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Neurotoxicity of Environmental Metal Toxicants

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A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Toxicology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 38615

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Special Issue Editors

Dr. Richard Ortega

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Guest Editor

Chemical Imaging and Speciation, CENBG, CNRS, University of Bordeaux, France
Interests: metals; neurotoxicology; neurodegenerative diseases; chemical speciation; chemical imaging; micro- and nano-particles; radioelements

Dr. Asuncion Carmona

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Guest Editor

Chemical Imaging and Speciation, CENBG, CNRS, University of Bordeaux, France
Interests: metals; chemical imaging; chemical speciation; neurotoxicology; neurodegenerative diseases; radioelements

Special Issue Information

Environmental exposure to metallic neurotoxicants is a matter of growing concern, since it may have very significant consequences for human health, from impairing child neurodevelopment to the neurodegeneration processes involved in ageing.

This Special Issue will focus on the neurotoxicity 1) of well-established metallic environmental toxicants either in inorganic or in organometallic chemical forms and 2) of emerging metallic neurotoxicants such as high-technology metals, nanoparticles, or radioelements. For all these metallic compounds, the evaluation of the risks associated with their release in the environment, the speciation analysis in environmental and biological samples, and the definition of relevant biological models to assess neurotoxicity are important research objectives. Many questions have also arisen about multi-element (cocktail) exposure effects, as can occur in the drinking water of some developing countries. The description of the speciation of the metallic compounds in the environment, and of the molecular mechanisms driving metal neurotoxicity, are key to prevent exposure and to suggest new treatments.

The aim of this Special Issue on the ‘’Neurotoxicity of Environmental Metal Toxicants’’ is to give a broad overview of the current work being performed in the field of the neurotoxicology of metallic contaminants, from the identification of emerging toxic compounds, to the assessment of environmental exposures and associated risks, to the description of the molecular mechanisms involved in neurotoxicity.

The scientific community will have to face many challenges to identify and prevent the detrimental effects of environmental metal exposure on brain health. We hope that this Special Issue will serve to increase the visibility in this research field, intensify collaborations, and proliferate information exchange between the different scientific communities involved in this research topic.

Dr. Richard Ortega
Dr. Asuncion Carmona
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neurotoxicity
neurodevelopmental toxicity
metals
organometallic toxicants
nanoparticles
radioelements
environmental exposure
synergistic (cocktail) effects
chemical speciation
molecular mechanisms

Published Papers (11 papers)

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Editorial

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3 pages, 196 KiB

Open AccessEditorial

Neurotoxicity of Environmental Metal Toxicants: Special Issue

by Richard Ortega and Asuncion Carmona

Toxics 2022, 10(7), 382; https://doi.org/10.3390/toxics10070382 - 9 Jul 2022

Cited by 4 | Viewed by 1550

Abstract

Environmental exposure to metallic neurotoxicants is a matter of growing concern, since it may have very significant consequences for human health, from impairing neurodevelopment in children to the neurodegeneration processes involved in aging [...] Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

Research

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16 pages, 756 KiB

Open AccessFeature PaperArticle

Relationship of Blood and Urinary Manganese Levels with Cognitive Function in Elderly Individuals in the United States by Race/Ethnicity, NHANES 2011–2014

by Arturo J. Barahona, Zoran Bursac, Emir Veledar, Roberto Lucchini, Kim Tieu and Jason R. Richardson

Toxics 2022, 10(4), 191; https://doi.org/10.3390/toxics10040191 - 14 Apr 2022

Cited by 9 | Viewed by 2672

Abstract

Manganese (Mn) is an essential metal with a biphasic relationship with health outcomes. High-level exposure to Mn is associated with manganism, but few data explore the effects of chronic, lower-level Mn on cognitive function in adults. We sought to determine the relationship between blood/urinary manganese levels and cognitive function in elderly individuals using 2011–2014 data from the National Health and Nutrition Examination Survey (NHANES). Weighted multivariate regression models were used to determine correlations, adjusting for several covariates. Blood Mn was inversely associated with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) immediate learning of new verbal information (p-value = 0.04), but lost significance after adjusting for medical history (p-value = 0.09). In addition, blood Mn was inversely associated with Animal Fluency scores after adjusting for all covariates. Urinary Mn was inversely associated with CERAD immediate learning after adjusting for all covariates (p-value = 0.01) and inversely associated with the Digit Symbol Substitution Test scores (p-value = 0.0002), but lost significance after adjusting for medical history (p-value = 0.13). Upon stratifying by race/ethnicity, other Races and Non-Hispanic (NH)-Blacks had significantly higher blood Mn levels when compared to NH-Whites. Collectively, these findings suggest that increased blood and urinary Mn levels are associated with poorer cognitive function in an elderly US population. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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20 pages, 4021 KiB

