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Mechanisms of Heavy Metal Toxicity: 3rd Edition
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Mechanisms of Heavy Metal Toxicity: 3rd Edition

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: 30 June 2025 | Viewed by 7720

Special Issue Editor

Prof. Dr. Toshiyuki Kaji

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Guest Editor
Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
Interests: signaling and cell response; transporter; vascular toxicity; extracellular matrix; atherosclerosis; blood coagulation-fibrinolytic system; growth factors; cytokines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

This Special Issue is a continuation of our previous Special Issue, entitled “Mechanisms of Heavy Metal Toxicity 2.0” (https://www.mdpi.com/journal/ijms/special_issues/H84PU90OTN).

The toxicity of heavy metals has been a popular research topic for a long time. In the past, it was important to elucidate the actual health hazards caused by environmental pollution, accidents, and crimes, involving metals, metalloids, and metal compounds, but now the main issues are related to the elucidation of the mechanisms of their toxicity and defense mechanisms against said toxicity.

This Special Issue is under production, with the aim of addressing this contemporary issue. In this Special Issue, we welcome the submission of full reviews, original research papers, short communications, and perspectives that cover the following topics:

  • Cellular and molecular mechanisms underlying heavy metals, metalloids, and metal(loid)-containing compounds;
  • Mechanisms underlying the induction of metallothionein;
  • Cellular defense systems against the toxicity of heavy metals, metalloids, and metal(loid)-containing compounds;
  • The regulation and mechanisms of the expression of metal transporters, such as SLC39A8;
  • Research that does not fit into the above topics but may contribute to them is also welcome.

By sharing these studies, we aim to make significant progress in metal toxicology.

Prof. Dr. Toshiyuki Kaji
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

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Published Papers (6 papers)

