International Journal of Molecular Sciences

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16 pages, 2634 KiB

Open AccessArticle

A New Bioassay for the Detection of Paralytic and Amnesic Biotoxins Based on Motor Behavior Impairments of Zebrafish Larvae

by Javiera F. De la Paz, Nicolás O. Zambrano, Fernando C. Ortiz and Alejandra Llanos-Rivera

Int. J. Mol. Sci. 2023, 24(8), 7466; https://doi.org/10.3390/ijms24087466 - 18 Apr 2023

Cited by 1 | Viewed by 1270

Abstract

The global concern about the increase of harmful algal bloom events and the possible impacts on food safety and aquatic ecosystems presents the necessity for the development of more accessible techniques for biotoxin detection for screening purposes. Considering the numerous advantages that zebrafish [...] Read more.

The global concern about the increase of harmful algal bloom events and the possible impacts on food safety and aquatic ecosystems presents the necessity for the development of more accessible techniques for biotoxin detection for screening purposes. Considering the numerous advantages that zebrafish present as a biological model and particularly as a toxicants sentinel, we designed a sensitive and accessible test to determine the activity of paralytic and amnesic biotoxins using zebrafish larvae immersion. The ZebraBioTox bioassay is based on the automated recording of larval locomotor activity using an IR microbeam locomotion detector, and manual assessment of four complementary responses under a simple stereoscope: survival, periocular edema, body balance, and touch response. This 24 h acute static bioassay was set up in 96-well microplates using 5 dpf zebrafish larvae. For paralytic toxins, a significant decrease in locomotor activity and touch response of the larvae was detected, allowing a detection threshold of 0.1–0.2 µg/mL STXeq. In the case of the amnesic toxin the effect was reversed, detecting hyperactivity with a detection threshold of 10 µg/mL domoic acid. We propose that this assay might be used as a complementary tool for environmental safety monitoring. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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11 pages, 2720 KiB

Open AccessArticle

Prostaglandin Metabolome Profiles in Zebrafish (Danio rerio) Exposed to Acetochlor and Butachlor

by Shenggan Wu, Xinzong Zhou, Weiwei Qin, Xuehua An, Feidi Wang, Lu Lv, Tao Tang, Xinju Liu and Yueping He

Int. J. Mol. Sci. 2023, 24(4), 3488; https://doi.org/10.3390/ijms24043488 - 9 Feb 2023

Cited by 1 | Viewed by 1430

Abstract

Prostaglandins (PGs) are critically important signaling molecules that play key roles in normal and pathophysiological processes. Many endocrine-disrupting chemicals have been found to suppress PG synthesis; however, studies about the effects of pesticides on PGs are limited. The effects of two known endocrine [...] Read more.

Prostaglandins (PGs) are critically important signaling molecules that play key roles in normal and pathophysiological processes. Many endocrine-disrupting chemicals have been found to suppress PG synthesis; however, studies about the effects of pesticides on PGs are limited. The effects of two known endocrine disrupting herbicides, acetochlor (AC) and butachlor (BC), on PG metabolites in zebrafish (Danio rerio) females and males were studied using widely targeted metabolomics analysis based on ultraperformance liquid chromatography—tandem mass spectrometry (UPLC—MS/MS). In total, 40 PG metabolites were detected in 24 zebrafish samples, including female and male samples, with and without exposure to AC or BC at the sub-lethal concentration of 100 μg/L for 96 h. Among them, 19 PGs significantly responded to AC or BC treatment, including 18 PGs that were upregulated. The enzyme-linked immunosorbent assay (ELISA) test in zebrafish showed BC could cause significant upregulation of an isoprostane metabolite, 5-iPF2a-VI, which is positively related to the elevated level of reactive oxygen species (ROS). The present study guides us to conduct a further study to determine whether PG metabolites, including isoprostanes, could be potential biomarkers for chloracetamide herbicides. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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18 pages, 3913 KiB

Open AccessArticle

Behavioral and Sensory Deficits Associated with Dysfunction of GABAergic System in a Novel shank2-Deficient Zebrafish Model

by Yi Wang, Chunxue Liu, Jingxin Deng, Qiong Xu, Jia Lin, Huiping Li, Meixin Hu, Chunchun Hu, Qiang Li and Xiu Xu

Int. J. Mol. Sci. 2023, 24(3), 2208; https://doi.org/10.3390/ijms24032208 - 22 Jan 2023

Cited by 1 | Viewed by 2036

Abstract

Hyper-reactivity to sensory inputs is a common and debilitating symptom of autism spectrum disorder (ASD), but the underlying neural abnormalities remain unclear. Two of three patients in our clinical cohort screen harboring de novo SHANK2 mutations also exhibited high sensitivity to visual, auditory, [...] Read more.

