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1.
Braz J Biol ; 83: e242942, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34468508

RESUMO

Thimerosal is an organomercurial compound, which is used in the preparation of intramuscular immunoglobulin, antivenoms, tattoo inks, skin test antigens, nasal products, ophthalmic drops, and vaccines as a preservative. In most of animal species and humans, the kidney is one of the main sites for mercurial compounds deposition and target organs for toxicity. So, the current research was intended to assess the thimerosal induced nephrotoxicity in male rats. Twenty-four adult male albino rats were categorized into four groups. The first group was a control group. Rats of Group-II, Group-III, and Group-IV were administered with 0.5µg/kg, 10µg/kg, and 50µg/kg of thimerosal once a day, respectively. Thimerosal administration significantly decreased the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione reductase (GR), glutathione (GSH), and protein content while increased the thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) levels dose-dependently. Blood urea nitrogen (BUN), creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, urinary albumin and creatinine clearance was reduced dose-dependently in thimerosal treated groups. The results demonstrated that thimerosal significantly increased the inflammation indicators including nuclear factor kappaB (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activities, DNA and histopathological damages dose-dependently. So, the present findings ascertained that thimerosal exerted nephrotoxicity in male albino rats.


Assuntos
Estresse Oxidativo , Timerosal , Animais , Peróxido de Hidrogênio/metabolismo , Rim , Masculino , Ratos , Superóxido Dismutase/metabolismo , Timerosal/metabolismo , Timerosal/toxicidade
2.
Metallomics ; 9(8): 1060-1072, 2017 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-28702563

RESUMO

Humans are environmentally exposed to potentially toxic Cd and Hg species and to the Hg compound thimerosal (THI), an antibactericidal vaccine additive. Previous studies have revealed that Cd2+, Hg2+ and CH3Hg+ are taken up by red blood cells (RBCs) and bind to cytosolic glutathione (GSH) and/or hemoglobin (Hb). Since interactions in the cytosol of RBCs may be linked to their hemolysis, a more comprehensive characterization of these interactions was sought. After the addition of each Cd and Hg species to RBC lysate, the mixtures were analyzed after 5 min, 2 h and 6 h by size-exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma atomic emission spectrometer (ICP-AES). In contrast to previous studies, however, reducing conditions were maintained by employing a 100 mM Tris buffer mobile phase (pH 7.4), which contained ∼2.5 mM of glutathione (GSH). At ≥2 h, ∼85% of Cd2+ weakly interacted with hemoglobin (Hb), while ∼13% eluted as (GS)xCd and ∼2% bound to a ≥70 kDa Cd-binding protein. In contrast, ∼6% of Hg2+ co-eluted with Hb at all time points, while ∼94% eluted as (GS)xHg. The results for CH3Hg+ showed that ∼5% of Hg co-eluted with Hb, while for THI this percentage gradually increased to 12% (6 h). The remaining Hg eluted as GS-HgCH3 and GS-HgCH2CH3. Our results revealed remarkable differences in the interaction of the investigated Cd and Hg species with cytosolic RBC constituents. The formation of (Hb)xHg species, regardless of which Hg compound was added, suggests their mammalian toxicology to be intertwined with the metabolism of Fe.


Assuntos
Cádmio/química , Eritrócitos/metabolismo , Mercúrio/química , Compostos de Metilmercúrio/química , Timerosal/química , Animais , Cádmio/metabolismo , Cromatografia em Gel , Feminino , Glutationa/metabolismo , Hemólise , Mercúrio/metabolismo , Metalotioneína/metabolismo , Compostos de Metilmercúrio/metabolismo , Coelhos , Espectrofotometria Atômica , Timerosal/metabolismo
3.
Ecotoxicol Environ Saf ; 130: 37-42, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27062344