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Research

13 pages, 5555 KiB  
Article
Evaluation of Metal Accumulation in Escherichia coli Expressing SPL2 by Single-Cell Inductively Coupled Plasma Mass Spectrometry
by Yasunori Fukumoto, Enhui Li, Yu-ki Tanaka, Noriyuki Suzuki and Yasumitsu Ogra
Int. J. Mol. Sci. 2025, 26(5), 1905; https://doi.org/10.3390/ijms26051905 - 22 Feb 2025
Viewed by 638
Abstract
Rare earth elements, comprising 17 elements including 15 lanthanides, are essential components in numerous high-tech applications. While physicochemical methods are commonly employed to remove toxic heavy metals (e.g., cadmium and mercury) from industrial wastewater, biological approaches offer increasingly attractive alternatives. Biomining, which utilizes [...] Read more.
Rare earth elements, comprising 17 elements including 15 lanthanides, are essential components in numerous high-tech applications. While physicochemical methods are commonly employed to remove toxic heavy metals (e.g., cadmium and mercury) from industrial wastewater, biological approaches offer increasingly attractive alternatives. Biomining, which utilizes microorganisms to extract valuable metals from ores and industrial wastes, and bioremediation, which leverages microorganisms to adsorb and transport metal ions into cells via active transport, provide eco-friendly solutions for resource recovery and environmental remediation. In this study, we investigated the potential of three recently identified lanthanide-binding proteins—SPL2, lanpepsy, and lanmodulin—for applications in these areas using single-cell inductively coupled plasma mass spectrometry (scICP-MS). Our results demonstrate that SPL2 exhibits superior characteristics for lanthanide and cadmium bioremediation. Heterologous expression of a cytosolic fragment of SPL2 in bacteria resulted in high expression levels and solubility. Single-cell ICP-MS analysis revealed that these recombinant bacteria accumulated lanthanum, cobalt, nickel, and cadmium, effectively sequestering lanthanum and cadmium from the culture media. Furthermore, SPL2 expression conferred enhanced bacterial tolerance to cadmium exposure. These findings establish SPL2 as a promising candidate for developing recombinant bacterial systems for heavy metal bioremediation and rare earth element biomining. Full article
(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity: 3rd Edition)
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17 pages, 4693 KiB  
Article
Cadmium-Induced Oxidative Damage and the Expression and Function of Mitochondrial Thioredoxin in Phascolosoma esculenta
by Shenwei Gu, Xuebin Zheng, Xinming Gao, Yang Liu, Yiner Chen and Junquan Zhu
Int. J. Mol. Sci. 2024, 25(24), 13283; https://doi.org/10.3390/ijms252413283 - 11 Dec 2024
Cited by 3 | Viewed by 857
Abstract
Phascolosoma esculenta is a unique aquatic invertebrate native to China, whose habitat is highly susceptible to environmental pollution, making it an ideal model for studying aquatic toxicology. Mitochondrial thioredoxin (Trx2), a key component of the Trx system, plays an essential role in scavenging [...] Read more.
Phascolosoma esculenta is a unique aquatic invertebrate native to China, whose habitat is highly susceptible to environmental pollution, making it an ideal model for studying aquatic toxicology. Mitochondrial thioredoxin (Trx2), a key component of the Trx system, plays an essential role in scavenging reactive oxygen species (ROS), regulating mitochondrial membrane potential, and preventing ROS-induced oxidative stress and apoptosis. This study investigated the toxicity of cadmium (Cd) on P. esculenta and the role of P. esculenta Trx2 (PeTrx2) in Cd detoxification. The results showed that Cd stress altered the activities of T-SOD and CAT, as well as the contents of GSH and MDA in the intestine. After 96 h of exposure, histological damages such as vacuolization, cell necrosis, and mitophagy were observed. Suggesting that Cd stress caused oxidative damage in P. esculenta. Furthermore, with the prolongation of stress time, the expression level of intestinal PeTrx2 mRNA initially increased and then decreased. The recombinant PeTrx2 (rPeTrx2) protein displayed dose-dependent redox activity and antioxidant capacity and enhanced Cd tolerance of Escherichia coli. After RNA interference (RNAi) with PeTrx2, significant changes in the expression of apoptosis-related genes (Caspase-3, Bax, Bcl-2, and Bcl-XL) were observed. Proving that PeTrx2 rapidly responded to Cd stress and played a vital role in mitigating Cd-induced oxidative stress and apoptosis. Our study demonstrated that PeTrx2 is a key factor for P. esculenta to endure the toxicity of Cd, providing foundational data for further exploration of the molecular mechanisms underlying heavy metal resistance in P. esculenta. Full article
(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity: 3rd Edition)
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14 pages, 2014 KiB  
Article
