Exposure to acifluorfen induces developmental toxicity in the early life stage of zebrafish.

Acifluorfen, a selective herbicide from the diphenyl ether family, targets broad leaf weeds. Diphenyl ether inhibits chlorophyll production in green plants by inhibiting protoporphyrinogen oxidase (PPO), causing cellular damage. Despite its known impacts on plants, the influence of acifluorfen on zebrafish embryo development remains unclear. In this study, we explored the LC50 of acifluorfen in early-stage wild-type zebrafish, determining it to be 54.99 mg/L. Subsequent examinations revealed morphological changes in zebrafish, including reduced body length. Using the cmlc2:dsRED transgenic model, we observed heart dysfunction in acifluorfen-exposed zebrafish, marked by an enlarged heart area, edema, and decreased heart rate. In response to dose-dependent acifluorfen exposure, the inhibition of angiogenesis in the brain was observed in transgenic zebrafish models (fli1a:eGFP). Organ malformations, specifically in the liver and pancreas, were noted, in lfabp:dsRED;elastase:eGFP transgenic models, indicating reduced organ size in acifluorfen-exposed zebrafish. Furthermore, acifluorfen heightened the expression of apoptosis-related genes (casp8, casp9, and tp53) in zebrafish embryos. We then determined whether acifluorfen affected the viability of zebrafish liver (ZFL) cells based on its effects on liver development in vivo. The results indicated that the proliferation of ZFL cells decreased significantly in a dose-dependent manner. Additionally, acifluorfen-treated ZFL cells exhibited a slight increase in apoptotic cells stained with annexin V and propidium iodide. In summary, these findings establish a baseline concentration for acifluorfen's effects on aquatic ecosystems and non-target organisms.

Bifenox induces hepatotoxicity and vascular toxicity in zebrafish embryos via ROS production and alterations in signaling pathways.

Existing evidence shows that currently used pesticides pose toxicological risks to exposed wildlife. Chemically, bifenox belongs to diphenyl ethers, a well-known group of herbicides. Its mechanism of action primarily involves inducing lipid peroxidation and blocking protoporphyrinogen oxidases. Toxicity of diphenyl ether herbicides has been elucidated in animal cells; however, in vivo toxicological evaluations of bifenox are required to determine its unexpected effects. This study aimed to determine the negative effects of bifenox, and its effects on higher eukaryotes. We found that early stages of zebrafish embryo exposed to bifenox demonstrated increased mortality and physiological defects, based on the LC50 value. Bifenox severely inhibited blood vessel growth by reducing key elements of complex connectivity; fluorescently tagged transgenic lines (fli1a:EGFP) showed morphological changes. Additionally, transgenic lines that selectively identified hepatocytes (fabp10a:DsRed) showed reduced fluorescence, indicating that bifenox may inhibit liver development. To evaluate the level of oxidative stress, we used 2',7'-dichlorofluorescein diacetate (DCFH-DA) probes in zebrafish embryos to identify the underlying mechanisms causing developmental damage. Our findings demonstrate that exposure to bifenox causes abnormalities in the hepatic and cardiovascular systems during zebrafish embryogenesis. Therefore, this study provides new information for the evaluation of toxicological risks of bifenox in vertebrates.

Importance of Site Diversity and Connectivity in Electrochemical CO Reduction on Cu.