RESUMO

Environmental contamination of mercury (Hg) has caused public health concerns with focuses on the neurotoxic substance methylmercury, due to its bioaccumulation and biomagnification in food chains. The goals of the present study were to examine: (i) the transformation of methylmercury, thimerosal, phenylmercuric acetate and mercuric chloride by cultures of Pseudomonas putida V1, (ii) the presence of the genes merA and merB in P. putida V1, and (iii) the degradation pathways of methylmercury by P. putida V1. Strain V1 cultures readily degraded methylmercury, thimerosal, phenylmercury acetate, and reduced mercuric chloride into gaseous Hg(0). However, the Hg transformation in LB broth by P. putida V1 was influenced by the type of Hg compounds. The merA gene was detected in P. putida V1, on the other hand, the merB gene was not detected. The sequencing of this gene, showed high similarity (100%) to the mercuric reductase gene of other Pseudomonas spp. Furthermore, tests using radioactive (14)C-methylmercury indicated an uncommon release of (14)CO2 concomitant with the production of Hg(0). The results of the present work suggest that P. putida V1 has the potential to remove methylmercury from contaminated sites. More studies are warranted to determine the mechanism of removal of methylmercury by P. putida V1.


Assuntos
Compostos de Metilmercúrio/metabolismo , Pseudomonas putida/metabolismo , Proteínas de Bactérias/genética , Poluentes Ambientais/metabolismo , Recuperação e Remediação Ambiental , Liases/genética , Cloreto de Mercúrio/metabolismo , Oxirredutases/genética , Acetato de Fenilmercúrio/metabolismo , Pseudomonas putida/genética , Timerosal/metabolismo
4.
Toxicology ; 347-349: 1-5, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26945727

RESUMO

A latency period preceding neurotoxicity is a common characteristic in the dose-response relationship induced by organic mercury. Latency periods have typically been observed with genotoxicants in carcinogenesis, with cancer being manifested a long time after the initiating event. These observations indicate that even a very small dose may cause extensive adverse effects later in life, so the toxicity of the genotoxic compound is dose and time-dependent. In children, methylmercury exposure during pregnancy (in utero) has been associated with delays in reaching developmental milestones (e.g., age at first walking) and decreases in intelligence, increasing in severity with increasing exposure. Ethylmercury exposure from thimerosal in some vaccines has been associated, in some studies, with autism and other neurological disorders in children. In this paper, we have examined whether dose-response data from in vitro and in vivo organic mercury toxicity studies fit the Druckrey-Küpfmüller equation c·t(n)=constant (c=exposure concentration, t=latency period), first established for genotoxic carcinogens, and whether or not irreversible effects are enhanced by time of exposure (n≥1), or else toxic effects are dose-dependent while time has only minor influence on the adverse outcome (n<1). The mode of action underlying time-dependent toxicity is irreversible binding to critical receptors causing adverse and cumulative effects. The results indicate that the Druckrey-Küpfmüller equation describes well the dose-response characteristics of organic mercury induced neurotoxic effects. This amounts to a paradigm shift in chemical risk assessment of mercurial compounds and highlights that it is vital to perform toxicity testing geared to investigate time-dependent effects.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Compostos de Metilmercúrio/toxicidade , Síndromes Neurotóxicas , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Mercúrio/administração & dosagem , Mercúrio/metabolismo , Mercúrio/toxicidade , Compostos de Metilmercúrio/administração & dosagem , Compostos de Metilmercúrio/metabolismo , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Gravidez , Timerosal/administração & dosagem , Timerosal/metabolismo , Timerosal/toxicidade , Testes de Toxicidade/métodos , Testes de Toxicidade/normas
5.
Hum Vaccin Immunother ; 10(8): 2328-35, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25424939

RESUMO

Thimerosal is a preservative used in multidose vials of vaccine formulations to prevent bacterial and fungal contamination. We recently reported that nanomolar concentrations of thimerosal induce cell cycle arrest of human T cells activated via the TCR and inhibition of proinflammatory cytokine production, thus interfering with T-cell functions. Given the essential role of dendritic cells (DCs) in T-cell polarization and vaccine immunity, we studied the influence of non-toxic concentrations of thimerosal on DC maturation and functions. Ex-vivo exposure of human monocyte-derived DCs to nanomolar concentrations of thimerosal prevented LPS-induced DC maturation, as evidenced by the inhibition of morphological changes and a decreased expression of the maturation markers CD86 and HLA-DR. In addition thimerosal dampened their proinflammatory response, in particular the production of the Th1 polarizing cytokine IL-12, as well as TNF-α and IL-6. DC-dependent T helper polarization was altered, leading to a decreased production of IFN-γ IP10 and GM-CSF and increased levels of IL-8, IL-9, and MIP-1α. Although multi-dose vials of vaccines containing thimerosal remain important for vaccine delivery, our results alert about the ex-vivo immunomodulatory effects of thimerosal on DCs, a key player for the induction of an adaptive response.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Fatores Imunológicos/metabolismo , Interleucina-12/metabolismo , Conservantes Farmacêuticos/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Timerosal/metabolismo , Adulto , Células Cultivadas , Quimiocinas/metabolismo , Células Dendríticas/fisiologia , Humanos
6.
Anal Bioanal Chem ; 406(7): 1909-16, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24442014

