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

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 34636

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Prof. Dr. Reinhard Dallinger

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Institute of Zoology, University of Innsbruck, Technikerstr. 25, 6020 Innsbruck, Austria
Interests: environmental toxicology and ecotoxicology; molecular physiology; microevolution of metal sensitivity; evolution; biochemistry and gene regulation of metallothioneins; metal-specific pathways in animal physiology; metal detoxification; metal-related biological indicators and biomarkers
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Special Issue Information

Dear Colleagues,

After the publication of two issues in the International Journal of Molecular Sciences dedicated to “Metal Metabolism in Animals” (in 2016 and 2017), one may ask about the reasonableness of adding a third issue to this series. In fact, the subject of metal metabolism in animals in this journal has so far been treated in a very thorough manner. In the first issue (“Metal Metabolism in Animals I”, edited 2016), articles were dedicated to subjects like the significance of metals, metal-binding features and the role of metals in metalloproteins, metal homeostasis and detoxification, as well as trace element supplementation in animals. In the second issue (“Metal Metabolism in Animals II”, edited 2017), the perspective was extended to human beings with articles focusing on aspects of metal allergy and immunology, models of metal uptake and effects during pregnancy, as well as toxicological and pathological effects of metals on animals and humans.

During the last years, an increasing number of publications has appeared dealing with the molecular evolutionary aspects of metal handling in organisms. Thus, it was shown that in addition to traditional aspects of metallomics, evolutionary approaches could help one to better understand how strategies of metal handling have gradually been shaped through generations and lineages of organisms from all domains of life, and how this may have fostered adaptation to their different environments. This has undoubtedly increased our perception of these processes of adaptation. An evolutionary view may also increase our understanding of how ancestral metal handling features may have been optimized towards more complex and, perhaps, more efficient mechanisms and interconnections.

Although articles dealing with molecular evolutionary aspects of metal metabolism were not explicitly excluded in the former issues, we would like on this occasion to put a particular focus on these subjects, including now living organisms across all domains of life.

Thus, in particular, we welcome articles with a strong molecular and metallomic focus, dealing with the following topics:

The molecular evolutionary aspects of mechanisms and strategies of trace-element uptake, regulation, and homeostasis in all kinds or organisms;
The evolution of metal-binding proteins and metallo-enzymes, and their interaction with other cellular components through time and across lineages and populations;
The evolution of metal regulatory gene-networks;
The evolutionary, micro-evolutionary, and population-specific effects of metal handling in all species of organisms, both under laboratory conditions and in the wild;
The epigenetic aspects and mechanisms of metal-handling strategies;
The effects of metal toxicity under an epigenetic perspective;
Evolutionary engineering and optimization in the laboratory or in the field of metal-handling proteins and of genes involved in metal metabolism;
Any other topic focusing, in an integrative manner, on the evolution and phylogeny of metal-handling mechanisms and metal metabolism in all kinds of organisms.

Prof. Dr. Reinhard Dallinger
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

molecular evolution
phylogeny
epigenetics
adaptation
gene networks
metal metabolism
metal toxicity
metal homeostasis
metallo-enzymes and metallo-proteins
evolutionary engineering

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Published Papers (10 papers)

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Research

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14 pages, 5412 KiB

Open AccessArticle

Effects of Cadmium Exposure on Gut Villi in Danio rerio

by Chiara Maria Motta, Emanuela Califano, Rosaria Scudiero, Bice Avallone, Chiara Fogliano, Salvatore De Bonis, Anja Raggio and Palma Simoniello

Int. J. Mol. Sci. 2022, 23(4), 1927; https://doi.org/10.3390/ijms23041927 - 9 Feb 2022

