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Are Neuropathological Conditions Relevant to Ethylmercury Exposure?
Abstract
Mercury and mercurial compounds are among the environmentally ubiquitous substances most toxic to both wildlife and humans. Once released into the environment from both natural and anthropogenic sources, mercury exists mainly as three different molecular species: elemental, inorganic, and organic. Potential health risks have been reported from exposure to all forms; however, of particular concern for human exposure relate to the potent neurotoxic effects of methylmercury (MeHg), especially for the developing nervous system. The general population is primarily exposed to MeHg by seafood consumption. In addition, some pharmaceuticals, including vaccines, have been, and some continue to be, a ubiquitous source of exposure to mercurials. A significant controversy has been whether the vaccine preservative ethylmercury thiosalicylate, commonly known as thimerosal, could cause the development of autism. In this review, we have discussed the hypothesis that exposure to thimerosal during childhood may be a primary cause of autism. The conclusion is that there are no reliable data indicating that administration of vaccines containing thimerosal is a primary cause of autism. However, one cannot rule out the possibility that the individual gene profile and/or gene-environment interactions may play a role in modulating the response to acquired risk by modifying the individual susceptibility.
... In contrast, no significant associations were noted concerning thimerosal exposure. This discrepancy is attributed to ethyl mercury's faster breakdown rate compared to methylmercury, resulting in a lower risk of brain damage from ethyl mercury [38]. Additionally, exposure to methylmercury through maternal fish consumption has been significantly linked to an increased risk of ADHD in offspring, with both the duration and dose of mercury exposure influencing the disorder's incidence and prevalence [36]. ...
Motto: Living with ADHD is like being locked in a room with 100 televisions and 100 radios all playing. None of them have power buttons so you can turn them off and the door is locked from the outside-Sarah Young [1]. Abstract Recent research on Attention-Deficit/Hyperactivity Disorder (ADHD) underscores the significance of prenatal environmental factors alongside the well-documented genetic influences in the disorder's development. Studies have shown that approximately 5% of children and 2.5% of adults globally are affected by ADHD, with symptoms that severely impact various aspects of life. While genetics play a crucial role, accounting for 70% to 80% of ADHD's heritability, factors such as maternal diet, exposure to pollutants and teratogens, psychological stress, and prenatal inflammation are gaining attention for their potential impact on fetal brain development. These environmental factors could increase the risk of ADHD by altering critical developmental pathways, as evidenced by the association between maternal stress, dietary patterns during pregnancy, and increased ADHD symptoms in offspring. Furthermore, exposure to substances like alcohol and tobacco, as well as maternal inflammation, are linked to a higher risk of developing ADHD, highlighting the complex interplay between genetic predisposition and environmental exposures. This growing body of evidence calls for a comprehensive approach to prenatal care, emphasizing the importance of mitigating environmental and nutritional risks to prevent the development of ADHD and improve long-term outcomes for children.
... In contrast, no significant associations were noted concerning thimerosal exposure. This discrepancy is attributed to ethyl mercury's faster breakdown rate compared to methylmercury, resulting in a lower risk of brain damage from ethyl mercury [38]. Additionally, exposure to methylmercury through maternal fish consumption has been significantly linked to an increased risk of ADHD in offspring, with both the duration and dose of mercury exposure influencing the disorder's incidence and prevalence [36]. ...
... In contrast, no significant associations were noted concerning thimerosal exposure. This discrepancy is attributed to ethyl mercury's faster breakdown rate compared to methylmercury, resulting in a lower risk of brain damage from ethyl mercury [38]. Additionally, exposure to methylmercury through maternal fish consumption has been significantly linked to an increased risk of ADHD in offspring, with both the duration and dose of mercury exposure influencing the disorder's incidence and prevalence [36]. ...
Motto: Living with ADHD is like being locked in a room with 100 televisions and 100 radios all playing. None of them have power buttons so you can turn them off and the door is locked from the outside-Sarah Young [1]. Abstract Recent research on Attention-Deficit/Hyperactivity Disorder (ADHD) underscores the significance of prenatal environmental factors alongside the well-documented genetic influences in the disorder's development. Studies have shown that approximately 5% of children and 2.5% of adults globally are affected by ADHD, with symptoms that severely impact various aspects of life. While genetics play a crucial role, accounting for 70% to 80% of ADHD's heritability, factors such as maternal diet, exposure to pollutants and teratogens, psychological stress, and prenatal inflammation are gaining attention for their potential impact on fetal brain development. These environmental factors could increase the risk of ADHD by altering critical developmental pathways, as evidenced by the association between maternal stress, dietary patterns during pregnancy, and increased ADHD symptoms in offspring. Furthermore, exposure to substances like alcohol and tobacco, as well as maternal inflammation, are linked to a higher risk of developing ADHD, highlighting the complex interplay between genetic predisposition and environmental exposures. This growing body of evidence calls for a comprehensive approach to prenatal care, emphasizing the importance of mitigating environmental and nutritional risks to prevent the development of ADHD and improve long-term outcomes for children.
