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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 (20 October 2023) | Viewed by 19244

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Special Issue Editor

Prof. Dr. Kuenyuh Wu

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Guest Editor

1. Institute of Food Safety and Health, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
2. Department of Public Health, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
3. Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
Interests: biomarker; risk assessment; toxicology; metabolites
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Special Issue Information

Dear Colleagues,

With increases in the use of agricultural pesticides to continuously improve the quality and yields of crops, the general public can simultaneously be exposed to multiple pesticides through the inhalation of air and the consumption of food and water. The potential health effects have been of great concern. The assessment of co-exposures to multiple pesticides and corresponding health risks will require the integration of toxicological mechanisms of individual pesticides to establish their mode of action for cumulative assessment. Probabilistic cumulative exposure assessment through multiple media and routes can be performed to characterize the variability of exposures and associated risks for the study population. Sensitivity analysis can be simultaneously conducted to identify the significant parameters associated with exposures and risks. Results from these assessments will present the cumulative exposures to multiple pesticides and potential health risks in the daily life of the general public as well as the measures to reduce the exposures and risks.

Prof. Dr. Kuenyuh Wu
Guest Editor

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Keywords

multiple pesticides
cumulative assessment
probabilistic assessment
mechanisms of molecular toxicology

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Published Papers (9 papers)

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Research

17 pages, 3225 KiB

Open AccessArticle

Transcriptome Profiling of Etridiazole-Exposed Zebrafish (Danio rerio) Embryos Reveals Pathways Associated with Cardiac and Ocular Toxicities

by Bala Murali Krishna Vasamsetti, Kyongmi Chon, Chang-Young Yoon, Juyeong Kim, Ji-Yeong Choi, Sojeong Hwang and Kyeong-Hun Park

Int. J. Mol. Sci. 2023, 24(20), 15067; https://doi.org/10.3390/ijms242015067 - 11 Oct 2023

Cited by 5 | Viewed by 1466

Abstract

Etridiazole (EDZ) is a thiadiazole-containing fungicide commonly used to control Pythium and Phytophthora spp. Although previous studies have shown that EDZ is teratogenic, the exact molecular mechanisms underlying its toxicity remain unknown. In this study, a zebrafish (Danio rerio; ZF) model was used to explore the molecular pathways associated with EDZ toxicity. The whole transcriptome of ZF embryos exposed to 96 h of EDZ was analyzed, along with developmental abnormalities. EDZ-induced malformations were primarily related to the eyes, heart, and growth of the ZF. Compared to untreated ZF, etridiazole-treated ZF had 2882 differentially expressed genes (DEGs), consisting of 1651 downregulated genes and 1231 upregulated genes. Gene ontology enrichment analysis showed that DEGs were involved in biological processes, such as sensory perception, visual perception, sensory organ development, and visual system development, and showed transmembrane transporter and peptidase regulator activities. Metabolism, phototransduction, aminoacyl-tRNA biosynthesis, MAPK signaling pathway, calcium signaling pathway, and vascular smooth muscle contraction were among the most enriched KEGG pathways. The qPCR analyses of the eight random genes were in good agreement with the transcriptome data. These results suggest several putative mechanisms underlying EDZ-induced developmental deformities in ZF. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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19 pages, 4329 KiB

Open AccessArticle

The Protective Role of Oleuropein Aglycone against Pesticide-Induced Toxicity in a Human Keratinocytes Cell Model

by Manuela Leri, Marzia Vasarri, Emanuela Barletta, Nicola Schiavone, Maria Camilla Bergonzi, Monica Bucciantini and Donatella Degl’Innocenti

Int. J. Mol. Sci. 2023, 24(19), 14553; https://doi.org/10.3390/ijms241914553 - 26 Sep 2023