Hyper-reactivity to sensory inputs is a common and debilitating symptom of autism spectrum disorder (ASD), but the underlying neural abnormalities remain unclear. Two of three patients in our clinical cohort screen harboring de novo SHANK2 mutations also exhibited high sensitivity to visual, auditory, and tactile stimuli, so we examined whether shank2 deficiencies contribute to sensory abnormalities and other ASD-like phenotypes by generating a stable shank2b-deficient zebrafish model (shank2b^−/−). The adult shank2b^−/− zebrafish demonstrated reduced social preference and kin preference as well as enhanced behavioral stereotypy, while larvae exhibited hyper-sensitivity to auditory noise and abnormal hyperactivity during dark-to-light transitions. This model thus recapitulated the core developmental and behavioral phenotypes of many previous genetic ASD models. Expression levels of γ-aminobutyric acid (GABA) receptor subunit mRNAs and proteins were also reduced in shank2b^−/− zebrafish, and these animals exhibited greater sensitivity to drug-induced seizures. Our results suggest that GABAergic dysfunction is a major contributor to the sensory hyper-reactivity in ASD, and they underscore the need for interventions that target sensory-processing disruptions during early neural development to prevent disease progression. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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14 pages, 3081 KiB

Open AccessArticle

Ipconazole Disrupts Mitochondrial Homeostasis and Alters GABAergic Neuronal Development in Zebrafish

by Giyoung Lee, Amit Banik, Juneyong Eum, Byung Joon Hwang, Seung-Hae Kwon and Yun Kee

Int. J. Mol. Sci. 2023, 24(1), 496; https://doi.org/10.3390/ijms24010496 - 28 Dec 2022

Cited by 3 | Viewed by 2206

Abstract

Ipconazole, a demethylation inhibitor of fungal ergosterol biosynthesis, is widely used in modern agriculture for foliar and seed treatment, and is authorized for use in livestock feed. Waste from ipconazole treatment enters rivers and groundwater through disposal and rain, posing potential toxicity to [...] Read more.

Ipconazole, a demethylation inhibitor of fungal ergosterol biosynthesis, is widely used in modern agriculture for foliar and seed treatment, and is authorized for use in livestock feed. Waste from ipconazole treatment enters rivers and groundwater through disposal and rain, posing potential toxicity to humans and other organisms. Its metabolites remain stable under standard hydrolysis conditions; however, their neurodevelopmental toxicity is unknown. We investigated the potential neurodevelopmental toxicity of ipconazole pesticides in zebrafish (Danio rerio). Our behavioral monitoring demonstrated that the locomotive activity of ipconazole-exposed zebrafish larvae was reduced during early development, even when morphological abnormalities were undetected. Molecular profiling demonstrated that the mitochondrial-specific antioxidants, superoxide dismutases 1 and 2, and the genes essential for mitochondrial genome maintenance and functions were specifically reduced in ipconazole-treated (0.02 μg/mL) embryos, suggesting underlying ipconazole-driven oxidative stress. Consistently, ipconazole treatment substantially reduced hsp70 expression and increased ERK1/2 phosphorylation in a dose-dependent manner. Interrupted gad1b expression confirmed that GABAergic inhibitory neurons were dysregulated at 0.02 μg/mL ipconazole, whereas glutamatergic excitatory and dopaminergic neurons remained unaffected, resulting in an uncoordinated neural network. Additionally, ipconazole-treated (2 μg/mL) embryos exhibited caspase-independent cell death. This suggests that ipconazole has the potential to alter neurodevelopment by dysregulating mitochondrial homeostasis. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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17 pages, 9896 KiB