Cited by 8 | Viewed by 2559

Abstract

In aquatic organisms, cadmium exposure occurs from ovum to death and the route of absorption is particularly wide, being represented by skin, gills and gastrointestinal tract, through which contaminated water and/or preys are ingested. It is known that cadmium interferes with the gut; however, less information is available on cadmium effects on an important component of the gut, namely goblet cells, specialized in mucus synthesis. In the present work, we studied the effects of two sublethal cadmium concentrations on the gut mucosa of Danio rerio. Particular attention was paid to changes in the distribution of glycan residues, and in metallothionein expression in intestinal cells. The results show that cadmium interferes with gut mucosa and goblet cells features. The effects are dose- and site-dependent, the anterior gut being more markedly affected than the midgut. Cadmium modifies the presence and/or distribution of glycans in the brush border and cytoplasm of enterocytes and in the goblet cells’ cytoplasm and alters the metallothionein expression and localization. The results suggest a significant interference of cadmium with mucosal efficiency, representing a health risk for the organism in direct contact with contamination and indirectly for the trophic chain. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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15 pages, 1873 KiB

Open AccessArticle

Two Unconventional Metallothioneins in the Apple Snail Pomacea bridgesii Have Lost Their Metal Specificity during Adaptation to Freshwater Habitats

by Mario García-Risco, Sara Calatayud, Michael Niederwanger, Ricard Albalat, Òscar Palacios, Mercè Capdevila and Reinhard Dallinger

Int. J. Mol. Sci. 2021, 22(1), 95; https://doi.org/10.3390/ijms22010095 - 24 Dec 2020

Cited by 7 | Viewed by 2326

Abstract

Metallothioneins (MTs) are a diverse group of proteins responsible for the control of metal homeostasis and detoxification. To investigate the impact that environmental conditions might have had on the metal-binding abilities of these proteins, we have characterized the MTs from the apple snail Pomacea bridgesii, a gastropod species belonging to the class of Caenogastropoda with an amphibious lifestyle facing diverse situations of metal bioavailability. P. bridgesii has two structurally divergent MTs, named PbrMT1 and PbrMT2, that are longer than other gastropod MTs due to the presence of extra sequence motifs and metal-binding domains. We have characterized the Zn(II), Cd(II), and Cu(I) binding abilities of these two MTs after their heterologous expression in E. coli. Our results have revealed that despite their structural differences, both MTs share an unspecific metal-binding character, and a great ability to cope with elevated amounts of different metal ions. Our analyses have also revealed slight divergences in their metal-binding features: PbrMT1 shows a more pronounced Zn(II)-thionein character than PbrMT2, while the latter has a stronger Cu(I)-thionein character. The characterization of these two unconventional PbrMTs supports the loss of the metal-binding specificity during the evolution of the MTs of the Ampullariid family, and further suggests an evolutionary link of this loss with the adaptation of these gastropod lineages to metal-poor freshwater habitats. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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17 pages, 1489 KiB

Open AccessArticle

A “Population Dynamics” Perspective on the Delayed Life-History Effects of Environmental Contaminations: An Illustration with a Preliminary Study of Cadmium Transgenerational Effects over Three Generations in the Crustacean Gammarus

by Pauline Cribiu, Alain Devaux, Laura Garnero, Khédidja Abbaci, Thérèse Bastide, Nicolas Delorme, Hervé Quéau, Davide Degli Esposti, Jean-Luc Ravanat, Olivier Geffard, Sylvie Bony and Arnaud Chaumot

Int. J. Mol. Sci. 2020, 21(13), 4704; https://doi.org/10.3390/ijms21134704 - 1 Jul 2020

Cited by 10 | Viewed by 2641

Abstract

We explore the delayed consequences of parental exposure to environmentally relevant cadmium concentrations on the life-history traits throughout generations of the freshwater crustacean Gammarus fossarum. We report the preliminary results obtained during a challenging one-year laboratory experiment in this environmental species and propose the use of population modeling to interpret the changes in offspring life-history traits regarding their potential demographic impacts. The main outcome of this first long-term transgenerational assay is that the exposure of spawners during a single gametogenesis cycle (3 weeks) could result in severe cascading effects on the life-history traits along three unexposed offspring generations (one year). Indeed, we observed a decrease in F1 reproductive success, an early onset of F2 offspring puberty with reduced investment in egg yolk reserves, and finally a decrease in the growth rate of F3 juveniles. However, the analysis of these major transgenerational effects by means of a Lefkovitch matrix population model revealed only weak demographic impacts. Population compensatory processes mitigating the demographic consequences of parental exposure seem to drive the modification of life-history traits in offspring generations. This exploratory study sheds light on the role of population mechanisms involved in the demographic regulation of the delayed effects of environmental toxicity in wild populations. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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12 pages, 6679 KiB

