotherapy.

Animals↗
PubMed2001

Epidemiology of contact allergy in adults.

BACKGROUND: We aimed to determine the prevalence of contact sensitization in the general population and to investigate associations with important sociodemographic and medical characteristics. METHODS: Within a population-based nested, case-control study in Germany, we performed patch tests with 25 standard allergens in 1141 adults (50.4% female, age median 50 years). Additional information was obtained by a dermatologic examination, a standardized interview, and blood analysis. RESULTS: At least one positive reaction was exhibited by 40.0% of the subjects, with reactions most frequently observed to fragrance mix (15.9%), nickel (13.1%), thimerosal (4.7%), and balsam of Peru (3.8%). Women were sensitized more often than men (50.2% vs 29.9%, OR 2.36, CI 1.84-3.03), and this was also significant for fragrance mix, nickel, turpentine, cobalt chloride, and thimerosal. Contact sensitization was more frequent in subjects who reported adverse skin reactions (53.8% vs. 32.6%; OR 2.41, CI 1.85-3.14), and this was particularly true for sensitization to nickel (45.5% vs 8.8%, OR 8.64, CI 5.67-13.17) and fragrance mix (29.0% vs 14.0%, OR 2.51, CI 1.60-3.91) and the corresponding intolerance of fashion jewelry and fragrances. Contact sensitization decreased with increasing degree of occupational training (unskilled 45.9%, apprenticeship 40.1%, technical college 40.4%, and school of engineering 12.5%; P=0.023; trend test P=0.042). Significant associations of contact sensitization and presence of allergen-specific IgE antibodies, atopic eczema, or psoriasis were not observed. Frequency estimates for the general adult population based on these findings were 28.0% for overall contact sensitization and 11.4% for fragrance mix, 9.9% for nickel, and 3.2% for thimerosal. CONCLUSIONS: It is concluded that contact allergy is influenced by sociodemographic parameters and plays an important role in the general population.

Adult↗
PubMed1992

Different triggers for calcium oscillations in mouse eggs involve a ryanodine-sensitive calcium store.

Relative intracellular free Ca2+ concentrations ([Ca2+]i) were monitored in mature unfertilized mouse eggs by measuring fluorescence of intracellular fluo3. A number of different agents were found to cause sustained repetitive transient [Ca2+]i oscillations. These were microinjection of a cytosolic sperm factor, sustained injection of Ins-(1,4,5)P1, or extracellular addition of the thiol reagent thimerosal. Stimulating G-protein activity by injection of guanosine 5'-[gamma-thio]triphosphate plus application of carbachol also caused [Ca2+]i oscillations, but less reliably than other stimuli. A role for Ca(2+)-induced Ca2+ release and a ryanodine-sensitive Ca2+ channel in mouse eggs was suggested by the finding that microinjection, or external addition, of ryanodine also caused [Ca2+]i increases. Furthermore, ryanodine, along with thimerosal, increased the sensitivity of eggs to Ca(2+)-induced [Ca2+]i oscillations. When ryanodine was added to eggs oscillating in response to the sperm factor, InsP3 or thimerosal, it caused a decrease in amplitude of oscillations and eventually a block of [Ca2+]i oscillations associated with a sustained elevation of [Ca2+]i. These data suggest that a ryanodine-sensitive Ca(2+)-release mechanism exists in mouse eggs and that a ryanodine-sensitive Ca2+ store plays a role in generating intracellular [Ca2+]i oscillations.

Animals↗
PubMed1998

Differential effect of pH upon cyclic-ADP-ribose and nicotinate-adenine dinucleotide phosphate-induced Ca2+ release systems.

We investigated the pH dependence and the effects of thimerosal and dithiothreitol (DTT) upon the Ca2+ release induced by cADP-ribose (cADPR) and nicotinate-adenine dinucleotide phosphate (NAADP) in sea urchin egg homogenates. Both Ca2+ release triggered by cADPR and the binding of [3H]cADPR to sea urchin egg homogenates were decreased by alkalization of the assay media from pH 7.2 to 8.9. In contrast, NAADP-triggered Ca2+ release was not influenced by changes in pH. The Ca2+ release induced by cADPR was potentiated by thimerosal and inhibited by DTT, but neither thimerosal nor DTT had any effect upon the Ca2+ release induced by NAADP. We conclude that cADPR-sensitive Ca2+-release mechanisms are dependent on pH of the assay media and are sensitive to thiol group modification. On the other hand, these functional properties are not shared by NAADP-regulated Ca2+ channels.