Electrochemical CO2 reduction on Cu is a promising approach to produce value-added chemicals using renewable feedstocks, yet various Cu preparations have led to differences in activity and selectivity toward single and multicarbon products. Here, we find, surprisingly, that the effective catalytic activity toward ethylene improves when there is a larger fraction of less active sites acting as reservoirs of *CO on the surface of Cu nanoparticle electrocatalysts. In an adaptation of chemical transient kinetics to electrocatalysis, we measure the dynamic response of a gas diffusion electrode (GDE) cell when the feed gas is abruptly switched between Ar (inert) and CO. When switching from Ar to CO, CO reduction (COR) begins promptly, but when switching from CO to Ar, COR can be maintained for several seconds (delay time) despite the absence of the CO reactant in the gas phase. A three-site microkinetic model captures the observed dynamic behavior and shows that Cu catalysts exhibiting delay times have a less active *CO reservoir that exhibits fast diffusion to active sites. The observed delay times and the estimated *CO reservoir sizes are affected by catalyst preparation, applied potential, and microenvironment (electrolyte cation identity, electrolyte pH, and CO partial pressure). Notably, we estimate that the *CO reservoir surface coverage can be as high as 88 ± 7% on oxide-derived Cu (OD-Cu) at high overpotentials (-1.52 V vs SHE) and this increases in reservoir coverage coincide with increased turnover frequencies to ethylene. We also estimate that *CO can travel substantial distances (up to 10s of nm) prior to desorption or reaction. It appears that active C-C coupling sites by themselves do not control selectivity to C2+ products in electrochemical COR; the supply of CO to those sites is also a crucial factor. More generally, the overall activity of Cu electrocatalysts cannot be approximated from linear combinations of individual site activities. Future designs must consider the diversity of the catalyst network and account for intersite transportation pathways.

Meptyldinocap induces implantation failure by forcing cell cycle arrest, mitochondrial dysfunction, and endoplasmic reticulum stress in porcine trophectoderm and endometrial luminal epithelial cells.

Meptyldinocap is a dinitrophenol fungicide used to control powdery mildew. Although other dinitrophenol pesticides have been found to exhibit reproductive toxicity, studies of meptyldinocaps are scarce. This study investigated the adverse effects of meptyldinocap on porcine trophectoderm (pTr) and porcine endometrial luminal epithelial (pLE) cells, which play crucial roles in implantation. We confirmed that meptyldinocap decreased cell viability, induced apoptosis, and inhibited proliferation by decreasing proliferation-related gene expression and inducing changes in the cell cycle. Furthermore, meptyldinocap treatment caused mitochondrial dysfunction, endoplasmic reticulum stress, and disruption of calcium homeostasis. Moreover, it induces alterations in mitogen-activated protein kinase signaling cascades and reduces the migration ability, leading to implantation failure. Our findings suggest that meptyldinocap reduces the cellular functions of pTr and pLE cells, which are important for the implantation process, and interferes with interactions between the two cell lines, potentially leading to implantation failure. We also propose a mechanism by which the understudied fungicide meptyldinocap exerts its cytotoxicity.

Hexaconazole induces developmental toxicities via apoptosis, inflammation, and alterations of Akt and MAPK signaling cascades.

Hexaconazole is a highly effective triazole fungicide that is frequently applied in various countries to elevate crop productivity. Given its long half-life and high water solubility, this fungicide is frequently detected in the environment, including water sources. Moreover, hexaconazole exerts hazardous effects on nontarget organisms. However, little is known about the toxic effects of hexaconazole on animal development. Thus, this study aimed to investigate the developmental toxicity of hexaconazole to zebrafish, a valuable animal model for toxicological studies, and elucidate the underlying mechanisms. Results showed that hexaconazole affected the viability and hatching rate of zebrafish at 96 h postfertilization. Hexaconazole-treated zebrafish showed phenotypic defects, such as reduced size of head and eyes and enlarged pericardiac edema. Moreover, hexaconazole induced apoptosis, DNA fragmentation, and inflammation in developing zebrafish. Various organ defects, including neurotoxicity, cardiovascular toxicity, and hepatotoxicity, were observed in transgenic zebrafish models olig2:dsRed, fli1:eGFP, and l-fabp:dsRed. Furthermore, hexaconazole treatment altered the Akt and MAPK signaling pathways, which possibly triggered the organ defects and other toxic mechanisms. This study demonstrated the developmental toxicity of hexaconazole to zebrafish and elucidated the underlying mechanisms.

Relevance of the endoplasmic reticulum-mitochondria axis in cancer diagnosis and therapy.

