Toxicity of thimerosal in biological systems: Conformational changes in human hemoglobin, decrease of oxygen binding capacity, increase of protein glycation and amyloid's formation

Silva, Marina de Magalhães; Dantas, Maria Dayanne de A.; Silva-Filho, Reginaldo; Sales, Marcos Vinicius dos Santos; Xavier, Jadriane A.; Leite, Antônio Cesar Rios; Goulart, Marília Oliveira Fonseca; Grillo, Luciano Aparecido Meireles; Barros, Wellington Alves de; Fátima, Ângelo de; Figueiredo, Isis M.; Santos, Josué Carinhanha Caldas

doi:10.1016/j.ijbiomac.2020.03.156

Cited by 25 publications

(5 citation statements)

References 58 publications

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“…Thimerosal can spontaneously degrade into thiosalicylic acid and ethylmercury in aqueous media. The strong affinity of mercuric ions (Hg 2+ ) and their alkyl derivatives towards sulfhydryl groups (-SH) in amino acids, peptides and proteins is well documented [ [27] , [28] , [29] ]. An in vivo study in humans performed by Trümpler et al.…”

Section: Discussionmentioning

confidence: 99%

Capsid destabilization and epitope alterations of human papillomavirus 18 in the presence of thimerosal

Huang

Nie

et al. 2021

Journal of Pharmaceutical Analysis

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Thimerosal has been widely used as a preservative in drug and vaccine products for decades. Due to the strong propensity to modify thiols in proteins, conformational changes could occur due to covalent bond formation between ethylmercury (a degradant of thimerosal) and thiols. Such a conformational change could lead to partial or even complete loss of desirable protein function. This study aims to investigate the effects of thimerosal on the capsid stability and antigenicity of recombinant human papillomavirus (HPV) 18 virus-like particles (VLPs). Dramatic destabilization of the recombinant viral capsid upon thimerosal treatment was observed. Such a negative effect on the thermal stability of VLPs preserved with thimerosal was shown to be dependent on the thimerosal concentration. Two highly neutralizing antibodies, 13H12 and 3C3, were found to be the most sensitive to thimerosal treatment. The kinetics of antigenicity loss, when monitored with 13H12 or 3C3 as probes, yielded two distinctly different sets of kinetic parameters, while the data from both monoclonal antibodies (mAbs) followed a biphasic exponential decay model. The potential effect of thimerosal on protein function, particularly for thiol-containing proteinaceous active components, needs to be comprehensively characterized during formulation development when a preservative is necessary.

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Section: Discussionmentioning

confidence: 99%

Capsid destabilization and epitope alterations of human papillomavirus 18 in the presence of thimerosal

Huang

Nie

et al. 2021

Journal of Pharmaceutical Analysis

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“…Question mark indicates processes that need to be proven (potential). Some authors state the dealkylation of MeHg into InoHg occurs in the brain with the ratio of InoHg to MeHg increasing with age [76,77]. Potential explanations have linked the MeHg demethylation processes with a possibly limited ability of InoHg to be eliminated across the blood brain barrier (BBB) due in part to an insoluble complex formed between InoHg and Se [39,78,79].…”

Section: Organomercurials Kineticsmentioning

confidence: 99%

Evidence on Neurotoxicity after Intrauterine and Childhood Exposure to Organomercurials

Azevedo

Karpova

Rocha

et al. 2023

IJERPH

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Although the molecular mechanisms underlying methylmercury toxicity are not entirely understood, the observed neurotoxicity in early-life is attributed to the covalent binding of methylmercury to sulfhydryl (thiol) groups of proteins and other molecules being able to affect protein post-translational modifications from numerous molecular pathways, such as glutamate signaling, heat-shock chaperones and the antioxidant glutaredoxin/glutathione system. However, for other organomercurials such as ethylmercury or thimerosal, there is not much information available. Therefore, this review critically discusses current knowledge about organomercurials neurotoxicity—both methylmercury and ethylmercury—following intrauterine and childhood exposure, as well as the prospects and future needs for research in this area. Contrasting with the amount of epidemiological evidence available for methylmercury, there are only a few in vivo studies reporting neurotoxic outcomes and mechanisms of toxicity for ethylmercury or thimerosal. There is also a lack of studies on mechanistic approaches to better investigate the pathways involved in the potential neurotoxicity caused by both organomercurials. More impactful follow-up studies, especially following intrauterine and childhood exposure to ethylmercury, are necessary. Childhood vaccination is critically important for controlling infectious diseases; however, the safety of mercury-containing thimerosal and, notably, its effectiveness as preservative in vaccines are still under debate regarding its potential dose-response effects to the central nervous system.

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“…The formation of adducts between a toxic metal species and a metalloprotein can have important toxicological ramifications. For example, the binding of CH 3 CH 2 Hg + to Hb is associated with its conformational change, which significantly decreases its O 2 binding capacity [98]. To date, the application of LC-based metallomics tools has provided important new insight into the bioinorganic chemistry of toxic metal(loid)s in the bloodstream (Table 3) by observing bi-and trimetallic complexes that contain essential and toxic metals [69], which contributed important insight into the biomolecular mechanisms that mediate organ damage (Figure 3) [86].…”

Section: Toxic Metal(loid) Species At the Plasma-rbc-organ Nexusmentioning

confidence: 99%

Integrative Metallomics Studies of Toxic Metal(loid) Substances at the Blood Plasma–Red Blood Cell–Organ/Tumor Nexus

Doroudian

Gailer

2022

Inorganics

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Globally, an estimated 9 million deaths per year are caused by human exposure to environmental pollutants, including toxic metal(loid) species. Since pollution is underestimated in calculations of the global burden of disease, the actual number of pollution-related deaths per year is likely to be substantially greater. Conversely, anticancer metallodrugs are deliberately administered to cancer patients, but their often dose-limiting severe adverse side-effects necessitate the urgent development of more effective metallodrugs that offer fewer off-target effects. What these seemingly unrelated events have in common is our limited understanding of what happens when each of these toxic metal(loid) substances enter the human bloodstream. However, the bioinorganic chemistry that unfolds at the plasma/red blood cell interface is directly implicated in mediating organ/tumor damage and, therefore, is of immediate toxicological and pharmacological relevance. This perspective will provide a brief synopsis of the bioinorganic chemistry of AsIII, Cd2+, Hg2+, CH3Hg+ and the anticancer metallodrug cisplatin in the bloodstream. Probing these processes at near-physiological conditions and integrating the results with biochemical events within organs and/or tumors has the potential to causally link chronic human exposure to toxic metal(loid) species with disease etiology and to translate more novel anticancer metal complexes to clinical studies, which will significantly improve human health in the 21st century.

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Toxicity of thimerosal in biological systems: Conformational changes in human hemoglobin, decrease of oxygen binding capacity, increase of protein glycation and amyloid's formation

Cited by 25 publications

References 58 publications

Capsid destabilization and epitope alterations of human papillomavirus 18 in the presence of thimerosal

Capsid destabilization and epitope alterations of human papillomavirus 18 in the presence of thimerosal

Evidence on Neurotoxicity after Intrauterine and Childhood Exposure to Organomercurials

Integrative Metallomics Studies of Toxic Metal(loid) Substances at the Blood Plasma–Red Blood Cell–Organ/Tumor Nexus

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