Open AccessArticle

Cross-Reactivity of Palladium in a Murine Model of Metal-induced Allergic Contact Dermatitis

by Hiroaki Shigematsu, Kenichi Kumagai, Motoaki Suzuki, Takanori Eguchi, Ryota Matsubara, Yasunari Nakasone, Keisuke Nasu, Takamasa Yoshizawa, Haruno Ichikawa, Takahiro Mori, Yoshiki Hamada and Ryuji Suzuki

Int. J. Mol. Sci. 2020, 21(11), 4061; https://doi.org/10.3390/ijms21114061 - 5 Jun 2020

Cited by 6 | Viewed by 3929

Abstract

Metal allergy is usually diagnosed by patch testing, however, the results do not necessarily reflect the clinical symptoms because of cross-reactivity between different metals. In this study, we established the novel mouse model of cross-reactive metal allergy, and aimed to elucidate the immune response in terms of T-cell receptor repertoire. This model was classified into two groups: the sensitization to nickel and challenge with palladium group, and the sensitization to chromium and challenge with palladium group. This model developed spongiotic edema with intra- and peri-epithelial infiltration of CD4⁺ T cells in the inflamed skin that resembles human contact dermatitis. Using T cell receptor analysis, we detected a high proportion of T cells bearing Trav8d-1-Traj49 and Trav5-1-Traj37 in the Ni- and Cr-sensitized Pd-challenged mice. Furthermore, mucosal-associated invariant T cells and invariant natural killer T cells were also detected. Our results indicated that T cells bearing Trav8d-1-Traj49 and Trav5-1-Traj37 induced the development of palladium-cross reactive allergy, and that mucosal-associated invariant T and invariant natural killer T cells were also involved in the cross-reactivity between different metals. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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12 pages, 2016 KiB

Open AccessArticle

by Martina Höckner, Claudio Adriano Piechnik, Birgit Fiechtner, Birgit Weinberger and Lars Tomanek

Int. J. Mol. Sci. 2020, 21(2), 599; https://doi.org/10.3390/ijms21020599 - 17 Jan 2020

Cited by 9 | Viewed by 3393

Abstract

The heavy metal cadmium (Cd) is known to modulate the immune system, challenging soil-dwelling organisms where environmental Cd pollution is high. Since earthworms lack adaptive immunity, we determined Cd-related effects on coelomocytes, the cellular part of innate immunity, which is also the site of detoxification processes. A proteomics approach revealed a set of immunity-related proteins as well as gene products involved in energy metabolism changing in earthworms in response to Cd exposure. Based on these results, we conducted extracellular flux measurements of oxygen and acidification to reveal the effect of Cd on coelomocyte metabolism. We observed a significantly changing oxygen consumption rate, extracellular acidification, as well as metabolic potential, which can be defined as the response to an induced energy demand. Acute changes in intracellular calcium levels were also observed, indicating impaired coelomocyte activation. Lysosomes, the cell protein recycling center, and mitochondrial parameters did not change. Taken together, we were able to characterize coelomocyte metabolism to reveal a potential link to an impaired immune system upon Cd exposure. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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14 pages, 3478 KiB

Open AccessArticle

In Vivo Metabolic Response upon Exposure to Gold Nanorod Core/Silver Shell Nanostructures: Modulation of Inflammation and Upregulation of Dopamine

by Haiyun Li, Tao Wen, Tao Wang, Yinglu Ji, Yaoyi Shen, Jiaqi Chen, Haiyan Xu and Xiaochun Wu

Int. J. Mol. Sci. 2020, 21(2), 384; https://doi.org/10.3390/ijms21020384 - 8 Jan 2020