Dynamic interactions between organelles are responsible for a variety of intercellular functions, and the endoplasmic reticulum (ER)-mitochondrial axis is recognized as a representative interorganelle system. Several studies have confirmed that most proteins in the physically tethered sites between the ER and mitochondria, called mitochondria-associated ER membranes (MAMs), are vital for intracellular physiology. MAM proteins are involved in the regulation of calcium homeostasis, lipid metabolism, and mitochondrial dynamics and are associated with processes related to intracellular stress conditions, such as oxidative stress and unfolded protein responses. Accumulating evidence has shown that, owing to their extensive involvement in cellular homeostasis, alterations in the ER-mitochondrial axis are one of the etiological factors of tumors. An in-depth understanding of MAM proteins and their impact on cell physiology, particularly in cancers, may help elucidate their potential as diagnostic and therapeutic targets for cancers. For example, the modulation of MAM proteins is utilized not only to target diverse intracellular signaling pathways within cancer cells but also to increase the sensitivity of cancer cells to anticancer reagents and regulate immune cell activities. Therefore, the current review summarizes and discusses recent advances in research on the functional roles of MAM proteins and their characteristics in cancers from a diagnostic perspective. Additionally, this review provides insights into diverse therapeutic strategies that target MAM proteins in various cancer types.

Automated vehicles for older adults with cognitive impairment: a survey study.

As the population is ageing, the number of older adults with cognitive impairment (CI) is increasing. Automated vehicles (AVs) can improve independence and enhance the mobility of these individuals. This study aimed to: (1) understand the perception of older adults (with and without CI) and stakeholders providing services and supports regarding care and transportation about AVs, and (2) suggest potential solutions to improve the perception of AVs for older adults with mild or moderate CI. A survey was conducted with 435 older adults with and without CI and 188 stakeholders (e.g. caregivers). The results were analysed using partial least square - structural equation modelling and multiple correspondence analysis. The findings suggested relationships between older adults' level of cognitive impairment, mobility, knowledge of AVs, and perception of AVs. The results provided recommendations to improve older adults' perception of AVs including education and adaptive driving simulation-based training. Practitioner summary: This study investigated the perception of older adults and other stakeholders regarding AVs. The findings suggested relationships between older adults' level of cognitive impairment, mobility, knowledge of AVs, and perception of AVs. The results provided guidelines to improve older adults' perception of AVs.

Pyridaben induces apoptosis and inflammation in bovine mammary epithelial cells by disturbance of calcium homeostasis and upregulation of MAPK cascades.

Pyridaben is a widely used pyridazinone insecticide used to protect crops against insects and mites. The toxicity of pyridaben has been reported in mice, zebrafish, the human reproductive system, nervous system, and respiratory system. Pyridaben can also be ingested by dairy cattle through feed. However, the toxicity of pyridaben in cattle has not been investigated on. Thus, this study focuses on demonstrating the toxicity of pyridaben in the bovine mammary glands and with the generation milk in the bovine mammary epithelial cells, as it is crucial to the continuance of the amount and the quality of the milk produced. We started by analyzing the intracellular toxicity along with the impact of pyridaben on the cell cycle distribution and the transcription of associated genes. Pyridaben treatment induced cell cycle arrest accompanied the disruption in G1 and S phases with imbalanced cytosolic and mitochondrial calcium ion homeostasis, and caused a destruction of mitochondrial membrane potential. This eventually led to apoptosis of MAC-T cells. We also investigated in the impact that pyridaben has on MAPK signaling proteins, where phosphorylation of ERK1/2, JNK, and p38 were upregulateed. Moreover, examination of the effect of pyridaben in the inflammatory genes revealed hyperactivation of the inflammatory gene transcription. This is the first research to assess the negative outcomes that pyridaben could impose on dairy cattle and milk production.

Evaluation of a Nondepleted Plasma Multiprotein-Based Model for Discriminating Psychiatric Disorders Using Multiple Reaction Monitoring-Mass Spectrometry: Proof-of-Concept Study.