Cited by 1 | Viewed by 1375

Abstract

The extensive use of agricultural pesticides to improve crop quality and yield significantly increased the risk to the public of exposure to small but repeated doses of pesticides over time through various routes, including skin, by increasing the risk of disease outbreaks. Although much work was conducted to reduce the use of pesticides in agriculture, little attention was paid to prevention, which could reduce the toxicity of pesticide exposure by reducing its impact on human health. Extra virgin olive oil (EVOO), a major component of the Mediterranean diet, exerts numerous health-promoting properties, many of which are attributed to oleuropein aglycone (OleA), the deglycosylated form of oleuropein, which is the main polyphenolic component of EVOO. In this work, three pesticides with different physicochemical and biological properties, namely oxadiazon (OXA), imidacloprid (IMID), and glyphosate (GLYPHO), were compared in terms of metabolic activity, mitochondrial function and epigenetic modulation in an in vitro cellular model of human HaCaT keratinocytes to mimic the pathway of dermal exposure. The potential protective effect of OleA against pesticide-induced cellular toxicity was then evaluated in a cell pre-treatment condition. This study showed that sub-lethal doses of OXA and IMID reduced the metabolic activity and mitochondrial functionality of HaCaT cells by inducing oxidative stress and altering intracellular calcium flux and caused epigenetic modification by reducing histone acetylation H3 and H4. GLYPHO, on the other hand, showed no evidence of cellular toxicity at the doses tested. Pretreatment of cells with OleA was able to protect cells from the damaging effects of the pesticides OXA and IMID by maintaining metabolic activity and mitochondrial function at a controlled level and preventing acetylation reduction, particularly of histone H3. In conclusion, the bioactive properties of OleA reported here could be of great pharmaceutical and health interest, as they could be further studied to design new formulations for the prevention of toxicity from exposure to pesticide use. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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21 pages, 2675 KiB

Open AccessArticle

Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging

by Karin Grillberger, Eike Cöllen, Claudia Immacolata Trivisani, Jonathan Blum, Marcel Leist and Gerhard F. Ecker

Int. J. Mol. Sci. 2023, 24(17), 13170; https://doi.org/10.3390/ijms241713170 - 24 Aug 2023

Cited by 2 | Viewed by 1994

Abstract

Neonicotinoid pesticides were initially designed in order to achieve species selectivity on insect nicotinic acetylcholine receptors (nAChRs). However, concerns arose when agonistic effects were also detected in human cells expressing nAChRs. In the context of next-generation risk assessments (NGRAs), new approach methods (NAMs) should replace animal testing where appropriate. Herein, we present a combination of in silico and in vitro methodologies that are used to investigate the potentially toxic effects of neonicotinoids and nicotinoid metabolites on human neurons. First, an ensemble docking study was conducted on the nAChR isoforms α7 and α3β4 to assess potential crucial molecular initiating event (MIE) interactions. Representative docking poses were further refined using molecular dynamics (MD) simulations and binding energy calculations using implicit solvent models. Finally, calcium imaging on LUHMES neurons confirmed a key event (KE) downstream of the MIE. This method was also used to confirm the predicted agonistic effect of the metabolite descyano-thiacloprid (DCNT). Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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14 pages, 1845 KiB

Open AccessArticle

Single and Combined Effects of Chlorpyrifos and Glyphosate on the Brain of Common Carp: Based on Biochemical and Molecular Perspective

by Dongfang Zhang, Weikai Ding, Wei Liu, Liuying Li, Gongming Zhu and Junguo Ma

Int. J. Mol. Sci. 2023, 24(16), 12934; https://doi.org/10.3390/ijms241612934 - 18 Aug 2023

Cited by 4 | Viewed by 1588

Abstract

Chlorpyrifos (CPF) and glyphosate (GLY) are the most widely used organophosphate insecticide and herbicide worldwide, respectively; co-occurrence of CPF and GLY in aquatic environments occurs where they inevitably have potential hazards to fish. However, the potential mechanisms of CPF and GLY to induce toxicity have not been fully explored. To identify the adverse impacts of CPF and GLY on fish, either alone or in combination (MIX), CPF (25 μg/L) and GLY (3.5 mg/L) were set up according to an environmentally relevant concentration to expose to common carp for 21 days. After exposure, CPF and GLY decreased the activities of acetylcholinesterase and Na⁺/K⁺-ATPase, altered monoamine oxidase levels, decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione S-transferase and glutamic reductase), and induced the accumulation of malondialdehyde in the carp brain. The parameters in the MIX groups had a greater impact compared to that in the CPF or GLY group, suggesting that both single and combined exposure could affect neurological signaling systems and cause oxidative stress and lipid peroxidation damage in carp brains, and that MIX exposure increases the impact of each pollutant. RNA-seq results showed that single or combined exposure to CPF and GLY induced global transcriptomic changes in fish brains, and the number of differentially expressed genes in MIX-treated carp brains were globally increased compared to either the CPF or GLY groups, suggesting that the effects of co-exposure were greater than single exposure. Further analysis results revealed that the global transcriptomic changes participated in oxidative stress, immune dysfunction, and apoptosis of fish brains, and identified that the P13k-Akt signaling pathway participates in both single and combined exposure of CPF- and GLY-induced toxicity. Taken together, our results demonstrated that the interaction of CPF and GLY might be synergic and provided novel insights into the molecular mechanisms of fish brains coping with CPF and GLY. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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24 pages, 6011 KiB