RESUMO

In order to reveal the time-depending mercury species uptake by human astrocytes, a novel approach for total mercury analysis is presented, which uses an accelerated sample introduction system combined on-line with an inductively coupled plasma mass spectrometer equipped with a collision/reaction cell. Human astrocyte samples were incubated with inorganic mercury (HgCl2), methylmercury chloride (MeHgCl), and thimerosal. After 1-h incubation with Hg(2+), cellular concentrations of 3 µM were obtained, whereas for organic species, concentrations of 14-18 µM could be found. After 24 h, a cellular accumulation factor of 0.3 was observed for the cells incubated with Hg(2+), whereas the organic species both showed values of about 5. Due to the obtained steady-state signals, reliable results with relative standard deviations of well below 5 % and limits of detection in the concentration range of 1 ng L(-1) were obtained using external calibration and species-unspecific isotope dilution analysis approaches. The results were further validated using atomic fluorescence spectrometry.


Assuntos
Astrócitos/metabolismo , Cloreto de Mercúrio/análise , Compostos de Metilmercúrio/análise , Espectrofotometria Atômica/métodos , Timerosal/análise , Calibragem , Técnicas de Cultura de Células , Células Cultivadas , Desenho de Equipamento , Humanos , Limite de Detecção , Cloreto de Mercúrio/metabolismo , Isótopos de Mercúrio/análise , Compostos de Metilmercúrio/metabolismo , Padrões de Referência , Reprodutibilidade dos Testes , Soluções , Espectrometria de Fluorescência , Espectrofotometria Atômica/instrumentação , Relação Estrutura-Atividade , Timerosal/metabolismo , Fatores de Tempo
7.
Int J Environ Res Public Health ; 10(8): 3771-800, 2013 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-23965928

RESUMO

Autism spectrum disorder (ASD) is a neurological disorder in which a significant number of the children experience a developmental regression characterized by a loss of previously acquired skills and abilities. Typically reported are losses of verbal, nonverbal, and social abilities. Several recent studies suggest that children diagnosed with an ASD have abnormal sulfation chemistry, limited thiol availability, and decreased glutathione (GSH) reserve capacity, resulting in a compromised oxidation/reduction (redox) and detoxification capacity. Research indicates that the availability of thiols, particularly GSH, can influence the effects of thimerosal (TM) and other mercury (Hg) compounds. TM is an organomercurial compound (49.55% Hg by weight) that has been, and continues to be, used as a preservative in many childhood vaccines, particularly in developing countries. Thiol-modulating mechanisms affecting the cytotoxicity of TM have been identified. Importantly, the emergence of ASD symptoms post-6 months of age temporally follows the administration of many childhood vaccines. The purpose of the present critical review is provide mechanistic insight regarding how limited thiol availability, abnormal sulfation chemistry, and decreased GSH reserve capacity in children with an ASD could make them more susceptible to the toxic effects of TM routinely administered as part of mandated childhood immunization schedules.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/etiologia , Transtornos Globais do Desenvolvimento Infantil/metabolismo , Glutationa/metabolismo , Compostos de Sulfidrila/metabolismo , Timerosal/efeitos adversos , Timerosal/metabolismo , Animais , Criança , Transtornos Globais do Desenvolvimento Infantil/patologia , Humanos , Mercúrio/metabolismo , Oxirredução , Conservantes Farmacêuticos/efeitos adversos , Conservantes Farmacêuticos/metabolismo , Fatores de Risco , Vacinação , Vacinas
8.
Metallomics ; 3(8): 847-52, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21706086