Open AccessArticle

Cobalt Neurotoxicity: Transcriptional Effect of Elevated Cobalt Blood Levels in the Rodent Brain

by Sara Gómez-Arnaiz, Rothwelle J. Tate and Mary Helen Grant

Toxics 2022, 10(2), 59; https://doi.org/10.3390/toxics10020059 - 28 Jan 2022

Cited by 6 | Viewed by 3642

Abstract

Metal-on-metal (MoM) hip implants made of cobalt chromium (CoCr) alloy have shown early failure compared with other bearing materials. A consequence of the abnormal wear produced by these prostheses is elevated levels of cobalt in the blood of patients, which can lead to systemic conditions involving cardiac and neurological symptoms. In order to better understand the implications for patients with these implants, we carried out metal content and RNA-Seq analysis of excised tissue from rats treated intraperitonially for 28 days with low concentrations of cobalt. Cobalt blood levels in dosed rats were found to be similar to those seen in some patients with MoM implants (range: 4–38 μg/L Co in blood). Significant accumulation of cobalt was measured in a range of tissues including kidney, liver, and heart, but also in brain tissue. RNA-Seq analysis of neural tissue revealed that exposure to cobalt induces a transcriptional response in the prefrontal cortex (pref. cortex), cerebellum, and hippocampus. Many of the most up- and downregulated genes appear to correspond to choroid plexus transcripts. These results indicate that the choroid plexus could be the brain tissue most affected by cobalt. More specifically, the differentially expressed genes show a disruption of steroidogenesis and lipid metabolism. Several other transcripts also demonstrate that cobalt induces an immune response. In summary, cobalt exposure induces alterations in the brain transcriptome, more specifically, the choroid plexus, which is in direct contact with neurotoxicants at the blood–cerebrospinal fluid barrier. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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21 pages, 2957 KiB

Open AccessArticle

Manganese-Induced Neurotoxicity through Impairment of Cross-Talk Pathways in Human Neuroblastoma Cell Line SH-SY5Y Differentiated with Retinoic Acid

by Raúl Bonne Hernández, Nadja C. de Souza-Pinto, Jos Kleinjans, Marcel van Herwijnen, Jolanda Piepers, Houman Moteshareie, Daniel Burnside and Ashkan Golshani

Toxics 2021, 9(12), 348; https://doi.org/10.3390/toxics9120348 - 9 Dec 2021

Cited by 3 | Viewed by 2963

Abstract

Manganese (Mn) is an important element; yet acute and/or chronic exposure to this metal has been linked to neurotoxicity and neurodegenerative illnesses such as Parkinson’s disease and others via an unknown mechanism. To better understand it, we exposed a human neuroblastoma cell model (SH-SY5Y) to two Mn chemical species, MnCl₂ and Citrate of Mn(II) (0–2000 µM), followed by a cell viability assay, transcriptomics, and bioinformatics. Even though these cells have been chemically and genetically modified, which may limit the significance of our findings, we discovered that by using RA-differentiated cells instead of undifferentiated SH-SY5Y cell line, both chemical species induce a similar toxicity, potentially governed by disruption of protein metabolism, with some differences. The MnCl₂ altered amino acid metabolism, which affects RNA metabolism and protein synthesis. Citrate of Mn(II), however, inhibited the E3 ubiquitin ligases–target protein degradation pathway, which can lead to the buildup of damaged/unfolded proteins, consistent with histone modification. Finally, we discovered that Mn(II)-induced cytotoxicity in RA-SH-SY5Y cells shared 84 percent of the pathways involved in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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19 pages, 1954 KiB

Open AccessFeature PaperArticle

Methylmercury-Induced Metabolic Alterations in Caenorhabditis elegans Are Diet-Dependent

by Nicole Crawford, Megan Martell, Tyson Nielsen, Belal Khalil, Farooq Imtiaz, Etienne Nguidjo, Jennifer L. Newell-Caito, Julia Bornhorst, Tanja Schwerdtle and Samuel W. Caito