Open AccessArticle

Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro

by María del Pilar Navarrete-Meneses, Consuelo Salas-Labadía, María del Rocío Juárez-Velázquez, Dafné Moreno-Lorenzana, Fernando Gómez-Chávez, Alberto Olaya-Vargas and Patricia Pérez-Vera

Int. J. Mol. Sci. 2023, 24(7), 6259; https://doi.org/10.3390/ijms24076259 - 26 Mar 2023

Cited by 2 | Viewed by 3109

Abstract

The evidence supporting the biological plausibility of the association of permethrin and malathion with hematological cancer is limited and contradictory; thus, further studies are needed. This study aimed to investigate whether in vitro exposure to 0.1 μM permethrin and malathion at 0, 24, 48 and 72 h after cell culture initiation induced changes in the gene expression and DNA methylation in mononuclear cells from bone marrow and peripheral blood (BMMCs, PBMCs). Both pesticides induced several gene expression modifications in both tissues. Through gene ontology analysis, we found that permethrin deregulates ion channels in PBMCs and BMMCs and that malathion alters genes coding proteins with nucleic acid binding capacity, which was also observed in PBMCs exposed to permethrin. Additionally, we found that both insecticides deregulate genes coding proteins with chemotaxis functions, ion channels, and cytokines. Several genes deregulated in this study are potentially associated with cancer onset and development, and some of them have been reported to be deregulated in hematological cancer. We found that permethrin does not induce DNA hypermethylation but can induce hypomethylation, and that malathion generated both types of events. Our results suggest that these pesticides have the potential to modify gene expression through changes in promoter DNA methylation and potentially through other mechanisms that should be investigated. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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17 pages, 3133 KiB

Open AccessArticle

Ternary Mixture of Azoxystrobin, Boscalid and Pyraclostrobin Disrupts the Gut Microbiota and Metabolic Balance of Honeybees (Apis cerana cerana)

by Jie Dong, Minjie Huang, Haikun Guo, Jiawen Zhang, Xiaodong Tan and Deqian Wang

Int. J. Mol. Sci. 2023, 24(6), 5354; https://doi.org/10.3390/ijms24065354 - 10 Mar 2023

Cited by 6 | Viewed by 2037

Abstract

There is a growing risk of pollinators being exposed to multiple fungicides due to the widespread use of fungicides for plant protection. A safety assessment of honeybees exposed to multiple commonly used fungicides is urgently required. Therefore, the acute oral toxicity of the ternary mixed fungicide of ABP (azoxystrobin: boscalid: pyraclostrobin = 1:1:1, m/m/m) was tested on honeybees (Apis cerana cerana), and its sublethal effect on foragers’ guts was evaluated. The results showed that the acute oral median lethal concentration (LD₅₀) of ABP for foragers was 12.6 μg a.i./bee. ABP caused disorder of the morphological structure of midgut tissue and affected the intestinal metabolism; the composition and structure of the intestinal microbial community was perturbed, which altered its function. Moreover, the transcripts of genes involved in detoxification and immunity were strongly upregulated with ABP treatment. The study implies that exposure to a fungicide mixture of ABP can cause a series of negative effects on the health of foragers. This work provides a comprehensive understanding of the comprehensive effects of common fungicides on non-target pollinators in the context of ecological risk assessment and the future use of fungicides in agriculture. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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12 pages, 1557 KiB

Open AccessArticle

Baseline Susceptibility, Cross-Resistance, and Sublethal Effects of Broflanilide, a Novel Meta-Diamide Pesticide, in Spodoptera litura

by Yunyi Li, Cheng Qu, Qinghe Zhang, Liping Zhang, Chen Luo and Ran Wang

Int. J. Mol. Sci. 2023, 24(6), 5351; https://doi.org/10.3390/ijms24065351 - 10 Mar 2023