RESUMO

Thimerosal (THI) is used as a preservative in many vaccines throughout the world. Ethylmercury (EtHg(+)), released from THI in aqueous media, has a high affinity to thiol functions of proteins. In blood, hemoglobin is a likely target protein because of its high abundance and its several free thiol functions. In comparison to hemoglobin of human origin, hemoglobin of rats exhibits almost twice as many free thiol groups, which might lead to different binding behavior and therefore a limited comparability between the situation in man and in rats, which are frequently used as models for mercury species toxicity investigations. Thus, the adduct formation of EtHg(+) with hemoglobin of humans and rats was compared under simulated physiological conditions by using gradient reversed-phase liquid chromatography (LC) with electrospray time-of-flight mass spectrometry (ESI-TOF-MS) detection. The binding stoichiometry correlated with the number of free thiols in the α- and ß-chain of hemoglobin. The use of rats to verify the safety of additives in vaccines like Thimerosal is therefore doubtful and should be reevaluated.


Assuntos
Hemoglobinas/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Timerosal/metabolismo , Animais , Cromatografia Líquida , Hemoglobinas/química , Humanos , Hidrólise , Peso Molecular , Ratos , Timerosal/química
9.
Vaccine ; 29(15): 2682-90, 2011 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-21316500

RESUMO

Intact (146S) foot-and-mouth disease virions (FMDVs) can dissociate into specific (12S) viral capsid degradation products. Using two single-domain antibody fragments that bind specifically to either 146S or 12S particles we developed two ELISAs for the quantification of these particles in FMDV antigen preparations used for vaccine manufacturing. Only O serotype strains are detected in the 146S specific ELISA whereas strains of most serotypes are detected in the 12S specific ELISA. However, the 146S concentration of A and Asia 1 serotype strains could be measured indirectly using the 12S specific ELISA by prior conversion of 146S into 12S particles by heat treatment. This allowed us to demonstrate that addition of the preservative thiomersal to FMDV antigens stimulates the dissociation into 12S particles of O, A and Asia 1 serotype strains upon prolonged storage at 4°C. FMDV dissociation is known to result in a strongly reduced immunogenicity, which was experimentally confirmed here. Therefore, we recommend to omit thiomersal from FMD vaccines to increase its shelf life.


Assuntos
Vírus da Febre Aftosa/efeitos dos fármacos , Timerosal/metabolismo , Vacinas Virais/química , Vírion/efeitos dos fármacos , Animais , Ásia , Ensaio de Imunoadsorção Enzimática/métodos , Vírus da Febre Aftosa/química , Estados Unidos , Vírion/química , Virologia/métodos
10.
Toxicology ; 274(1-3): 1-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20457211

RESUMO

Thimerosal, a mercury derivative composed of ethyl mercury chloride (EtHgCl) and thiosalicylic acid (TSA), is widely used as a preservative in vaccines and cosmetic products and causes cutaneous reactions. Since dendritic cells (DCs) play an essential role in the immune response, the sensitization potency of chemicals was studied in vitro using U937, a human promyelomonocytic cell line that is used as a surrogate of monocytic differentiation and activation. Currently, this cell line is under ECVAM (European Center for the Validation of Alternative Methods) validation as an alternative method for discriminating chemicals. Thimerosal and mercury derivatives induced in U937 an overexpression of CD86 and interleukin (IL)-8 secretion similarly to 1-chloro-2,4-dinitrobenzene (DNCB), a sensitizer used as a positive control for DC activation. Non-sensitizers, dichloronitrobenzene (DCNB), TSA and sodium dodecyl sulfate (SDS), an irritant, had no effect. U937 activation was prevented by cell pretreatment with N-acetyl-L-cysteine (NAC) but not with thiol-independent antioxidants except vitamin E which affected CD86 expression by preventing lipid peroxidation of cell membranes. Thimerosal, EtHgCl and DNCB induced glutathione (GSH) depletion and reactive oxygen species (ROS) within 15 min; another peak was detected after 2h for mercury compounds only. MitoSOX, a specific mitochondrial fluorescent probe, confirmed that ROS were essentially produced by mitochondria in correlation with its membrane depolarization. Changes in mitochondrial membrane permeability induced by mercury were reversed by NAC but not by thiol-independent antioxidants. Thimerosal and EtHgCl also induced a calcium (Ca2+) influx with a peak at 3h, suggesting that Ca2+ influx is a secondary event following ROS induction as Ca2+ influx was suppressed after pretreatment with NAC but not with thiol-independent antioxidants. Ca2+ influx was also suppressed when culture medium was deprived of Ca2+ confirming the specificity of the measure. In conclusion, these data suggest that thimerosal induced U937 activation via oxidative stress from mitochondrial stores and mitochondrial membrane depolarization with a primordial effect of thiol groups. A cross-talk between ROS and Ca2+ influx was demonstrated.


