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Molecular and Morphological Research on the Toxicity of Pollutants

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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: closed (31 August 2022) | Viewed by 30816

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Prof. Dr. Elvira Brunelli

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Department of Biology, Ecology and Earth Science, University of Calabria, 87036 Rende, Italy
Interests: diseases in animals especially in vertebrates; organic and inorganic pollutants; reproduction and development; innovative methods for eco-toxicology; in vivo models; use and development of molecular and morpho-functional approaches in toxicological studies; respiratory organs, their diseases and early stage of development and alterations
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Dear Colleagues,

The widespread use of chemicals for industrial, domestic, and agricultural purposes leads to a large discharge into different environmental compartments. Nowadays, pollution is an ecological issue of great concern.

Morpho-functional analysis and molecular biochemical approaches are commonly used to study the toxic effects and mechanisms of environmental pollutants, and they provide a valuable tool for quickly assessing the health of organisms. Linking the organismal dysfunction with the presence of pollutants should be based on sound scientific evidence.

The special issue focuses on molecular and morphological research on the ecotoxicity of pollutants. We seek manuscripts (e.g., reviews, original research articles) that found evidence of a link between the morphological and functional response of the organism to environmental disturbance.

Dr. Elvira Brunelli
Guest Editor

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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.

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Keywords

pollutants
ecotoxicity
organismal dysfunction
functional response
toxicity effect
toxicity mechanism

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Published Papers (10 papers)

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10 pages, 1148 KiB

Open AccessArticle

Metallothionein Expression as a Physiological Response against Metal Toxicity in the Striped Rockcod Trematomus hansoni

by Rigers Bakiu, Sara Pacchini, Elisabetta Piva, Sophia Schumann, Anna Maria Tolomeo, Diana Ferro, Paola Irato and Gianfranco Santovito

Int. J. Mol. Sci. 2022, 23(21), 12799; https://doi.org/10.3390/ijms232112799 - 24 Oct 2022

Cited by 17 | Viewed by 1874

Abstract

Metal bioaccumulation and metallothionein (MT) expression were investigated in the gills and liver of the red-blooded Antarctic teleost Trematomus hansoni to evaluate the possibility for this species to face, with adequate physiological responses, an increase of copper and cadmium concentrations in its tissues. Specimens of this Antarctic fish were collected from Terra Nova Bay (Ross Sea) and used for a metal exposure experiment in controlled laboratory conditions. The two treatments led to a significant accumulation of both metals and increased gene transcription only for the MT-1. The biosynthesis of MTs was verified especially in specimens exposed to Cd, but most of these proteins were soon oxidized, probably because they were involved in cell protection against oxidative stress risk by scavenging reactive oxygen species. The obtained data highlighted the phenotypic plasticity of T. hansoni, a species that evolved in an environment characterized by naturally high concentrations of Cu and Cd, and maybe the possibility for the Antarctic fish to face the challenges of a world that is becoming more toxic every day. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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16 pages, 3168 KiB

Open AccessArticle

Cadmium–Zinc Interaction in Mus musculus Fibroblasts

by Ettore Priante, Edoardo Pietropoli, Elisabetta Piva, Gianfranco Santovito, Sophia Schumann and Paola Irato

Int. J. Mol. Sci. 2022, 23(19), 12001; https://doi.org/10.3390/ijms231912001 - 9 Oct 2022

Cited by 2 | Viewed by 1468

Abstract

This work aimed to evaluate the effects of zinc (Zn) relating to cadmium (Cd)-induced toxicity and the role played by MTF-1. This transcription factor regulates the expression of genes encoding metallothioneins (MTs), some Zn transporters and the heavy chain of γ-glutamylcysteine synthetase. For this reason, two cell lines of mouse fibroblasts were used: a wild-type strain and a knockout strain to study the effects. Cells were exposed to complete medium containing: (1) 50 μM ZnSO₄ (Zn), (2) 1 μM CdCl₂ (Cd 1), (3) 2 μM CdCl₂ (Cd 2), (4) 50 μM ZnSO₄ + 1 μM CdCl₂ (ZnCd 1) and (5) 50 μM ZnSO₄ + 2 μM CdCl₂ (ZnCd 2) for 4, 18 and 24 h. Following exposure, cell viability, the intracellular content of metals, glutathione (GSH) and MT and the gene expression of the two isoforms of MT was evaluated. The results obtained suggest that a lower Cd content in the co-treatments is responsible for the protection offered by Zn due to the probable competition for a common transporter. Furthermore, Zn determines an increase in GSH in co-treatments compared to treatments with Cd alone. Finally, the MTF-1 factor is essential for the expression of MT-1 but not of MT-2 nor probably for the heavy chain of γ-glutamylcysteine synthetase. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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15 pages, 2116 KiB