Effect of Long-Term Cisplatin Exposure on the Proliferative Potential of Immortalized Renal Progenitor Cells
by Eloho Ighofose, Scott H. Garrett, Sarmad Al-Marsoummi, Aaron A. Mehus, Donald A. Sens, Sandeep K. Singhal, Sonalika Singhal and Seema Somji
Int. J. Mol. Sci. 2024, 25(23), 12553; https://doi.org/10.3390/ijms252312553 - 22 Nov 2024
Viewed by 898
Abstract
Cisplatin (CisPt) is a widely used chemotherapeutic agent. However, its nephrotoxic effects pose significant risks, particularly for the development of acute kidney injury (AKI) and potential progression to chronic kidney disease (CKD). The present study investigates the impact of non-lethal exposure of CisPt [...] Read more.
Cisplatin (CisPt) is a widely used chemotherapeutic agent. However, its nephrotoxic effects pose significant risks, particularly for the development of acute kidney injury (AKI) and potential progression to chronic kidney disease (CKD). The present study investigates the impact of non-lethal exposure of CisPt to immortalized human renal epithelial precursor TERT cells (HRTPT cells) that co-express PROM1 and CD24, markers characteristic of renal progenitor cells. Over eight serial passages, HRTPT cells were exposed to 1.5 µM CisPt, leading to an initial growth arrest, followed by a gradual recovery of proliferative capacity. Despite maintaining intracellular platinum (Pt) levels, the cells exhibited normal morphology by passage eight (P8), with elevated expression of renal stress and damage markers. However, the ability to form domes was not restored. RNA-seq analysis revealed 516 differentially expressed genes between CisPt-exposed and control cells, with significant correlations to cell cycle and adaptive processes, as determined by the Reactome, DAVID, and Panther analysis programs. The progenitor cells treated with CisPt displayed no identity, or close identity, with cells of the normal human nephron. Additionally, several upregulated genes in P8 cells were linked to cancer cell lines, suggesting a complex interaction between CisPt exposure and cellular repair mechanisms. In conclusion, our study demonstrates that renal progenitor cells can recover from CisPt exposure and regain proliferative potential in the continued presence of both extracellular CisPt and intracellular Pt. Full article
(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity: 3rd Edition)
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16 pages, 3271 KiB  
Article
Mechanisms Underlying Sensory Nerve-Predominant Damage by Methylmercury in the Peripheral Nervous System
by Tsuyoshi Nakano, Eiko Yoshida, Yu Sasaki, Shigekatsu Kazama, Fumika Katami, Kazuhiro Aoki, Tomoya Fujie, Ke Du, Takato Hara, Chika Yamamoto, Tsutomu Takahashi, Yasuyuki Fujiwara, Komyo Eto, Yoichiro Iwakura, Yo Shinoda and Toshiyuki Kaji
Int. J. Mol. Sci. 2024, 25(21), 11672; https://doi.org/10.3390/ijms252111672 - 30 Oct 2024
Cited by 1 | Viewed by 1372
Abstract
Sensory disturbances and central nervous system symptoms are important in patients with Minamata disease. In the peripheral nervous system of these patients, motor nerves are not strongly injured, whereas sensory nerves are predominantly affected. In this study, we investigated the mechanisms underlying the [...] Read more.
Sensory disturbances and central nervous system symptoms are important in patients with Minamata disease. In the peripheral nervous system of these patients, motor nerves are not strongly injured, whereas sensory nerves are predominantly affected. In this study, we investigated the mechanisms underlying the sensory-predominant impairment of the peripheral nervous system caused by methylmercury. We found that the types of cell death in rat dorsal root ganglion (DRG) neurons caused by methylmercury included apoptosis, necrosis, and necroptosis. Methylmercury induced apoptosis in cultured rat DRG neurons but not in anterior horn neurons or Schwann cells. Additionally, methylmercury activated both caspase 8 and caspase 3 in DRG neurons. It increased the expression of tumor necrosis factor (TNF) receptor-1 and the phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL). The expression of TNF-α was increased in macrophage-like RAW264.7 cells by methylmercury. The increase was suggested to be mediated by the NF-κB pathway. Moreover, methylmercury induced neurological symptoms, evaluated by a hindlimb extension response, were significantly less severe in TNF-α knockout mice. Based on these results and our previous studies, we propose the following hypothesis regarding the pathogenesis of sensory nerve-predominant damage by methylmercury: First, methylmercury accumulates within sensory nerve neurons and initiates cell death mechanisms, such as apoptosis, on a small scale. Second, cell death triggers the infiltration of macrophages into the sensory fibers. Third, the macrophages are stimulated by methylmercury and secrete TNF-α through the NF-κB pathway. Fourth, TNF-α induces cell death mechanisms, including necrosis, apoptosis through the caspase 8/3 pathway, and necroptosis through the TNFR1-RIP1-RIP3-MLKL pathway, activated by methylmercury in sensory neurons. Consequently, methylmercury exhibits potent cytotoxicity specific to the DRG/sensory nerve cells in the peripheral nervous system. This chain of events caused by methylmercury may contribute to sensory disturbances in patients with Minamata disease. Full article