Assuntos
Espécies Reativas de Oxigênio/metabolismo , Timerosal/farmacologia , Acetilcisteína/metabolismo , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antígeno B7-2/metabolismo , Cálcio/metabolismo , Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cisteína/metabolismo , Cisteína/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Dinitrobenzenos , Dinitroclorobenzeno/metabolismo , Dinitroclorobenzeno/farmacologia , Europa (Continente) , Glutationa/metabolismo , Glutationa/farmacologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Monócitos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Conservantes Farmacêuticos/metabolismo , Conservantes Farmacêuticos/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Salicilatos , Compostos de Sulfidrila/metabolismo , Compostos de Sulfidrila/farmacologia , Timerosal/metabolismo , Vitamina E/metabolismo , Vitamina E/farmacologia
11.
Acta Paediatr ; 98(8): 1244-50, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19594471

RESUMO

AIM: This article explores the role of breastfeeding in different aspects of vaccination in the first 6 months when infants are still developing: (1) pain management; (2) immunomodulation of infants' vaccine responses; (3) metabolism of thimerosal. METHODS: Major databases were searched for studies that addressed outcomes of related issues. RESULTS: Studies reveal that breastfeeding can: (1) help mothers and infants to cope with the stressful situations that accompany parenteral vaccines; (2) improve response to vaccines in the still maturing immunologic and enterohepatic systems of infants; (3) influence physiologic parameters that can change metabolism of ethylmercury derived from some vaccines. CONCLUSION: Health promotion that supports vaccinations should also emphasize early initiation and maintenance of exclusive breastfeeding up until 6 months for maximum protection of the infants with a possible beneficial effect on the vaccine response. Paediatric professionals should inform mothers of the proven benefits of breastfeeding and its importance in complementing vaccination and lowering stress and the risk of untoward reactions on susceptible infants.


Assuntos
Aleitamento Materno , Leite Humano/imunologia , Timerosal/metabolismo , Vacinação , Vacinas/imunologia , Alérgenos/imunologia , Aleitamento Materno/psicologia , Humanos , Lactente , Recém-Nascido , Dor/etiologia , Manejo da Dor , Estresse Psicológico , Vacinação/efeitos adversos
12.
Toxicology ; 261(1-2): 25-32, 2009 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-19386279

RESUMO

Effects of thimerosal and its metabolites, ethyl mercury and thiosalicylate, on the expression of metallothionein (MT) mRNAs in mouse cerebellum microglia cell line, C8-B4 cells, were studied. The level of MT-1 mRNA significantly decreased at early hours and recovered time-dependently 24h after thimerosal was added to the C8-B4 cells. However, MT-2 and MT-3 mRNA expressions did not change from the control group. In contrast, the expression of MT-1 mRNA increased in a mouse neuroblastoma cell line 6h after incubation with thimerosal. In addition, the level of MT-1 mRNA decreased in C8-B4 cells 6h after the addition of thiosalicylate, but ethyl mercury induced MT-1 mRNA expression. When cell viability was compared with thimerosal, thiosalicylate, and ethyl mercury, the viability of C8-B4 cells decreased dose-dependently 24h after either thimerosal or ethyl mercury was added; however, the viability increased dose-dependently until 15 microM thiosalicylate was added. From the present results, it is concluded that the expression of MT-1 mRNA may be mediated by different factors than the expression of MT-2 mRNA in C8-B4 cells. The reduction of MT-1 mRNA level by thiosalicylate may affect the proliferation of C8-B4 cells.