Open AccessArticle

Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A

by Vidhya A Nair, Lara J Bou Malhab and Wael M. Abdel-Rahman

Int. J. Mol. Sci. 2022, 23(19), 11620; https://doi.org/10.3390/ijms231911620 - 1 Oct 2022

Cited by 3 | Viewed by 2595

Abstract

Colorectal cancer is a common cancer with a poor prognosis in both males and females. The influence of bisphenol A (BPA), a widely used environmental contaminant, in colon cancer development and progression is not well identified, in spite of the fact that the most common mode of exposure to BPA is ingestion. The aim of this work is to elucidate the carcinogenic effects of BPA in the colon in vitro. We analyzed BPA’s effects on human colon epithelial (HCoEpiC) and colon cancer (HCT116) cells. BPA exerted cytotoxic effects and augmented the 5FU cytotoxicity on both cell lines at high doses, while it did not show this effect at low doses. Therefore, we focused on studying the effects of low-dose (0.0043 nM) exposure on normal colonic epithelial cells for a long period of time (two months), which is more consistent with environmental exposure levels and patterns. BPA increased cellular invasiveness through collagen and the ability to anchorage-independent cell growth, as measured by colony formation in soft agar, which could support oncogenicity. To gain insights into the mechanism of these actions, we performed transcriptomic analysis using next-generation sequencing, which revealed 340 differentially expressed transcripts by BPA in HCT116 and 75 in HCoEpiC. These transcripts belong in many cancer-related pathways such as apoptosis, cell proliferation, signal transduction, and angiogenesis. Some of the significant genes (FAM83H, CXCL12, PITPNA, HMOX1, DGKZ, NR5A2, VMP1, and ID1) were confirmed by quantitative RT-PCR. Furthermore, BPA induced the phosphorylation of protein kinases such as JNK1/2/3, GSK-3α/β, AMPKα1, AKT1/2/3, AMPKα2, HSP27, β-catenin, STAT2, Hck, Chk2, FAK, and PRAS40 in HCoEpiC, as well as GSK-3α/β, p53, AKT1/2/3, p70 S6 kinase, and WNK1 in HCT116. The majority of these proteins are involved in potential carcinogenic pathways. Taken together, these data suggest that BPA plays a role in colon carcinogenesis, and they provide insights into the molecular mechanisms of colon epithelial cell transformation by BPA. Increasing exposure to environmental toxins such as BPA can explain the increasing incidence of colorectal cancer. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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18 pages, 4541 KiB

Open AccessArticle

Wnt/β-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging

by Yanyi Xu, Junru Liu, Yonghui Tian, Zuo Wang, Zan Song, Kemin Li, Shengxiang Zhang and Haiyu Zhao

Int. J. Mol. Sci. 2022, 23(19), 11434; https://doi.org/10.3390/ijms231911434 - 28 Sep 2022