Adenosine Diphosphate Ribose↗
PubMedDate not supplied

Anti-D prozone and membrane sulfhydryl modification.

An IgG anti-D prozone is produced by progressive inactivation of the D antigen following red cell exposure to increasing concentrations of thimerosal and phenol present as antibody excess is achieved. Partial inactivation of the D antigen by routinely added thimerosal, an organic mercurial, and phenol is associated with an unstable D antigen-antibody complex resulting in an increased rate of dissociation of anti-D and with a decreased reactivity of the cell-bound anti-D in the antiglobulin reaction. Complete D inactivation occurs with concentrations in excess of 0.43 microM thimerosal. If attributable to inactivation of a surface-exposed sulfhydryl group, it suggests that less than 5 percent of these are involved in D-antigen activity. The data do not exclude the possibility that D inactivation may result from alteration of sulfhydryl groups other than those exposed at the surface.

Antibody Affinity↗
PubMed2006

Ethyl mercury poisoning during a protein A immunoadsorption treatment.

We describe the case of a 38-year-old woman with Guillain-Barré syndrome who was accidentally intoxicated with thimerosal, a column disinfectant containing ethyl mercury, during a protein A immunoadsorption treatment. The 1-time overdose caused by an equipment handling error led to a maximum blood serum mercury level of 2,250 microg/L, thus exceeding the normal blood reference range by a factor of approximately 200. Although the patient did not show short-or long-term clinical signs of mercury intoxication, she was treated with chelation therapy, and we replaced thimerosal with a commercially available mercury-free disinfectant, suggesting that thimerosal is no longer indicated for preservation of protein A columns.

Adult↗
PubMed2001

Autism: a novel form of mercury poisoning.

Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 US children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their first two years, may have received a quantity of mercury that exceeds safety guidelines. A review of medical literature and US government data suggests that: (i) many cases of idiopathic autism are induced by early mercury exposure from thimerosal; (ii) this type of autism represents an unrecognized mercurial syndrome; and (iii) genetic and non-genetic factors establish a predisposition whereby thimerosal's adverse effects occur only in some children.

Autistic Disorder↗
PubMed1996

Regulation of the inositol 1,4,5-trisphosphate-activated Ca2+ channel by activation of G proteins.

Streptolysin O-permeable pancreatic acini were used to study the regulation of the inositol 1,4,5-trisphosphate (IP3)-activated Ca2+ channel (IPACC) by agonists and antagonists. Measurements of the apparent affinity for IP3 (KappIP3) showed that the IPACC is dynamically controlled during cell stimulation and inhibition, i.e. agonists decreased and antagonists increased KappIP3. KappIP3 was also independently regulated by thimerosal, Ca2+ content of the stores, the incubation temperature, activation of protein kinases, and inhibition of protein phosphatases, but none of these mechanisms contributed to the regulation by agonists and antagonists. Incubating the cells with low concentration of GTPgammaS or AIF3 reproduced the effect of the agonist on KappIP3. Moreover, low [GTPgammaS] allowed activation of the IPACC by agonists at basal levels of IP3 and markedly impaired channel inactivation by antagonists. Channel sensitization by GTPgammaS also restored the ability of thimerosal to mobilize Ca2+ from internal stores with no change in cellular IP3 levels. The combination of low [GTPgammaS] and thimerosal locked the channel in an open, antagonist-insensitive state. All modulatory effects of GTPgammaS are independent of phospholipase C activation and IP3 production. We propose that the dynamic regulation of the IPACC by a G protein-dependent mechanism can play a major role in triggering and maintaining Ca2+ oscillations at low agonist concentrations when minimal or no changes in IP3 level take place.

Animals↗