Psychiatric evaluation relies on subjective symptoms and behavioral observation, which sometimes leads to misdiagnosis. Despite previous efforts to utilize plasma proteins as objective markers, the depletion method is time-consuming. Therefore, this study aimed to enhance previous quantification methods and construct objective discriminative models for major psychiatric disorders using nondepleted plasma. Multiple reaction monitoring-mass spectrometry (MRM-MS) assays for quantifying 453 peptides in nondepleted plasma from 132 individuals [35 major depressive disorder (MDD), 47 bipolar disorder (BD), 23 schizophrenia (SCZ) patients, and 27 healthy controls (HC)] were developed. Pairwise discriminative models for MDD, BD, and SCZ, and a discriminative model between patients and HC were constructed by machine learning approaches. In addition, the proteins from nondepleted plasma-based discriminative models were compared with previously developed depleted plasma-based discriminative models. Discriminative models for MDD versus BD, BD versus SCZ, MDD versus SCZ, and patients versus HC were constructed with 11 to 13 proteins and showed reasonable performances (AUROC = 0.890-0.955). Most of the shared proteins between nondepleted and depleted plasma models had consistent directions of expression levels and were associated with neural signaling, inflammatory, and lipid metabolism pathways. These results suggest that multiprotein markers from nondepleted plasma have a potential role in psychiatric evaluation.

Pyridaben impaired cell cycle progression through perturbation of calcium homeostasis and PI3K/Akt pathway in zebrafish hepatocytes.

Environmental pollution caused by pesticides is a growing concern. Pyridaben, a widely used organochlorine insecticide, is a representative water pollutant. Owing to its extensive usage, it has been detected in various aquatic ecosystems, including rivers and oceans. Pyridaben is highly toxic to aquatic organisms; however, the mechanism of its toxicity in the liver, which is important in toxicant metabolism, has not been studied. Therefore, we employed zebrafish and its well-characterized liver cell line, ZFL to assess pyridaben hepatotoxicity and explore its potential mechanisms of action. Pyridaben led to reduction of the liver size and fluorescence intensity of dsRed-labeled Tg (fabp10a:dsRed) zebrafish. It reduced the viability and proliferation of ZFL cells in vitro by inducing apoptosis and cell cycle arrest. These changes might be primarily linked to uncontrolled intracellular calcium flow in ZFL cells exposed to pyridaben. Additionally, it also downregulates the PI3K/Akt signaling cascade, leading to the inactivation of Gsk3ß and nuclear translocation of ß-catenin. Taken together, our findings suggest that pyridaben could have hepatotoxic effects on aquatic organisms. This study is the first to provide insight into the hepatotoxic mechanism of pyridaben using both in vivo and in vitro models.

Multiplexed Quantitative Proteomics Reveals Proteomic Alterations in Two Rodent Traumatic Brain Injury Models.

In many cases of traumatic brain injury (TBI), conspicuous abnormalities, such as scalp wounds and intracranial hemorrhages, abate over time. However, many unnoticeable symptoms, including cognitive, emotional, and behavioral dysfunction, often last from several weeks to years after trauma, even for mild injuries. Moreover, the cause of such persistence of symptoms has not been examined extensively. Recent studies have implicated the dysregulation of the molecular system in the injured brain, necessitating an in-depth analysis of the proteome and signaling pathways that mediate the consequences of TBI. Thus, in this study, the brain proteomes of two TBI models were examined by quantitative proteomics during the recovery period to determine the molecular mechanisms of TBI. Our results show that the proteomes in both TBI models undergo distinct changes. A bioinformatics analysis demonstrated robust activation and inhibition of signaling pathways and core proteins that mediate biological processes after brain injury. These findings can help determine the molecular mechanisms that underlie the persistent effects of TBI and identify novel targets for drug interventions.

Bifenthrin induces cell death in bovine mammary epithelial cells via ROS generation, calcium ion homeostasis disruption, and MAPK signaling cascade alteration.