Toxics 2021, 9(11), 287; https://doi.org/10.3390/toxics9110287 - 2 Nov 2021

Cited by 9 | Viewed by 2480

Abstract

Methylmercury (MeHg) is a well-known neurotoxicant; however, its role in metabolic diseases has been gaining wider attention. Chronic exposure to MeHg in human populations shows an association with diabetes mellitus and metabolic syndrome (MS). As the incidences of both obesity and MS are on the rise globally, it is important to understand the potential role of MeHg in the development of the disease. There is a dearth of information on dietary interactions between MeHg and lipids, which play an important role in developing MS. We have previously shown that MeHg increases food seeking behaviors, lipid levels, fat storage, and pro-adipogenic gene expression in C. elegans fed the standard OP50 Escherichia coli diet. However, we hypothesized that these metabolic changes could be prevented if the worms were fed a bacterial diet lower in lipid content. We tested whether C. elegans developed metabolic alterations in response to MeHg if they were fed two alternative E. coli strains (HT115 and HB101) that are known absorb significantly less lipids from their media. Additionally, to explore the effect of a high-lipid and high-cholesterol diet on MeHg-induced metabolic dysfunction, we supplemented the OP50 strain with twice the standard concentration of cholesterol in the nematode growth media. Wild-type worms fed either the HB101 or HT115 diet were more resistant to MeHg than the worms fed the OP50 diet, showing a significant right-hand shift in the dose–response survival curve. Worms fed the OP50 diet supplemented with cholesterol were more sensitive to MeHg, showing a significant left-hand shift in the dose–response survival curve. Changes in sensitivity to MeHg by differential diet were not due to altered MeHg intake in the worms as measured by inductively coupled mass spectrometry. Worms fed the low-fat diets showed protection from MeHg-induced metabolic changes, including decreased food consumption, lower triglyceride content, and lower fat storage than the worms fed either of the higher-fat diets. Oxidative stress is a common characteristic of both MeHg exposure and high-fat diets. Worms fed either OP50 or OP50 supplemented with cholesterol and treated with MeHg had significantly higher levels of reactive oxygen species, carbonylated proteins, and loss of glutathione than the worms fed the HT115 or HB101 low-lipid diets. Taken together, our data suggest a synergistic effect of MeHg and dietary lipid levels on MeHg toxicity and fat metabolism in C. elegans, which may affect the ability of MeHg to cause metabolic dysfunction. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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13 pages, 1277 KiB

Open AccessArticle

Concentrations of Lead, Mercury, Selenium, and Manganese in Blood and Hand Grip Strength among Adults Living in the United States (NHANES 2011–2014)

by M. Corinaud J. Gbemavo and Maryse F. Bouchard

Toxics 2021, 9(8), 189; https://doi.org/10.3390/toxics9080189 - 17 Aug 2021

Cited by 9 | Viewed by 2550

Abstract

Exposure to lead and mercury can cause deficits in neuromotor function. Selenium and manganese are essential elements, hence both deficiency and excess could result in decreased neuromotor function. We aimed to examine hand grip strength, a marker of neuromotor function, and blood concentrations of lead, mercury, selenium, and manganese in the general U.S. population. We used data from the National Health and Nutrition Examination Survey (NHANES, 2011–2014) on 6199 participants ages 20–79 years. We assessed associations of blood concentration for these elements and grip strength with generalized regression models, and cubic splines to detect possible nonlinear relations, adjusting for confounders. The results showed that mercury and manganese were not associated with grip strength. Lead was associated with weaker grip strength in women (for 10-fold increase in lead, −2.4 kg; 95% CI: −4.2, −0.5), but not in men. Higher selenium was associated with stronger grip strength in women (8.5 kg; 95% CI: 1.9, 15.1) and men (4.6; 95% CI: −11.9, 21.0), although the association was not significant in the latter. In conclusion, lead exposure was associated with weaker grip strength in women, even at the low exposure levels in the population. Furthermore, low blood selenium level was associated with weaker grip strength, suggesting that some individuals might have selenium deficiency manifesting with poorer neuromotor function. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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Review

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15 pages, 1112 KiB

Open AccessFeature PaperReview

Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function

by Asuncion Carmona, Stéphane Roudeau and Richard Ortega

Toxics 2021, 9(9), 198; https://doi.org/10.3390/toxics9090198 - 27 Aug 2021

Cited by 26 | Viewed by 4239

Abstract

Environmental exposure to neurotoxic metals and metalloids such as arsenic, cadmium, lead, mercury, or manganese is a global health concern affecting millions of people worldwide. Depending on the period of exposure over a lifetime, environmental metals can alter neurodevelopment, neurobehavior, and cognition and cause neurodegeneration. There is increasing evidence linking environmental exposure to metal contaminants to the etiology of neurological diseases in early life (e.g., autism spectrum disorder) or late life (e.g., Alzheimer’s disease). The known main molecular mechanisms of metal-induced toxicity in cells are the generation of reactive oxygen species, the interaction with sulfhydryl chemical groups in proteins (e.g., cysteine), and the competition of toxic metals with binding sites of essential metals (e.g., Fe, Cu, Zn). In neurons, these molecular interactions can alter the functions of neurotransmitter receptors, the cytoskeleton and scaffolding synaptic proteins, thereby disrupting synaptic structure and function. Loss of synaptic connectivity may precede more drastic alterations such as neurodegeneration. In this article, we will review the molecular mechanisms of metal-induced synaptic neurotoxicity. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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16 pages, 2544 KiB