Cited by 9 | Viewed by 3753

Abstract

With the increasing applications of silver nanoparticles (Ag NPs), the concerns of widespread human exposure as well as subsequent health risks have been continuously growing. The acute and chronic toxicities of Ag NPs in cellular tests and animal tests have been widely investigated. Accumulating evidence shows that Ag NPs can induce inflammation, yet the overall mechanism is incomplete. Herein, using gold nanorod core/silver shell nanostructures (Au@Ag NRs) as a model system, we studied the influence on mice liver and lungs from the viewpoint of metabolism. In agreement with previous studies, Au@Ag NRs’ intravenous exposure caused inflammatory reaction, accompanying with metabolic alterations, including energy metabolism, membrane/choline metabolism, redox metabolism, and purine metabolism, the disturbances of which contribute to inflammation. At the same time, dopamine metabolism in liver was also changed. This is the first time to observe the production of dopamine in non-neural tissue after treatment with Ag NPs. As the upregulation of dopamine resists inflammation, it indicates the activation of antioxidant defense systems against oxidative stress induced by Au@Ag NRs. In the end, our findings deepened the understanding of molecular mechanisms of Ag NPs-induced inflammation and provide assistance in the rational design of their biomedical applications. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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14 pages, 2526 KiB

Open AccessArticle

Cadmium Pathways in Snails Follow a Complementary Strategy between Metallothionein Detoxification and Auxiliary Inactivation by Phytochelatins

by Martin Dvorak, Raimund Schnegg, Michael Niederwanger, Veronika Pedrini-Martha, Peter Ladurner, Herbert Lindner, Leopold Kremser, Reinhard Lackner and Reinhard Dallinger

Int. J. Mol. Sci. 2020, 21(1), 7; https://doi.org/10.3390/ijms21010007 - 18 Dec 2019

Cited by 10 | Viewed by 3740

Abstract

Metal detoxification is crucial for animals to cope with environmental exposure. In snails, a pivotal role in protection against cadmium (Cd) is attributed to metallothioneins (MTs). Some gastropod species express, in a lineage-specific manner, Cd-selective MTs devoted exclusively to the binding and detoxification of this single metal, whereas other species of snails possess non-selective MTs, but still show a high tolerance against Cd. An explanation for this may be that invertebrates and in particular snails may also synthetize phytochelatins (PCs), originally known to be produced by plants, to provide protection against metal or metalloid toxicity. Here we demonstrate that despite the fact that similar mechanisms for Cd inactivation exist in snail species through binding of the metal to MTs, the actual detoxification pathways for this metal may follow different traits in a species-specific manner. In particular, this depends on the detoxification capacity of MTs due to their Cd-selective or non-specific binding features. In the terrestrial slug Arion vulgaris, for example, Cd is solely detoxified by a Cd-selective MT isoform (AvMT1). In contrast, the freshwater snail Biomphalaria glabrata activates an additional pathway for metal inactivation by synthesizing phytochelatins, which compensate for the insufficient capacity of its non-selective MT system to detoxify Cd. We hypothesize that in other snails and invertebrate species, too, an alternative inactivation of the metal by PCs may occur, if their MT system is not Cd-selective enough, or its Cd loading capacity is exhausted. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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14 pages, 1705 KiB

Open AccessFeature PaperArticle

ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation

by Rebecca Lawson, Wolfgang Maret and Christer Hogstrand

Int. J. Mol. Sci. 2019, 20(21), 5485; https://doi.org/10.3390/ijms20215485 - 4 Nov 2019

Cited by 9 | Viewed by 4254

Abstract

The zinc transporter ZnT8 (SLC30A8) localises to insulin secretory granules of β-cells where it facilitates zinc uptake for insulin crystallisation. ZnT8 abundance has been linked to β-cell survival and functional phenotype. However, the consequences of ZnT8 haploinsufficiency for β-cell zinc trafficking and function remain unclear. Since investigations in human populations have shown SLC30A8 truncating polymorphisms to decrease the risk of developing Type 2 Diabetes, we hypothesised that ZnT8 haploinsufficiency would improve β-cell function and maintain the endocrine phenotype. We used CRISPR/Cas9 technology to generate ZnT8 haploinsufficient mouse MIN6 β-cells and showed that ZnT8 haploinsufficiency is associated with downregulation of mRNAs for Slc39a8 and Slc39a14, which encode for the zinc importers, Znt- and Irt-related proteins 8 (ZIP8) and 14 (ZIP14), and with lowered total cellular zinc content. ZnT8 haploinsufficiency disrupts expression of a distinct array of important β-cell markers, decreases cellular proliferation via mitogen-activated protein (MAP) kinase cascades and downregulates insulin gene expression. Thus, ZnT8 cooperates with zinc importers of the ZIP family to maintain β-cell zinc homeostasis. In contrast to the hypothesis, lowered ZnT8 expression reduces MIN6 cell survival by affecting zinc-dependent transcription factors that control the β-cell phenotype. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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13 pages, 2309 KiB