Bifenthrin is one of the widely used synthetic pyrethroid insecticides, employed for various purposes worldwide. As lipophilic pyrethroids can easily bind to soil particles, which is why their residues are detected in various environments. Consequently, the toxicity of bifenthrin to non-target organisms can be regarded as an environmental concern. The toxic effects of bifenthrin have been studied in various animal models and cell lines; however, its toxic effects on cattle remain unclear. In particular, gaining insights into the toxic effects of bifenthrin on the mammary lactation system is crucial for the dairy industry. Therefore, we proceeded to investigate the toxic effects of bifenthrin on the bovine mammary epithelial cells (MAC-T cells). We established that bifenthrin inhibited cell proliferation and triggered apoptosis in MAC-T cells. Additionally, bifenthrin induced mitochondrial dysfunction and altered inflammatory gene expression by disrupting mitochondrial membrane potential (MMP) and generating excessive reactive oxygen species (ROS). We also demonstrated that bifenthrin disrupted both cytosolic and mitochondrial calcium ion homeostasis. Furthermore, bifenthrin altered mitogen-activated protein kinase (MAPK) signaling cascades and downregulated casein-related genes. Collectively, we confirmed the multiple toxic effects of bifenthrin on MAC-T cells, which could potentially reduce milk yield and quality.

Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy.

Recepteur d'origine nantais (RON, MST1R) is a single-span transmembrane receptor tyrosine kinase (RTK) aberrantly expressed in numerous cancers, including various solid tumors. How naturally occurring splicing isoforms of RON, especially those which are constitutively activated, affect tumorigenesis and therapeutic response, is largely unknown. Here, we identified that presence of activated RON could be a possible factor for the development of resistance against anti-EGFR (cetuximab) therapy in colorectal cancer patient tissues. Also, we elucidated the roles of three splicing variants of RON, RON Δ155, Δ160, and Δ165 as tumor drivers in cancer cell lines. Subsequently, we designed an inhibitor of RON, WM-S1-030, to suppress phosphorylation thereby inhibiting the activation of the three RON variants as well as the wild type. Specifically, WM-S1-030 treatment led to potent regression of tumor growth in solid tumors expressing the RON variants Δ155, Δ160, and Δ165. Two mechanisms for the RON oncogenic activity depending on KRAS genotype was evaluated in our study which include activation of EGFR and Src, in a trimeric complex, and stabilization of the beta-catenin. In terms of the immunotherapy, WM-S1-030 elicited notable antitumor immunity in anti-PD-1 resistant cell derived mouse model, likely via repression of M1/M2 polarization of macrophages. These findings suggest that WM-S1-030 could be developed as a new treatment option for cancer patients expressing these three RON variants.

Discovery of Novel, Thienopyridine-Based Tyrosine Kinase Inhibitors Targeting Tumorigenic RON Splice Variants.

Herein, we report the identification, structural optimization, and biological efficacy of thieno[2,3-b]pyridines as potent inhibitors of splice variants of the tyrosine kinase recepteur d'origine nantais (RON). Among synthesized compounds, compound 15f exhibited excellent in vitro kinase inhibition and antiproliferative activity, as well as in vivo antineoplastic efficacy against RON splice variant-expressing tumors. Moreover, compound 15f with excellent pharmacokinetics demonstrated significant activity with greater tumor growth inhibition (74.9% at 10 mg/kg) than compounds 2 and 4 in a patient-derived xenograft model. Collectively, 15f represents a promising, novel anticancer agent targeting RON splice variants.

Developmental toxicity of flufenacet including vascular, liver, and pancreas defects is mediated by apoptosis and alters the Mapk and PI3K/Akt signal transduction in zebrafish.