(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity: 3rd Edition)
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15 pages, 6471 KiB  
Article
The Role of Heat Shock Factor 1 in Preserving Proteomic Integrity During Copper-Induced Cellular Toxicity
by Shruti Ghai, Rejina Shrestha, Ahmad Hegazi, Vanessa Boualoy, Shi-He Liu and Kuo-Hui Su
Int. J. Mol. Sci. 2024, 25(21), 11657; https://doi.org/10.3390/ijms252111657 - 30 Oct 2024
Cited by 1 | Viewed by 1732
Abstract
Copper is crucial for many physiological processes across mammalian cells, including energy metabolism, neurotransmitter synthesis, and antioxidant defense mechanisms. However, excessive copper levels can lead to cellular toxicity and “cuproptosis”, a form of programmed cell death characterized by the accumulation of copper within [...] Read more.
Copper is crucial for many physiological processes across mammalian cells, including energy metabolism, neurotransmitter synthesis, and antioxidant defense mechanisms. However, excessive copper levels can lead to cellular toxicity and “cuproptosis”, a form of programmed cell death characterized by the accumulation of copper within mitochondria. Tumor cells are less sensitive to this toxicity than normal cells, the mechanism for which remains unclear. We address this important issue by exploring the role of heat shock factor 1 (HSF1), a transcription factor that is highly expressed across several types of cancer and has a crucial role in tumor survival, in protecting against copper-mediated cytotoxicity. Using pancreatic ductal adenocarcinoma cells, we show that excessive copper triggers a proteotoxic stress response (PSR), activating HSF1 and that overexpressing HSF1 diminishes intracellular copper accumulation and prevents excessive copper-induced cell death and amyloid fibrils formation, highlighting HSF1′s role in preserving proteasomal integrity. Copper treatment decreases the lipoylation of dihydrolipoamide S-acetyltransferase (DLAT), an enzyme necessary for cuproptosis, induces DLAT oligomerization, and induces insoluble DLAT formation, which is suppressed by overexpressing HSF1, in addition to enhancing the interaction between HSF1 and DLAT. Our findings uncover how HSF1 protects against copper-induced damage in cancer cells and thus represents a novel therapeutic target for enhancing copper-mediated cancer cell death. Full article
(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity: 3rd Edition)
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14 pages, 1903 KiB  
Article
Metalloproteomics Reveals Multi-Level Stress Response in Escherichia coli When Exposed to Arsenite
by James Larson, Brett Sather, Lu Wang, Jade Westrum, Monika Tokmina-Lukaszewska, Jordan Pauley, Valérie Copié, Timothy R. McDermott and Brian Bothner
Int. J. Mol. Sci. 2024, 25(17), 9528; https://doi.org/10.3390/ijms25179528 - 2 Sep 2024
Viewed by 1476
Abstract
The arsRBC operon encodes a three-protein arsenic resistance system. ArsR regulates the transcription of the operon, while ArsB and ArsC are involved in exporting trivalent arsenic and reducing pentavalent arsenic, respectively. Previous research into Agrobacterium tumefaciens 5A has demonstrated that ArsR has regulatory [...] Read more.
The arsRBC operon encodes a three-protein arsenic resistance system. ArsR regulates the transcription of the operon, while ArsB and ArsC are involved in exporting trivalent arsenic and reducing pentavalent arsenic, respectively. Previous research into Agrobacterium tumefaciens 5A has demonstrated that ArsR has regulatory control over a wide range of metal-related proteins and metabolic pathways. We hypothesized that ArsR has broad regulatory control in other Gram-negative bacteria and set out to test this. Here, we use differential proteomics to investigate changes caused by the presence of the arsR gene in human microbiome-relevant Escherichia coli during arsenite (AsIII) exposure. We show that ArsR has broad-ranging impacts such as the expression of TCA cycle enzymes during AsIII stress. Additionally, we found that the Isc [Fe-S] cluster and molybdenum cofactor assembly proteins are upregulated regardless of the presence of ArsR under these same conditions. An important finding from this differential proteomics analysis was the identification of response mechanisms that were strain-, ArsR-, and arsenic-specific, providing new clarity to this complex regulon. Given the widespread occurrence of the arsRBC operon, these findings should have broad applicability across microbial genera, including sensitive environments such as the human gastrointestinal tract. Full article
(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity: 3rd Edition)
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