Assuntos
Cerebelo/efeitos dos fármacos , Metalotioneína/genética , Microglia/efeitos dos fármacos , Conservantes Farmacêuticos/toxicidade , RNA Mensageiro/metabolismo , Salicilatos/toxicidade , Compostos de Sulfidrila/toxicidade , Timerosal/toxicidade , Animais , Biotransformação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida , Camundongos , Microglia/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/genética , Conservantes Farmacêuticos/metabolismo , Ratos , Salicilatos/metabolismo , Compostos de Sulfidrila/metabolismo , Timerosal/metabolismo , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , alfa-Fetoproteínas/genética
13.
Biometals ; 22(5): 697-700, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19205900

RESUMO

Cadmium, arsenic, lead, and mercury have been linked to autism, attention deficit disorder, mental retardation and death of children. Mercury in thimerosal found in many vaccines and flu shots contributes significantly to these problems. Decomposition of the thimerosal can produce more toxic compounds, either methylethylmercury or diethylmercury, in the body. These compounds have a toxicity level similar to dimethylmercury. Within the human body, a mitochondrial disorder may release the more toxic form of mercury internally. Young children and pregnant women must minimize internal exposure to the vaccines and flu shots containing mercury.


Assuntos
Exposição Ambiental , Oligoelementos/toxicidade , Pré-Escolar , Feminino , Humanos , Masculino , Mercúrio/toxicidade , Gravidez , Timerosal/metabolismo , Timerosal/toxicidade , Vacinas/efeitos adversos
14.
Chem Res Toxicol ; 21(2): 483-93, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18197631

RESUMO

Thimerosal is an organic mercury compound that is widely used as a preservative in vaccines and other solution formulations. The use of thimerosal has caused concern about its ability to cause neurological abnormalities due to mercury accumulation during a normal schedule of childhood vaccinations. While the chemistry and the biological effects of methylmercury have been well-studied, those of thimerosal have not. Thimerosal reacted rapidly with cysteine, GSH, human serum albumin, and single-stranded DNA to form ethylmercury adducts that were detectable by mass spectrometry. These results indicated that thimerosal would be quickly metabolized in vivo because of its reactions with protein and nonprotein thiols. Thimerosal also potently inhibited the decatenation activity of DNA topoisomerase II alpha, likely through reaction with critical free cysteine thiol groups. Thimerosal, however, did not act as a topoisomerase II poison and the lack of cross-resistance with a K562 cell line with a decreased level of topoisomerase II alpha (K/VP.5 cells) suggested that inhibition of topoisomerase II alpha was not a significant mechanism for the inhibition of cell growth. Depletion of intracellular GSH with buthionine sulfoximine treatment greatly increased the K562 cell growth inhibitory effects of thimerosal, which showed that intracellular glutathione had a major role in protecting cells from thimerosal. Pretreatment of thimerosal with glutathione did not, however, change its K562 cell growth inhibitory effects, a result consistent with the rapid exchange of the ethylmercury adduct among various thiol-containing cellular reactants. Thimerosal-induced single and double strand breaks in K562 cells were consistent with a rapid induction of apoptosis. In conclusion, these studies have elucidated some of the chemistry and biological activities of the interaction of thimerosal with topoisomerase II alpha and protein and nonprotein thiols and with DNA.


Assuntos
Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Conservantes Farmacêuticos/toxicidade , Compostos de Sulfidrila/metabolismo , Timerosal/toxicidade , Inibidores da Topoisomerase II , Antígenos de Neoplasias , Linhagem Celular Tumoral , Cisteína/química , Cisteína/metabolismo , Adutos de DNA/análise , Adutos de DNA/efeitos dos fármacos , Dano ao DNA , DNA Topoisomerases Tipo II , DNA de Cadeia Simples/química , DNA de Cadeia Simples/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Glutationa/química , Glutationa/metabolismo , Humanos , Conservantes Farmacêuticos/química , Conservantes Farmacêuticos/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Compostos de Sulfidrila/química , Timerosal/química , Timerosal/metabolismo
15.
Eur J Pediatr ; 166(9): 935-41, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17237965