Release of agrochemicals from agricultural fields could unintentionally harm organisms that not targeted by pesticides. Flufenacet is one of the oxyacetamide herbicide applied in cultivation fields of crops and this has a possibility of unintentional exposure to diverse ecosystems including streams and surface water. Despite these environmental risks, limited information regarding toxicity of flufenacet on vertebrates is available. This study is aimed to assess environmental hazards and underlying toxic mechanisms of flufenacet by using a zebrafish model. Mortality measurements and morphological observations after the treatment of flufenacet suggested developmental toxicity of flufenacet in zebrafish. In addition, its toxicity on specific organs was evaluated using transgenic fluorescent zebrafish embryo. Adverse effects of flufenacet on vascular and hepatopancreatic development were demonstrated using Tg(flk1:EGFP) and Tg(fabp10a:DsRed; ela3l:EGFP) respectively. To address intracellular actions of flufenacet in zebrafish, cellular responses including apoptosis, cell cycle modulation, and Mapk and Akt signaling pathway were verified in transcriptional and protein levels. These results demonstrated developmental toxicity of flufenacet using the zebrafish model, providing essential information for assessing its potential hazards on vertebrates that are not directly targeted by the pesticide and for elucidating molecular mechanisms.

Dimethenamid promotes oxidative stress and apoptosis leading to cardiovascular, hepatic, and pancreatic toxicities in zebrafish embryo.

Dimethenamid, one of the acetamide herbicides, is widely used on soybeans and corns to inhibit weed growth. Although other acetamide herbicides have been reported to have several toxicities in non-target organisms including developmental toxicity, the toxicity of dimethenamid has not yet been studied. In this research, we utilized the zebrafish animal model to verify the developmental toxicity of dimethenamid. It not only led to morphological abnormalities in zebrafish larvae but also reduced their viability. ROS production and inflammation responses were promoted in zebrafish larvae. Also, uncontrolled apoptosis occurred when the gene expression level related to the cell cycle and apoptosis was altered by dimethenamid. These changes resulted in toxicities in the cardiovascular system, liver, and pancreas are observed in transgenic zebrafish models including fli1a:EGFP and L-fabp:dsRed;elastase:GFP. Dimethenamid triggered morphological defects in the heart and vasculature by altering the mRNA levels related to cardiovascular development. The liver and pancreas were also damaged through not only the changes of their morphology but also through the dysregulation in their function related to metabolic activity. This study shows the developmental defects induced by dimethenamid in zebrafish larvae and the possibility of toxicity in other non-target organisms.

Diminishing Psychological Reactance Through Self-Transcendent Media Experiences: A Self-Report and Psychophysiological Investigation.

Health communication scholars have provided ample evidence demonstrating the ways in which freedom-threatening language used in persuasive health messages evokes freedom-threat perceptions, state psychological reactance, and intentions to engage in behaviors opposite of those recommended by the health message. This study examined a novel mitigation strategy for diminishing these outcomes. We examined whether prior exposure to entertainment portrayals of moral virtue (versus a neutral video) can dampen audiences' psychological reactance, intentions to consume alcohol, and defensive message processing via their psychophysiological responses to a subsequent, freedom-threatening excessive alcohol consumption public service announcement (PSA). The results revealed that participants who viewed entertainment portrayals of moral virtue (N = 50 college-aged participants) self-reported higher levels of elevation, moved, and inspiration relative to participants in the control condition (N = 50 college-aged participants). Participants who were exposed to entertainment portrayals of moral virtue prior to the excessive alcohol consumption PSA also self-reported less psychological reactance and fewer behavioral intentions to consume alcohol following the excessive alcohol consumption PSA than participants in the control condition. Consistent with these self-report data, participants in the entertainment portrayals of moral virtue condition exhibited less defensive message processing of the excessive alcohol consumption PSA via their psychophysiological responses relative to the control group. The results indicate that initial exposure to entertainment portrayals of moral virtue can dampen audiences' cognitive, emotional, and behavioral responses to a subsequent, freedom-threatening health message, thereby increasing the chances of improved health outcomes.

A novel autonomous vehicle interface for older adults with cognitive impairment.

The population of older Americans with cognitive impairments, especially memory loss, is growing. Autonomous vehicles (AVs) have the potential to improve the mobility of older adults with cognitive impairment; however, there are still concerns regarding AVs' usability and accessibility in this population. Study objectives were to (1) better understand the needs and requirements of older adults with mild and moderate cognitive impairments regarding AVs, and (2) create a prototype for a holistic, user-friendly interface for AV interactions. An initial (Generation 1) prototype was designed based on the literature and usability principles. Based on the findings of phone interviews and focus group meetings with older adults and caregivers (n = 23), an enhanced interface (Generation 2) was developed. This generation 2 prototype has the potential to reduce the mental workload and anxiety of older adults in their interactions with AVs and can inform the design of future in-vehicle information systems for older adults.