Open AccessFeature PaperReview

Exposure to Environmental Arsenic and Emerging Risk of Alzheimer’s Disease: Perspective Mechanisms, Management Strategy, and Future Directions

by Md. Ataur Rahman, Md. Abdul Hannan, Md Jamal Uddin, Md Saidur Rahman, Md Mamunur Rashid and Bonglee Kim

Toxics 2021, 9(8), 188; https://doi.org/10.3390/toxics9080188 - 14 Aug 2021

Cited by 30 | Viewed by 5096

Abstract

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth’s crust, and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition, although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not yet clear. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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26 pages, 509 KiB

Open AccessReview

Mechanisms of Metal-Induced Mitochondrial Dysfunction in Neurological Disorders

by Hong Cheng, Bobo Yang, Tao Ke, Shaojun Li, Xiaobo Yang, Michael Aschner and Pan Chen

Toxics 2021, 9(6), 142; https://doi.org/10.3390/toxics9060142 - 17 Jun 2021

Cited by 24 | Viewed by 3907

Abstract

Metals are actively involved in multiple catalytic physiological activities. However, metal overload may result in neurotoxicity as it increases formation of reactive oxygen species (ROS) and elevates oxidative stress in the nervous system. Mitochondria are a key target of metal-induced toxicity, given their role in energy production. As the brain consumes a large amount of energy, mitochondrial dysfunction and the subsequent decrease in levels of ATP may significantly disrupt brain function, resulting in neuronal cell death and ensuing neurological disorders. Here, we address contemporary studies on metal-induced mitochondrial dysfunction and its impact on the nervous system. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

13 pages, 1895 KiB

Open AccessFeature PaperReview

Direct and Indirect Neurotoxic Potential of Metal/Metalloids in Plants and Fungi Used for Food, Dietary Supplements, and Herbal Medicine

by Peter S. Spencer and Valerie S. Palmer

Toxics 2021, 9(3), 57; https://doi.org/10.3390/toxics9030057 - 16 Mar 2021

Cited by 8 | Viewed by 2742

Abstract

Plants and mushrooms bioconcentrate metals/metalloids from soil and water such that high levels of potentially neurotoxic elements can occur in cultivated and wild species used for food. While the health effects of excessive exposure to metals/metalloids with neurotoxic potential are well established, overt neurological disease from prolonged ingestion of contaminated botanicals has not been recognized. However, the presence of metal elements may affect levels of botanical neurotoxins in certain plants and mushrooms that are established causes of acute and chronic neurological disease. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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11 pages, 1230 KiB

Open AccessFeature PaperReview

Commonalities between Copper Neurotoxicity and Alzheimer’s Disease

by Roshni Patel and Michael Aschner

Toxics 2021, 9(1), 4; https://doi.org/10.3390/toxics9010004 - 7 Jan 2021

Cited by 34 | Viewed by 4738

Abstract

Alzheimer’s disease, a highly prevalent form of dementia, targets neuron function beginning from the hippocampal region and expanding outwards. Alzheimer’s disease is caused by elevated levels of heavy metals, such as lead, zinc, and copper. Copper is found in many areas of daily life, raising a concern as to how this metal and Alzheimer’s disease are related. Previous studies have not identified the common pathways between excess copper and Alzheimer’s disease etiology. Our review corroborates that both copper and Alzheimer’s disease target the hippocampus, cerebral cortex, cerebellum, and brainstem, affecting motor skills and critical thinking. Additionally, Aβ plaque formation was analyzed beginning from synthesis at the APP parent protein site until Aβ plaque formation was completed. Structural changes were also noted. Further analysis revealed a relationship between amyloid-beta plaques and copper ion concentration. As copper ion levels increased, it bound to the Aβ monomer, expediting the plaque formation process, and furthering neurodegeneration. These conclusions can be utilized in the medical community to further research on the etiology of Alzheimer’s disease and its relationships to copper and other metal-induced neurotoxicity. Full article

(This article belongs to the Special Issue Neurotoxicity of Environmental Metal Toxicants)

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