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Cellular and Molecular Mechanisms of Heavy Metal Toxicity: From Death to Immortality 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 2786

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Special Issue Editor

Prof. Dr. Rolf Teschke

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Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University, 999035 Frankfurt, Germany
Interests: Heavy metals; Heavy metal uptake; Heavy metal disposition, Heavy metal homeostasis; Haber Weiss reaction; Fenton reaction; Benefits and risks for human health; Environmental pollution
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Special Issue Information

Dear Colleagues,

This is the continued issue of our successful Special Issue “Cellular and Molecular Mechanisms of Heavy Metal Toxicity: From Death to Immortality”.

The prevalence of toxic heavy metals, such as arsenic, cadmium, chromium, lead and mercury, in the environment poses increasing concern for human health following exposure via inhalation or ingestion. Once in the body, the metals are distributed in the bloodstream, reaching most organs where they can be taken up by cells using existing transport systems in a form of molecular mimicry. Chronic exposures result in cellular accumulation of heavy metals and once a protective threshold has been exceeded, stress, defense and adaptive responses are initiated.

Pivotal to the cellular response to heavy metal toxicity are reactive oxygen species (ROS), which lead to DNA damage, lipid peroxidation, alteration of signaling and transport proteins or modulation of enzyme activities. Heavy metals may alter the cellular redox status by increasing ROS generation or damaging ROS-scavenging defenses, both resulting in elevated ROS levels, and impacting physiological ROS signaling as well as downstream signaling pathways involved in cellular life and death decisions.

In this context for this Special Issue, investigators and experts in the field are invited to submit high quality original articles reporting novel findings regarding molecular and cellular mechanisms of heavy metals (single or mixtures) or review articles summarizing the status-quo and postulating updated and stimulating hypotheses.

Prof. Dr. Rolf Teschke
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

heavy metal
metal compound
metallothionein
cellular defense mechanism
metal transporter
oxidative stress
cell death
carcinogenesis
mutations
toxicology
molecular mimicry
signal transduction
redox status

Published Papers (3 papers)

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Research

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25 pages, 1730 KiB

Open AccessArticle

Effects of Copper or Zinc Organometallics on Cytotoxicity, DNA Damage and Epigenetic Changes in the HC-04 Human Liver Cell Line

by Daniel Desaulniers, Gu Zhou, Andrew Stalker and Cathy Cummings-Lorbetskie

Int. J. Mol. Sci. 2023, 24(21), 15580; https://doi.org/10.3390/ijms242115580 - 25 Oct 2023

Viewed by 1014

Abstract

Copper and zinc organometallics have multiple applications and many are considered “data-poor” because the available toxicological information is insufficient for comprehensive health risk assessments. To gain insight into the chemical prioritization and potential structure activity relationship, the current work compares the in vitro toxicity of nine “data-poor” chemicals to five structurally related chemicals and to positive DNA damage inducers (4-nitroquinoline-oxide, aflatoxin-B1). The HC-04 non-cancer human liver cell line was used to investigate the concentration–response effects (24 h and 72 h exposure) on cell proliferation, DNA damage (γH2AX and DNA unwinding assays), and epigenetic effects (global genome changes in DNA methylation and histone modifications using flow cytometry). The 24 h exposure screening data (DNA abundance and damage) suggest a toxicity hierarchy, starting with copper dimethyldithiocarbamate (CDMDC, CAS#137-29-1) > zinc diethyldithiocarbamate (ZDEDC, CAS#14324-55-1) > benzenediazonium, 4-chloro-2-nitro-, and tetrachlorozincate(2-) (2:1) (BDCN4CZ, CAS#14263-89-9); the other chemicals were less toxic and had alternate ranking positions depending on assays. The potency of CDMDC for inducing DNA damage was close to that of the human hepatocarcinogen aflatoxin-B1. Further investigation using sodium-DMDC (SDMDC, CAS#128-04-1), CDMDC and copper demonstrated the role of the interactions between copper and the DMDC organic moiety in generating a high level of CDMDC toxicity. In contrast, additive interactions were not observed with respect to the DNA methylation flow cytometry data in 72 h exposure experiments. They revealed chemical-specific effects, with hypo and hypermethylation induced by copper chloride (CuCl₂, CAS#10125-13-0) and zinc-DMDC (ZDMDC, CAS#137-30-4), respectively, but did not show any significant effect of CDMDC or SDMDC. Histone-3 hypoacetylation was a sensitive flow cytometry marker of 24 h exposure to CDMDC. This study can provide insights regarding the prioritization of chemicals for future study, with the aim being to mitigate chemical hazards. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Heavy Metal Toxicity: From Death to Immortality 2.0)

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Review

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35 pages, 811 KiB

Open AccessReview

Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update

by Rolf Teschke and Axel Eickhoff

Int. J. Mol. Sci. 2024, 25(9), 4753; https://doi.org/10.3390/ijms25094753 - 26 Apr 2024

Abstract

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu²⁺ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber–Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser–Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well=treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Heavy Metal Toxicity: From Death to Immortality 2.0)

23 pages, 2296 KiB

Open AccessReview

Bioactive Bismuth Compounds: Is Their Toxicity a Barrier to Therapeutic Use?

by Ângela Gonçalves, Mariana Matias, Jorge A. R. Salvador and Samuel Silvestre

Int. J. Mol. Sci. 2024, 25(3), 1600; https://doi.org/10.3390/ijms25031600 - 27 Jan 2024

Cited by 1 | Viewed by 1147

Abstract

Bismuth compounds are considered relatively non-toxic, with their low solubility in aqueous solutions (e.g., biological fluids) being the major contributing factor to this property. Bismuth derivatives are widely used for the treatment of peptic ulcers, functional dyspepsia, and chronic gastritis. Moreover, the properties of bismuth compounds have also been extensively explored in two main fields of action: antimicrobial and anticancer. Despite the clinical interest of bismuth-based drugs, several side effects have also been reported. In fact, excessive acute ingestion of bismuth, or abuse for an extended period of time, can lead to toxicity. However, evidence has demonstrated that the discontinuation of these compounds usually reverses their toxic effects. Notwithstanding, the continuously growing use of bismuth products suggests that it is indeed part of our environment and our daily lives, which urges a more in-depth review and investigation into its possible undesired activities. Therefore, this review aims to update the pharmaco-toxicological properties of bismuth compounds. A special focus will be given to in vitro, in vivo, and clinical studies exploring their toxicity. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Heavy Metal Toxicity: From Death to Immortality 2.0)

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