... Brain represents one of the organs most affected by MeHg, where its uptake occurs, at least in part, via MeHg-Cys complex by the Ltype neutral amino acid transporters (LAT) [5]. Although the stability of MeHg in mammalian cells is greater than of EtHg, the neurological impairments caused by MeHg intoxication have been correlated with the high and persistent levels of iHg in the brain after exposure to MeHg [59,60]. The dealkylation of EtHg into iHg is faster than MeHg [4]. ...
Background:
Methylmercury (MeHg) and ethylmercury (EtHg) are potent toxicants affecting the environment and human healthy. In this way, the present study aimed to investigate and compare the effects of MeHg and EtHg exposure on human peripheral blood mononuclear cells (PBMCs), which are critical components of the mammalian immune system.
Methods:
PBMCs were exposed to 2.5 μM MeHg or 2.5 μM EtHg. The number of cells and incubation times varied according to each assay. After exposures, the PBMCs were subjected to different evaluations, including cell viability, morphological aspects, cell cycle phases, indices of apoptosis and necrosis, reactive species (RS) production, and mitochondrial functionality.
Results:
PBMCs exposed to EtHg were characterized by decreased viability and size, increased granularity, RS production, and apoptotic indexes accompanied by an intensification of Sub-G1 and reduction in G0-G1 cell cycle phases. Preceding these effects, we found mitochondrial dysfunctions, namely a reduction in the electron transport system related to mitochondrial complex I. In contrast, PBMCs exposed to MeHg showed only reduced viability. By ICP-MS, we found that PBMCs treated with EtHg accumulated Hg + levels ~1.8-fold greater than MeHg-exposed cells.
Conclusions and significance:
Taken together, our findings provide important insights about mercury immunotoxicity, showing that EtHg is more immunotoxic to human PBMCs than MeHg.
... This relationship was first reported in 1998 in a Lancet article which was later retracted and, therefore, not cited here. Most studies report absence of correlation between human thimerosal exposure and childhood neuropsychological outcomes including ASD in the UK [143], Denmark [144,145] and in a review paper [146]. A few negative associations of thimerosal content in vaccines include lower finger-tapping scores in 10-11-year-old girls in Italy [147], speech disabilities in boys and girls, and lower verbal IQ in girls [148], and tics in boys [149] in 7 to 10 years old children in the USA. ...
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.
... A J;ignificant ontroversy has been whether the vaccine preservative thylniercury thlosatlcylate, commonly known 99 thimerosal, ould cause the development of autism. 13 Methylmercury has lso been demOnstrated to Induce reactive oxygen species OS) formation In astrocyles. 14 ...senlc (A9): ArsenIc Is a well-estabnshed hmnan cardnogen ri~/s ubiquitous In the environment For decades, arsenic has sen considered to be a hOn-genotoxic carcinogen because It . ...
... It was introduced in the 1930s and has been the most commonly used vaccine preservative since the 1930s [1][2][3]. Although there is no direct evidence to prove the health risk of thimerosal in vaccines, the use of thimerosal-containing vaccines has declined significantly since 1999 [4][5][6][7]. Currently, thimerosal is no longer used in single-dose vials or in paediatric vaccines. ...
Thimerosal has been widely used as a preservative in human vaccines for decades. Thimerosal, a thiol capping agent with ethyl mercury being the active degradant, could have impacts on the vaccine potency due to potential thiol modification. The effects on the antigenicity and immunogenicity of human papillomavirus (HPV) virus-like particles (VLPs) in the presence of thimerosal was studied. In general, reduced binding activity was observed between HPV antigens and monoclonal antibodies (mAbs) upon thimerosal treatment, accompanied by reduced protein conformational stability. The immunogenicity of a pentavalent vaccine formulation (HPV6, HPV11, HPV16, HPV18 and hepatitis E virus) with or without thimerosal was studied in mice. The functional antibody titres, as well as the binding titres, were determined, showing a substantial decrease for vaccine formulations containing thimerosal for HPV16/18. Similarly, epitope-specific competition assays using specific and functional mAbs as tracers also showed a significant reduction in immunogenicity for HPV16/18 in the presence of thimerosal. Structural alterations in the capsid protein for HPV18 were observed with cryo-electron microscopy and 3-dimensional reconstruction in the comparative structural analysis. The results should alert scientists in formulation development field on the choice for vaccine preservatives, in particular for thiol-containing antigens.