Cited by 8 | Viewed by 2417

Abstract

Spodoptera litura is a damaging and notorious insect pest of agricultural crops that has developed resistance to various insecticides. Broflanilide is a novel pesticide with a unique mode of action that displays high efficiency against lepidopterous larvae. We here determined the baseline susceptibility of a laboratory strain of S. litura to broflanilide and 10 other popular insecticides. Furthermore, we measured susceptibility and cross-resistance using three common insecticides in 11 field-collected S. litura populations. Broflanilide caused the highest toxicity among all tested insecticides, with the laboratory strain and all field-collected populations showing high susceptibility. Moreover, no cross-resistance was detected between broflanilide and the other tested insecticides. We subsequently evaluated the sublethal effects of broflanilide and found that treatment with the 25% lethal concentration (LC₂₅) prolonged the development duration in the larvae, reduced the pupation rate and pupae weight, and decreased egg hatchability. Finally, the activities of three detoxifying enzymes were measured in S. litura after treatment with the LC₂₅ dose. The results suggested that enhanced cytochrome P450 monooxygenase (P450) activity could be involved in broflanilide detoxification. Overall, these findings demonstrate the strong toxicity and significant sublethal effects of broflanilide in S. litura and suggest that increased P450 activity may be associated with broflanilide detoxification. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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9 pages, 1704 KiB

Open AccessArticle

Assessment of Genetic Damage Induced via Glyphosate and Three Commercial Formulations with Adjuvants in Human Blood Cells

by Carlos Alvarez-Moya and Mónica Reynoso-Silva

Int. J. Mol. Sci. 2023, 24(5), 4560; https://doi.org/10.3390/ijms24054560 - 25 Feb 2023

Cited by 2 | Viewed by 1780

Abstract

There is considerable controversy regarding the genotoxicity of glyphosate (N-(phosphonomethyl) glycine). It has been suggested that the genotoxicity of this herbicide is increased by the adjuvants added to commercial formulations based on glyphosate. The effect of various concentrations of glyphosate and three commercial glyphosate-based herbicides (GBH) on human lymphocytes was evaluated. Human blood cells were exposed to glyphosates of 0.1, 1, 10 and 50 mM as well as to equivalent concentrations of glyphosate on commercial formulations. Genetic damage (p < 0.05) was observed in all concentrations with glyphosate and with FAENA and TACKLE formulations. These two commercial formulations showed genotoxicity that was concentration-dependent but in a higher proportion compared to pure glyphosate only. Higher glyphosate concentrations increased the frequency and range of tail lengths of some migration groups, and the same was observed for FAENA and TACKLE, while in CENTELLA the migration range decreased but the frequency of migration groups increased. We show that pure glyphosate and commercial GBH (FAENA, TACKLE and CENTELLA) gave signals of genotoxicity in human blood samples in the comet assay. The genotoxicity increased in the formulations, indicating genotoxic activity also in the added adjuvants present in these products. The use of the MG parameter allowed us to detect a certain type of genetic damage associated with different formulations. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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13 pages, 1634 KiB

Open AccessArticle

Imidacloprid Impairs Glutamatergic Synaptic Plasticity and Desensitizes Mechanosensitive, Nociceptive, and Photogenic Response of Drosophila melanogaster by Mediating Oxidative Stress, Which Could Be Rescued by Osthole

by Chuan-Hsiu Liu, Mei-Ying Chen, Jack Cheng, Tsai-Ni Chuang, Hsin-Ping Liu and Wei-Yong Lin

Int. J. Mol. Sci. 2022, 23(17), 10181; https://doi.org/10.3390/ijms231710181 - 5 Sep 2022

Cited by 1 | Viewed by 2031

Abstract

Background: Imidacloprid (IMD) is a widely used neonicotinoid-targeting insect nicotine acetylcholine receptors (nAChRs). However, off-target effects raise environmental concerns, including the IMD’s impairment of the memory of honeybees and rodents. Although the down-regulation of inotropic glutamate receptor (iGluR) was proposed as the cause, whether IMD directly manipulates the activation or inhibition of iGluR is unknown. Using electrophysiological recording on fruit fly neuromuscular junction (NMJ), we found that IMD of 0.125 and 12.5 mg/L did not activate glutamate receptors nor inhibit the glutamate-triggered depolarization of the glutamatergic synapse. However, chronic IMD treatment attenuated short-term facilitation (STF) of NMJ by more than 20%. Moreover, by behavioral assays, we found that IMD desensitized the fruit flies’ response to mechanosensitive, nociceptive, and photogenic stimuli. Finally, the treatment of the antioxidant osthole rescued the chronic IMD-induced phenotypes. We clarified that IMD is neither agonist nor antagonist of glutamate receptors, but chronic treatment with environmental-relevant concentrations impairs glutamatergic plasticity of the NMJ of fruit flies and interferes with the sensory response by mediating oxidative stress. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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