Assessing workload in using electromyography (EMG)-based prostheses.

Using prosthetic devices requires a substantial cognitive workload. This study investigated classification models for assessing cognitive workload in electromyography (EMG)-based prosthetic devices with various types of input features including eye-tracking measures, task performance, and cognitive performance model (CPM) outcomes. Features selection algorithm, hyperparameter tuning with grid search, and k-fold cross-validation were applied to select the most important features and find the optimal models. Classification accuracy, the area under the receiver operation characteristic curve (AUC), precision, recall, and F1 scores were calculated to compare the models' performance. The findings suggested that task performance measures, pupillometry data, and CPM outcomes, combined with the naïve bayes (NB) and random forest (RF) algorithms, are most promising for classifying cognitive workload. The proposed algorithms can help manufacturers/clinicians predict the cognitive workload of future EMG-based prosthetic devices in early design phases.Practitioner summary: This study investigated the use of machine learning algorithms for classifying the cognitive workload of prosthetic devices. The findings suggested that the models could predict workload with high accuracy and low computational cost and could be used in assessing the usability of prosthetic devices in the early phases of the design process.Abbreviations: 3d: 3 dimensional; ADL: Activities for daily living; ANN: Artificial neural network; AUC: Area under the receiver operation characteristic curve; CC: Continuous control; CPM: Cognitive performance model; CPM-GOMS: Cognitive-Perceptual-Motor GOMS; CRT: Clothespin relocation test; CV: Cross validation; CW: Cognitive workload; DC: Direct control; DOF: Degrees of freedom; ECRL: Extensor carpi radialis longus; ED: Extensor digitorum; EEG: Electroencephalogram; EMG: Electromyography; FCR: Flexor carpi radialis; FD: Flexor digitorum; GOMS: Goals, Operations, Methods, and Selection Rules; LDA: Linear discriminant analysis; MAV: Mean absolute value; MCP: Metacarpophalangeal; ML: Machine learning; NASA-TLX: NASA task load index; NB: Naïve Bayes; PCPS: Percent change in pupil size; PPT: Purdue Pegboard Test; PR: Pattern recognition; PROS-TLX: Prosthesis task load index; RF: Random forest; RFE: Recursive feature selection; SHAP: Southampton hand assessment protocol; SFS: Sequential feature selection; SVC: Support vector classifier.

Fluchloralin induces developmental toxicity in heart, liver, and nervous system during early zebrafish embryogenesis.

The zebrafish is a prominent vertebrate model popularly used for toxicity testing because of its rapid development and transparent embryos. Fluchloralin, a dinitroaniline herbicide used to control weeds, inhibits microtubule formation and cell division. The structurally homologous substances ethalfluralin and pendimethalin, which belong to the dinitroaniline family, were found to be genotoxic and to exert developmental toxicity via mitochondrial dysfunction in a zebrafish model. To date, developmental toxicity of fluchloralin in zebrafish has not been reported. In the present study, we identified morphological changes in developing zebrafish, including decreased survival rate and body length, and increased yolk sac edema. In dose-dependent response to fluchloralin exposure, inhibition of neurogenesis in the spinal cord and motor neuron defects were observed in transgenic zebrafish models (olig2:dsRed). Zebrafish exposed to fluchloralin also displayed organ dysfunction in the heart, liver, and pancreas in cmlc2:dsRed and lfabp:dsRed;elastase:GFP transgenic models. Fluchloralin increased cell death in the brain by promoting apoptosis, visualized via acridine orange staining, and by activating apoptosis signaling proteins, including cytochrome c1, zBax, and Bcl-XL. This study provides novel evidence supporting the necessity of controlling pollutants in aquatic environments.