... It has been found that neurotoxic agents in specific patients genetically predisposed to ALS can activate the neurodegenerative processes occurring in this pathology (Cox et al., 2009;Miranda et al., 2008). The mercurial compounds are classified in three diverse Hg molecular classes: elemental (Hg), inorganic (Hg 2+ ), and organic (MeHg) (Aschner and Ceccatelli, 2010). Regarding a possible relationship between Hg exposure and the possibility to develop ALS, it has been reported that clinical symptoms comparable to those characteristic of ALS can develop in patients with continuing accidental Hg exposure or after brief but intense exposure to elemental mercury (Praline et al., 2007). ...
In humans, mutation of glycine 93 to alanine of Cu⁺⁺/Zn⁺⁺ superoxide dismutase type-1 (SOD1-G93 A) has been associated to some familial cases of Amyotrophic Lateral Sclerosis (ALS). Several evidence proposed the involvement of environmental pollutants that like mercury could accelerate ALS symptoms. SH-SY5Y cells stably transfected with SOD1 and G93 A mutant of SOD1 constructs were exposed to non-toxic concentrations (0.01 μM) of ethylmercury thiosalicylate (thimerosal) for 24 h. Interestingly, we found that thimerosal, in SOD1-G93 A cells, but not in SOD1 cells, reduced cell survival. Furthermore, thimerosal-induced cell death occurred in a concentration dependent-manner and was prevented by the Sirtuin 1 (SIRT1) activator Resveratrol (RSV). Moreover, thimerosal decreased the protein expression of transcription factor Downstream Regulatory Element Antagonist Modulator (DREAM), but not DREAM gene. Interestingly, DREAM reduction was blocked by co-treatment with RSV, suggesting the participation of SIRT1 in determining this effect. Immunoprecipitation experiments in SOD1-G93 A cells exposed to thimerosal demonstrated that RSV increased DREAM deacetylation and reduced its polyubiquitination. In addition, RSV counteracted thimerosal-enhanced prodynorphin (PDYN) mRNA, a DREAM target gene. Furthermore, cortical neurons transiently transfected with SOD1-G93 A construct and exposed to thimerosal (0.5 μM/24 h) showed a reduction of DREAM and an up-regulation of the prodynorphin gene. Importantly, both the treatment with RSV or the transfection of siRNA against prodynorphin significantly reduced thimerosal-induced neurotoxicity, while DREAM knocking-down potentiated thimerosal-reduced cell survival. These results demonstrate the particular vulnerability of SOD1-G93 A neuronal cells to thimerosal and that RSV via SIRT1 counteracts the neurodetrimental effect of this toxicant by preventing DREAM reduction and prodynorphin up-regulation.
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental problems with various genetic
and environmental components. The ASD diagnosis is based on symptom expression without reliance on any
biomarkers. The genetic contributions in ASD remain elusive. Various studies have linked ASD with iron. Since
iron plays a crucial role in brain development, neurotransmitter synthesis, neuronal myelination and mitochondrial
function, we hypothesized that iron dysregulation in the brain could play a role and contribute to the
pathogenesis of ASD. In this study, we investigated single nucleotide polymorphisms in ASD in various iron
metabolism genes, including the Transferrin Receptor (TFRC) gene (rs11915082), the Solute Carrier Family 11
Member 2 (SLC11A2) gene (rs1048230 and rs224589), the Solute Carrier Family 40 Member 1 (SLC40A1) gene
(rs1439816), and hepcidin antimicrobial peptide (HAMP) gene (rs10421768). We recruited 48 patients with ASD
and 88 matched non-ASD controls. Our results revealed a significant difference between ASD and controls in the
G allele of the TFRC gene rs11915082, and in the C allele of the SLC40A1 gene rs1439816. In silico analysis
demonstrated potential positive role of the indicated genetic variations in ASD development and pathogenesis.