Open AccessArticle

Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos

by Huan-Chau Lin, Ferry Saputra, Gilbert Audira, Yu-Heng Lai, Marri Jmelou M. Roldan, Honeymae C. Alos, Charlaine A. Aventurado, Ross D. Vasquez, Guan-Jhe Tsai, Ken-Hong Lim and Chung-Der Hsiao

Int. J. Mol. Sci. 2022, 23(19), 11711; https://doi.org/10.3390/ijms231911711 - 3 Oct 2022

Cited by 1 | Viewed by 2308

Abstract

BCR-ABL, a fusion protein kinase, is a druggable target exclusively expressed in patients with chronic myeloid leukemia (CML). Several anti-leukemia medicines targeting this protein have been developed in recent years. However, therapeutic options are limited for CML patients bearing multiple BCR-ABL1 mutations. Ponatinib [...] Read more.

BCR-ABL, a fusion protein kinase, is a druggable target exclusively expressed in patients with chronic myeloid leukemia (CML). Several anti-leukemia medicines targeting this protein have been developed in recent years. However, therapeutic options are limited for CML patients bearing multiple BCR-ABL1 mutations. Ponatinib (PON), a potent tyrosinase inhibitor, was one of the approved drugs for managing BCR-ABL1 T315I mutant disease. However, treatment of patients with PON reported severe side effects related to cardiovascular events. Asciminib (ASC) was the first allosteric inhibitor approved to target the myristoyl pocket of BCR-ABL protein to inhibit protein activity. The different mechanism of inhibition opens the possibility of co-exposure with both medicines. Reports on cardiovascular side effects due to the combination use of PON + ASC in pre-clinical and clinical studies are minimal. Thus, this study aimed to observe the potential cardiovascular-related side effect after co-exposure to ASC and PON using zebrafish as an animal model. In this study, zebrafish were acutely exposed to both compounds. The cardiovascular physiology parameters and gene expression related to cardiovascular development were evaluated. We demonstrate that combining ASC with PON at no observed effect concentration (NOEC) did not cause any significant change in the cardiac performance parameter in zebrafish. However, a significant increase in nkx2.5 expression level and a substantial decrease in blood flow velocity were recorded, suggesting that combining these compounds at NOEC can cause mild cardiovascular-related side effects. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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18 pages, 3940 KiB

Open AccessArticle

Embryonic Exposure to Cigarette Smoke Extract Impedes Skeletal Development and Evokes Craniofacial Defects in Zebrafish

by Omran Karmach, Joseph V. Madrid, Subham Dasgupta, David C. Volz and Nicole I. zur Nieden

Int. J. Mol. Sci. 2022, 23(17), 9904; https://doi.org/10.3390/ijms23179904 - 31 Aug 2022

Cited by 8 | Viewed by 2075

Abstract

Exposure to cigarette smoke represents the largest source of preventable death and disease in the United States. This may be in part due to the nature of the delayed harmful effects as well as the lack of awareness of the scope of harm [...] Read more.

Exposure to cigarette smoke represents the largest source of preventable death and disease in the United States. This may be in part due to the nature of the delayed harmful effects as well as the lack of awareness of the scope of harm presented by these products. The presence of “light” versions further clouds the harmful effects of tobacco products. While active smoking in expectant mothers may be reduced by educational and outreach campaigns, exposure to secondhand smoke is often involuntary yet may harm the developing embryo. In this study, we show that the main component of secondhand smoke, sidestream cigarette smoke, from several brands, including harm-reduction versions, triggered unsuccessful hatching at 3 dpf and reduced overall survival at 6 dpf in developing zebrafish. At non-lethal concentrations, craniofacial defects with different severity based on the cigarette smoke extract were noted by 6 dpf. All tested products, including harm-reduction products, significantly impacted cartilage formation and/or bone mineralization in zebrafish embryos, independent of whether the bones/cartilage formed from the mesoderm or neural crest. Together, these results in a model system often used to detect embryonic malformations imply that exposure of a woman to secondhand smoke while pregnant may lead to mineralization issues in the skeleton of her newborn, ultimately adding a direct in utero association to the increased fracture risk observed in children of mothers exposed to cigarette smoke. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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10 pages, 1346 KiB