Open AccessArticle

Distribution of Gadolinium in Rat Heart Studied by Fast Field Cycling Relaxometry and Imaging SIMS

by Claudia Bonechi, Marco Consumi, Marco Matteucci, Gabriella Tamasi, Alessandro Donati, Gemma Leone, Luca Menichetti, Claudia Kusmic, Claudio Rossi and Agnese Magnani

Int. J. Mol. Sci. 2019, 20(6), 1339; https://doi.org/10.3390/ijms20061339 - 16 Mar 2019

Cited by 2 | Viewed by 2979

Abstract

Research on microcirculatory alterations in human heart disease is essential to understand the genesis of myocardial contractile dysfunction and its evolution towards heart failure. The use of contrast agents in magnetic resonance imaging is an important tool in medical diagnostics related to this dysfunction. Contrast agents significantly improve the imaging by enhancing the nuclear magnetic relaxation rates of water protons in the tissues where they are distributed. Gadolinium complexes are widely employed in clinical practice due to their high magnetic moment and relatively long electronic relaxation time. In this study, the behavior of gadolinium ion as a contrast agent was investigated by two complementary methods, relaxometry and secondary ion mass spectrometry. The study examined the distribution of blood flow within the microvascular network in ex vivo Langendorff isolated rat heart models, perfused with Omniscan^® contrast agent. The combined use of secondary ion mass spectrometry and relaxometry allowed for both a qualitative mapping of agent distribution as well as the quantification of gadolinium ion concentration and persistence. This combination of a chemical mapping and temporal analysis of the molar concentration of gadolinium ion in heart tissue allows for new insights on the biomolecular mechanisms underlying the microcirculatory alterations in heart disease. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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Review

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12 pages, 2938 KiB

Open AccessReview

Exposure to Dichlorodiphenyldichloroethylene (DDE) and Metallothionein Levels in Rats Fed with Normocaloric or High-Fat Diet: A Review

by Vincenzo Migliaccio, Lillà Lionetti, Rosalba Putti and Rosaria Scudiero

Int. J. Mol. Sci. 2020, 21(5), 1903; https://doi.org/10.3390/ijms21051903 - 10 Mar 2020

Cited by 14 | Viewed by 4120

Abstract

The growing number of studies on metallothioneins (MTs), cysteine-rich metal-binding proteins, have been disclosing new functions of these proteins. Thanks to their inducibility, they were considered to play a pivotal role in regulating trace metals homeostasis and in detoxification from heavy metals; nowadays, it is known that they are involved in various physiological and pathological processes, such as regulation of apoptosis, elimination of free radicals, and protection of nucleic acids against toxic insults. MT induction has been demonstrated following stress factors other than heavy metals, such as endocrine-disrupting chemicals, insecticides, and herbicides. However, retrieved data are often controversial: in some cases, xenobiotics elicit MT expression and synthesis; under different conditions, they lead to a decrease in cellular MT content. This review describes the MT response to dichlorodiphenyltrichloroethane (DDT) contamination in mammalian tissues. In particular, attention focuses on changes in MT expression, synthesis, and localization in rat liver, kidneys, and testes following oral administration of dichlorodiphenyldichloroethylene (DDE), the main metabolite of DDT, under normal dietary conditions or in combination with a high fat diet potentially able to increase the cellular uptake of this lipophilic pesticide. The potential connection between MT expression and synthesis, lipophilic substances and trace metals availability is also discussed. Full article

(This article belongs to the Special Issue Advances in Metal Metabolism Research)

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