These results suggest that specific genetic variations in iron metabolism genes may represent part of early genetic
markers for early diagnosis of ASD. A significant effect of SNPs, groups (ASD/control) as well as interaction
between SNPs and groups was revealed. Follow-up post hoc tests showed a significant difference between the
ASD and control groups in rs11915082 (TFRC gene) and rs1439816 (SLC40A1 gene). Backward conditional
logistic regression using both the genotype and allele data showed similar ability in detecting ASD using allel
model (Nagelkerke R2 = 0.350 p = 0.967; Variables: rs1439816, rs11915082) compared to genotype model
(Nagelkerke R2 = 0.347, p = 0.430; Variables: rs1439816 G, rs1439816 C, rs10421768 A). ROC curve showed
54% sensitivity in detecting ASD compared to 47% for the genotype model. Both models differentiated controls
with high accuracy; the allele model had a specificity of 91% compared to 92% for the genotype model.
In conclusion, our findings suggest that specific genetic variations in iron metabolism may represent early
biomarkers for a diagnosis of ASD. Further research is needed to correlate these markers with specific blood iron
indicators and their contribution to brain development and behavior.
Autism is a neurodevelopmental disorder. Today it has observed a continuing and rapid increase in its prevalence. Autism increase, in combination with unknown factors that cause it, so far, has drawn the interest of several researchers (from different scientific fields). It could be characterized as a multiple-factors disorder. In recent decades, many researchers have implicated mainly environmental, chemical, genetic, hereditary, and biological factors. The present article focuses on environmental factors that their exposure causes irreversible brain damages (toxicity)-autism. Some of these factors are (mainly) mercury, brominated, thalidomide, misoprostol, valproic acid, chloropiryfos, ethanol etc. However, according to literature review, it has not been proved a direct correlation with the factors which have been implicated for autism disorder. As a result, the question "what causes autism" is still unanswered. Today, diagnostic criteria, early diagnosis, methods for autistic education and medication (under circumstances) are continuously improving.
This Policy Statement was retired January 2003
The effects of methylmercury (CH3Hg) or mercuric chloride (HgCl2) on neurite outgrowth and cell viability were quantified using undifferentiated (unprimed) and differentiated (primed) pheochromocytoma (PC12) cells. In unprimed cells, following 24-h exposure, CH3Hg significantly decreased NGF-stimulated neurite outgrowth at concentrations of 0.3‐3 mM. However, HgCl2 significantly increased both neurite outgrowth and the number of branch points, a component of neurite outgrowth. In primed PC12 cells, following 24-h exposure, both CH3Hg and HgCl2 inhibited NGF-stimulated neurite outgrowth with an EC50 of approximately 0.03 mM; however, there was a difference between CH3Hg and HgCl2 effects on the subcomponents of total neurite outgrowth. CH3Hg significantly decreased both the number of branch points (0.3 mM) and fragment length (0.01 mM), while HgCl2 only decreased fragment length (0.03 mM). Cell viability was assessed in the same cultures by trypan-blue exclusion. In unprimed cells, the EC50 for cytotoxicity of CH3Hg in the presence and absence of NGF was 0.21 6 0.04 and 0.87 6 0.12 mM, respectively, and for HgCl2 in the presence and absence of NGF was 8.18 6 1.52 and 5.02 6 0.74 mM, respectively. In primed cells, the EC50 for cytotoxicity of CH3Hg in the presence or absence of NGF was 1.17 6 0.38 and 0.73 6 0.14 mM, respectively, and for HgCl2 in the presence or absence of NGF was 3.96 6 0.82 and 3.81 6 0.91 mM, respectively. In the primed PC12 model, cytotoxicity occurred at concentrations that were at least 30-fold higher than the EC50 for neurite outgrowth, suggesting that the mercurial compounds can
Maternal consumption during pregnancy of methylmercury (MeHg)-contaminated fish in Japan and of MeHg-contaminated bread in Iraq caused psychomotor retardation in the offspring. Studies in Iraq suggested adverse fetal effects when maternal hair mercury concentrations were as low as 20 ppm. This prospective study involved 131 infant-mother pairs in Mancora, Peru with peak maternal hair MeHg levels during pregnancy from 1.2 ppm to 30.0 ppm, geometric mean 8.3. The MeHg was believed to be derived from marine fish in the diet. There was no increase in the frequency of neurodevelopmental abnormalities in early childhood. The possible role of selenium or other protective mechanisms in marine fish is discussed. This previously unpublished study was conducted between 1981 and 1984. Our report of August 1985 to the funding agencies has been circulated, and the data were presented at the Twelfth International Neurotoxicology Conference in Hot Spring, Arkansas, October 30 to November 2, 1994. The current account has not been modified or updated since 1985. For reference to interim publications on fetal MeHg studies in Iraq and New Zealand see Marsh et al., 1995.