RESUMO

Because of uncertainties associated with a possible rise in neuro-developmental deficits among vaccinated children, thimerosal-preserved vaccines have not been used since 2004 in the USA (with the exception of thimerosal-containing influenza vaccines which are routinely recommended for administration to pregnant women and children), and the EU but are widely produced and used in other countries. We investigated the impact of thimerosal on the total Hg in hair of 82 breast-fed infants during the first 6 months of life. The infants received three doses of the hepatitis-B vaccine (at birth, 1 and 6 months) and three DTP (diphtheria, tetanus, and pertussis) doses at 2, 4 and 6 months, according to the immunization schedule recommended by the Ministry of Health of Brazil. The thimerosal in vaccines provided an ethylmercury (EtHg) exposure of 25 microgHg at birth, 30, 60 and 120 days, and 50 microgHg at 180 days. The exposure to vaccine-EtHg represents 80% of that expected from total breast milk-Hg in the first month but only 40% of the expected exposure integrated in the 6 months of breastfeeding. However, the Hg exposure corrected for body weight at the day of immunization was much higher from thimerosal- EtHg (5.7 to 11.3 microgHg/kg b.w.) than from breastfeeding (0.266 microgHg/kg b.w.). While mothers showed a relative decrease (-57%) in total hair-Hg during the 6 months lactation there was substantial increase in the infant's hair-Hg (446%). We speculate that dose and parenteral mode of thimerosal-EtHg exposure modulated the relative increase in hair-Hg of breast-fed infants at 6 months of age.


Assuntos
Cabelo/química , Mercúrio/análise , Leite Humano/química , Conservantes Farmacêuticos/metabolismo , Timerosal/metabolismo , Vacinas/química , Adolescente , Adulto , Brasil , Aleitamento Materno , Estudos de Coortes , Compostos de Etilmercúrio/metabolismo , Feminino , Humanos , Esquemas de Imunização , Lactente , Recém-Nascido , Masculino , Mercúrio/metabolismo , Compostos de Metilmercúrio/metabolismo , Pessoa de Meia-Idade , Gravidez , Vacinas/efeitos adversos
16.
Water Res ; 39(15): 3511-22, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16076476

RESUMO

Thiomersal, a toxic organomercurial with a strong bactericidal effect, is the most widely used preservative in vaccine production. As a result, vaccine production wastewaters are frequently polluted with thiomersal concentrations above the European limit for mercury effluent discharges for which there is, presently, no remediation technology available. This work proposes a biotechnological process for the remediation of vaccine production wastewaters based on the biological degradation of thiomersal to metallic mercury, under aerobic conditions, by a mercury resistant bacterial strain. The kinetics of thiomersal degradation by a pure culture of Pseudomonas putida spi3 was firstly investigated in batch reactors using a thiomersal amended mineral medium. Subsequently, a continuous stirred tank reactor fed with the same medium was operated at a dilution rate of 0.05 h(-1), and the bioreactor performance and robustness was evaluated when exposed to thiomersal shock loads. In a second stage, the bioreactor was fed directly with a real vaccine wastewater contaminated with thiomersal and the culture ability to grow in the wastewater and remediate it was evaluated for dilution rates ranging from 0.022 to 0.1 h(-1).


Assuntos
Conservantes Farmacêuticos/metabolismo , Pseudomonas putida/metabolismo , Timerosal/metabolismo , Eliminação de Resíduos Líquidos/métodos , Poluentes Químicos da Água/metabolismo , Biodegradação Ambiental , Reatores Biológicos , Resíduos Industriais , Mercúrio/análise , Mercúrio/metabolismo , Conservantes Farmacêuticos/análise , Timerosal/análise , Vacinas , Poluentes Químicos da Água/análise
17.
Biochem J ; 381(Pt 1): 87-96, 2004 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15015936

RESUMO

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.


Assuntos
Canais de Cálcio/metabolismo , Cálcio/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Timerosal/farmacologia , Animais , Aorta/química , Aorta/efeitos dos fármacos , Aorta/embriologia , Aorta/metabolismo , Células COS , Canais de Cálcio/biossíntese , Canais de Cálcio/química , Canais de Cálcio/deficiência , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Galinhas , Chlorocebus aethiops , Glutationa Transferase/biossíntese , Glutationa Transferase/química , Receptores de Inositol 1,4,5-Trifosfato , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Conformação Proteica/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Ratos , Receptores Citoplasmáticos e Nucleares/biossíntese , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/deficiência , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Deleção de Sequência/genética , Deleção de Sequência/fisiologia , Compostos de Sulfidrila/farmacologia , Timerosal/metabolismo
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