Cited by 12 | Viewed by 2490

Abstract

Cadmium (Cd) is a toxic heavy metal and worldwide environmental pollutant which seriously threatens human health and ecosystems. It is easy to be adsorbed and deposited in organisms, exerting adverse effects on various organs including the brain. In a very recent study, making full use of a zebrafish model in both high-throughput behavioral tracking and live neuroimaging, we explored the potential developmental neurotoxicity of Cd²⁺ at environmentally relevant levels and identified multiple connections between Cd²⁺ exposure and neurodevelopmental disorders as well as microglia-mediated neuroinflammation, whereas the underlying neurotoxic mechanisms remained unclear. The canonical Wnt/β-catenin signaling pathway plays crucial roles in many biological processes including neurodevelopment, cell survival, and cell cycle regulation, as well as microglial activation, thereby potentially presenting one of the key targets of Cd²⁺ neurotoxicity. Therefore, in this follow-up study, we investigated the implication of the Wnt/β-catenin signaling pathway in Cd²⁺-induced developmental disorders and neuroinflammation and revealed that environmental Cd²⁺ exposure significantly affected the expression of key factors in the zebrafish Wnt/β-catenin signaling pathway. In addition, pharmacological intervention of this pathway via TWS119, which can increase the protein level of β-catenin and act as a classical activator of the Wnt signaling pathway, could significantly repress the Cd²⁺-induced cell cycle arrest and apoptosis, thereby attenuating the inhibitory effects of Cd²⁺ on the early development, behavior, and activity, as well as neurodevelopment of zebrafish larvae to a certain degree. Furthermore, activation and proliferation of microglia, as well as the altered expression profiles of genes associated with neuroimmune homeostasis triggered by Cd²⁺ exposure could also be significantly alleviated by the activation of the Wnt/β-catenin signaling pathway. Thus, this study provided novel insights into the cellular and molecular mechanisms of Cd²⁺ toxicity on the vertebrate central nervous system (CNS), which might be helpful in developing pharmacotherapies to mitigate the neurological disorders resulting from exposure to Cd²⁺ and many other environmental heavy metals. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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19 pages, 5700 KiB

Open AccessArticle

Chronic Exposure to Vinclozolin Induced Fibrosis, Mitochondrial Dysfunction, Oxidative Stress, and Apoptosis in Mice Kidney

by Davide Di Paola, Ramona D’Amico, Tiziana Genovese, Rosalba Siracusa, Marika Cordaro, Rosalia Crupi, Alessio Filippo Peritore, Enrico Gugliandolo, Livia Interdonato, Daniela Impellizzeri, Roberta Fusco, Salvatore Cuzzocrea and Rosanna Di Paola

Int. J. Mol. Sci. 2022, 23(19), 11296; https://doi.org/10.3390/ijms231911296 - 25 Sep 2022

Cited by 9 | Viewed by 2263

Abstract

Vinclozolin is one of the most used fungicides in the control of fungi in fruits, vegetables, and ornamental plants. The effects of its exposure on different organs have been described, but information regarding its relevance to vinclozolin-induced nephrotoxicity is largely missing. This study focuses on the potential mechanism of vinclozolin-induced nephrotoxicity. CD1 male mice were administered vinclozolin (100 mg/kg) by oral gavage for 28 days. Vinclozolin administration decreased body weight over the treatment period and at the end of the experiment, increased the ratio of kidney weight to body weight and increased serum urea nitrogen and creatinine contents. Vinclozolin also induced histopathological alterations, including tubular dilatation and necrosis and impaired the integrity of the renal-tubular architecture and kidney fibrosis. The analyses conducted showed that vinclozolin administration altered the mRNA levels of mitochondrial function-related proteins (SIRT3, SIRT1, PGC-1α, TFAM, NRF1, VDAC-1, and Cyt c) and oxidative stress (increased lipid peroxidation and decreased total antioxidative capacity, catalase, and superoxide dismutase activities, glutathione levels, and glutathione peroxidase activity) in the kidneys. Furthermore, vinclozolin induced toxicity that altered Nrf2 signalling and the related proteins (HO-1 and NQO-1). Vinclozolin administration also affected both the extrinsic and intrinsic apoptotic pathways, upregulating the expression of proapoptotic factors (Bax, Caspase 3, and FasL) and downregulating antiapoptotic factor (Bcl-2) levels. This study suggests that vinclozolin induced nephrotoxicity by disrupting the transcription of mitochondrial function-related factors, the Nrf2 signalling pathway, and the extrinsic and intrinsic apoptotic pathways. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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17 pages, 3402 KiB

Open AccessArticle

Morphological and Functional Alterations Induced by Two Ecologically Relevant Concentrations of Lead on Danio rerio Gills

by Vittoria Curcio, Rachele Macirella, Settimio Sesti, Abdalmoiz I. M. Ahmed, Federica Talarico, Antonio Tagarelli, Marcello Mezzasalma and Elvira Brunelli

Int. J. Mol. Sci. 2022, 23(16), 9165; https://doi.org/10.3390/ijms23169165 - 15 Aug 2022