Open AccessArticle

Assessing the Morphological and Behavioral Toxicity of Catechol Using Larval Zebrafish

by Michael G. Morash, Kelly H. Soanes, John C. Achenbach and Lee D. Ellis

Int. J. Mol. Sci. 2022, 23(14), 7985; https://doi.org/10.3390/ijms23147985 - 20 Jul 2022

Cited by 1 | Viewed by 1834

Abstract

Catechol is a ubiquitous chemical used in the manufacturing of fragrances, pharmaceuticals and flavorants. Environmental exposure occurs in a variety of ways through industrial processes, during pyrolysis and in effluent, yet despite its prevalence, there is limited information regarding its toxicity. While the [...] Read more.

Catechol is a ubiquitous chemical used in the manufacturing of fragrances, pharmaceuticals and flavorants. Environmental exposure occurs in a variety of ways through industrial processes, during pyrolysis and in effluent, yet despite its prevalence, there is limited information regarding its toxicity. While the genotoxicity and gastric carcinogenicity of catechol have been described in depth, toxicological studies have potentially overlooked a number of other effects relevant to humans. Here, we have made use of a general and behavioral larval zebrafish toxicity assay to describe previously unknown catechol-based toxicological phenomena. Behavioral testing revealed catechol-induced hypoactivity at concentrations an order of magnitude lower than observable endpoints. Catechol exposure also resulted in punctate melanocytes with concomitant decreases in the expression of pigment production and regulation markers mitfa, mc1r and tyr. Because catechol is converted into a number of toxic metabolites by tyrosinase, an enzyme found almost exclusively in melanocytes, an evaluation of the effects of catechol on these cells is critical to evaluating the safety of this chemical. This work provides insights into the toxic nature of catechol and highlights the benefits of the zebrafish larval testing platform in being able to dissect multiple aspects of toxicity with one model. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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18 pages, 6641 KiB

Open AccessArticle

Ferroptosis and Apoptosis Are Involved in the Formation of L-Selenomethionine-Induced Ocular Defects in Zebrafish Embryos

by Meng Gao, Jun Hu, Yuejie Zhu, Xianqing Wang, Shumin Zeng, Yijiang Hong and Guang Zhao

Int. J. Mol. Sci. 2022, 23(9), 4783; https://doi.org/10.3390/ijms23094783 - 26 Apr 2022

Cited by 8 | Viewed by 3167

Abstract

Selenium is an essential trace element for humans and other vertebrates, playing an important role in antioxidant defense, neurobiology and reproduction. However, the toxicity of excessive selenium has not been thoroughly evaluated, especially for the visual system of vertebrates. In this study, fertilized [...] Read more.

Selenium is an essential trace element for humans and other vertebrates, playing an important role in antioxidant defense, neurobiology and reproduction. However, the toxicity of excessive selenium has not been thoroughly evaluated, especially for the visual system of vertebrates. In this study, fertilized zebrafish embryos were treated with 0.5 µM L-selenomethionine to investigate how excessive selenium alters zebrafish eye development. Selenium-stressed zebrafish embryos showed microphthalmia and altered expression of genes required for retinal neurogenesis. Moreover, ectopic proliferation, disrupted mitochondrial morphology, elevated ROS-induced oxidative stress, apoptosis and ferroptosis were observed in selenium-stressed embryos. Two antioxidants—reduced glutathione (GSH) and N-acetylcysteine (NAC)—and the ferroptosis inhibitor ferrostatin (Fer-1) were unable to rescue selenium-induced eye defects, but the ferroptosis and apoptosis activator cisplatin (CDDP) was able to improve microphthalmia and the expression of retina-specific genes in selenium-stressed embryos. In summary, our results reveal that ferroptosis and apoptosis might play a key role in selenium-induced defects of embryonic eye development. The findings not only provide new insights into selenium-induced cellular damage and death, but also important implications for studying the association between excessive selenium and ocular diseases in the future. Full article

(This article belongs to the Special Issue Zebrafish Models in Toxicology Research)

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