Cited by 9 | Viewed by 1795

Abstract

Lead (Pb), due to its high toxicity and bioaccumulation tendency, is one of the top three pollutants of concern for both humans and wildlife and occupies second place in the Priority List of Hazardous Substances. In freshwater fish, Pb is mainly absorbed through the gills, where the greatest accumulation occurs. Despite the crucial role of gills in several physiological functions such as gas exchange, water balance, and osmoregulation, no studies evaluated the effects of environmentally relevant concentrations of Pb on this organ, and existing literature only refers to high levels of exposure. Herein we investigated for the first time the molecular and morphological effects induced by two low and environmentally relevant concentrations of Pb (2.5 and 5 μg/L) on the gills of Danio rerio, a model species with a high translational value for human toxicity. It was demonstrated that Pb administration at even low doses induces osmoregulatory dysfunctions by affecting Na⁺/K⁺-ATPase and AQP3 expression. It was also shown that Pb upregulates MTs as a protective response to prevent cell damage. Modulation of SOD confirms that the production of reactive oxygen species is an important toxicity mechanism of Pb. Histological and morphometric analysis revealed conspicuous pathological changes, both dose- and time-dependent. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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17 pages, 2241 KiB

Open AccessArticle

Effects of Human Activity on Markers of Oxidative Stress in the Intestine of Holothuria tubulosa, with Special Reference to the Presence of Microplastics

by Jessica Lombardo, Antònia Solomando, Amanda Cohen-Sánchez, Samuel Pinya, Silvia Tejada, Pere Ferriol, Guillem Mateu-Vicens, Antonio Box, Caterina Faggio and Antoni Sureda

Int. J. Mol. Sci. 2022, 23(16), 9018; https://doi.org/10.3390/ijms23169018 - 12 Aug 2022

Cited by 26 | Viewed by 2907

Abstract

Pollution in the seas and oceans is a global problem, which highlights emerging pollutants and plastics, specifically microplastics (MPs), which are tiny (1 μm to 5 mm) ubiquitous plastic particles present in marine environments that can be ingested by a wide range of organisms. Holothurians are benthic organisms that feed on sediment; therefore, they can be exposed to contaminants present in the particles they ingest. The objective was to evaluate the effects of human activity on Holothuria tubulosa through the study of biomarkers. Specimens were collected in three different areas throughout the island of Eivissa, Spain: (1) a highly urbanized area, with tourist uses and a marina; (2) an urbanized area close to the mouth of a torrent; (3) an area devoid of human activity and considered clean. The results showed a higher presence of microplastics (MPs) in the sediments from the highly urbanized area in relation to the other two areas studied. Similarly, a higher number of MPs were observed in the digestive tract of H. tubulosa from the most affected area, decreasing with the degree of anthropic influence. Both in the sediment and in the holothurians, fibers predominated with more than 75% of the items. In the three areas, mesoplastics were analyzed by means of FTIR, showing that the main polymer was polypropylene (27%) followed by low-density polyethylene (17%) and polystyrene (16%). Regarding the biomarkers of oxidative stress, the intestine of H. tubulosa from the most impacted areas showed higher catalase, superoxide dismutase (SOD), glutathione reductase (GRd), and glutathione S-transferase (GST) activities and reduced glutathione (GSH) levels compared to the control area. The intermediate area only presented significant differences in GRd and GST with respect to the clean area. The activities of acetylcholinesterase and the levels and malondialdehyde presented similar values in all areas. In conclusion, human activity evaluated with the presence of MPs induced an antioxidant response in H. tubulosa, although without evidence of oxidative damage or neurotoxicity. H. tubulosa, due to its benthic animal characteristics and easy handling, can be a useful species for monitoring purposes. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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16 pages, 2649 KiB

Open AccessArticle

Metabolomic and Transcript Analysis Revealed a Sex-Specific Effect of Glyphosate in Zebrafish Liver

by Christian Giommi, Claudia Ladisa, Oliana Carnevali, Francesca Maradonna and Hamid R. Habibi

Int. J. Mol. Sci. 2022, 23(5), 2724; https://doi.org/10.3390/ijms23052724 - 1 Mar 2022

Cited by 19 | Viewed by 2940

Abstract

Glyphosate is a component of commonly used herbicides for controlling weeds in crops, gardens and municipal parks. There is increasing awareness that glyphosate-based herbicides, in addition to acting on plants, may also exert toxicity in wildlife and humans. In this study, male and female adult zebrafish were exposed to 700 µg/L of glyphosate (GLY), for 28 days. We used the metabolomic approach and UHPLC-ESI-MS to analyze liver samples to investigate the adverse effects of glyphosate on hepatic metabolism. The impact of GLY was found to be sex-specific. In female, GLY exposure affected purine metabolism by decreasing the levels of AMP, GMP and inosinic acid, consequently increasing uric acid levels with respect to the control (CTRL). Exposure to GLY also caused a decrease of UMP levels in the pyrimidine metabolism pathway. In male, GLY exposure decreased the aminoadipic acid within the lysine degradation pathway. Transcript analysis of genes involved in stress response, oxidative stress and the immune system were also performed. Results demonstrated an increased stress response in both sexes, as suggested by higher nr3c1 expression. However, the hsp70.2 transcript level was increased in female but decreased in male. The results demonstrated reduced sod1, sod2, and gpx1a in male following exposure to GLY, indicating an impaired oxidative stress response. At the same time, an increase in the cat transcript level in female was observed. mRNA levels of the pro-inflammatory interleukins litaf and cxcl8b.1 were increased in female. Taken together, the results provide evidence of disrupted nucleotide hepatic metabolism, increased stress inflammatory response in female and disruption of oxidative stress response in male. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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17 pages, 2034 KiB

Open AccessCommunication

Proteome Analysis of Whole-Body Responses in Medaka Experimentally Exposed to Fish-Killing Dinoflagellate Karenia mikimotoi

by Celia Sze-Nga Kwok, Kaze King-Yip Lai, Winnie Lam, Steven Jing-Liang Xu, Sai-Wo Lam and Fred Wang-Fat Lee

Int. J. Mol. Sci. 2021, 22(21), 11625; https://doi.org/10.3390/ijms222111625 - 27 Oct 2021

Cited by 3 | Viewed by 2269

Abstract

Karenia mikimotoi is a well-known harmful algal bloom species. Blooms of this dinoflagellate have become a serious threat to marine life, including fish, shellfish, and zooplanktons and are usually associated with massive fish death. Despite the discovery of several toxins such as gymnocins and gymnodimines in K. mikimotoi, the mechanisms underlying the ichthyotoxicity of this species remain unclear, and molecular studies on this topic have never been reported. The present study investigates the fish-killing mechanisms of K. mikimotoi through comparative proteomic analysis. Marine medaka, a model fish organism, was exposed to K. mikimotoi for a three-part time period (LT₂₅, LT₅₀ and LT₉₀). Proteins extracted from the whole fish were separated by using two-dimensional gel electrophoresis, and differentially expressed proteins were identified with reference to an untreated control. The change in fish proteomes over the time-course of exposure were analyzed. A total of 35 differential protein spots covering 19 different proteins were identified, of which most began to show significant change in expression levels at the earliest stage of intoxication. Among the 19 identified proteins, some are closely related to the oxidative stress responses, energy metabolism, and muscle contraction. We propose that oxidative stress-mediated muscle damage might explain the symptoms developed during the ichthyotoxicity test, such as gasping for breath, loss of balance, and body twitching. Our findings lay the foundations for more in-depth studies of the mechanisms of K. mikimotoi’s ichthyotoxicity. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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Review

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19 pages, 1237 KiB

Open AccessReview

A Review of Toxicity Mechanism Studies of Electronic Cigarettes on Respiratory System

by Lilan Wang, Yao Wang, Jianwen Chen, Peiqing Liu and Min Li

Int. J. Mol. Sci. 2022, 23(9), 5030; https://doi.org/10.3390/ijms23095030 - 1 May 2022

Cited by 24 | Viewed by 9190

Abstract

Electronic cigarettes (e-cigarettes) have attracted much attention as a new substitute for conventional cigarettes. E-cigarettes are first exposed to the respiratory system after inhalation, and studies on the toxicity mechanisms of e-cigarettes have been reported. Current research shows that e-cigarette exposure may have potentially harmful effects on cells, animals, and humans, while the safety evaluation of the long-term effects of e-cigarette use is still unknown. Similar but not identical to conventional cigarettes, the toxicity mechanisms of e-cigarettes are mainly manifested in oxidative stress, inflammatory responses, and DNA damage. This review will summarize the toxicity mechanisms and signal pathways of conventional cigarettes and e-cigarettes concerning the respiratory system, which could give researchers a better understanding and direction on the effects of e-cigarettes on our health. Full article

(This article belongs to the Special Issue Molecular and Morphological Research on the Toxicity of Pollutants)

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