Diquat (DQ), a contact herbicide extensively utilized in both agricultural and nonagricultural domains, exhibits a high correlation with neuronal disorders. Nevertheless, the toxicity and underlying mechanisms associated with exposure to environmental concentrations of DQ remain ambiguous. Here, we report dose-dependent cellular neurotoxicity of DQ in Caenorhabditis elegans. First, DQ significantly compromised the development and brood size of worms, shortened the lifespan, and caused epidermal abnormalities. An unbiased transcriptomic analysis disclosed several pathways related to cell death and peroxisome homeostasis underlying this organismal-level toxicity. Moreover, exposure of DQ to C. elegans led to a notable increase of embryonic cell death. Concurrently, DQ exposure specifically caused the loss of dopamine neurons but not two other types of neurons in adulthood, which is in accordance with DQ-induced muscle-related defects such as pharyngeal pumping, body bends, and head thrashes. Mechanistically, DQ exposure induces the generation of reactive oxygen species (ROS) and enhances glutathione-related ROS scavenging pathway. Protein levels and activities of mitochondrial electron transport chain complexes were specifically impaired in the DQ-treated worms. Collectively, this study suggests an ROS-mediated cell death pathway involving the neuronal and behavioral toxicity of DQ, which offers a novel mitochondria-related perspective to elucidate the general toxicity caused by a widely distributed herbicide, DQ, at near-environment concentrations.

Polyhalogenated carbazoles (PHCZ) are emerging organic pollutants derived from a variety of natural and synthetic sources. While PHCZ have raised environmental concerns due to its persistence, bioaccumulation, and widespread distribution, its neuronal toxicity remains largely understudied. Here, the general and neuronal toxicity of PHCZ using the model organism Caenorhabditis elegans ( C. elegans ) is evaluated. It is found that PHCZ can induce significant dopaminergic neurodegeneration, in addition to exhibiting general toxicity affecting development and male gamete differentiation. Mechanistically, PHCZ promote liquid–liquid phase separation (LLPS) of the Parkinson's disease (PD)‐associated protein α‐synuclein (α‐syn), and reduces the fluidity of the resultant condensate both in vitro and in viv o . PHCZ disrupts general protein homeostasis and specifically activates the unfolded protein response in the ER (UPR ^ER ) through the IRE‐1 signaling axis. Moreover, PHCZ impairs mitochondrial functions, providing another mechanistic link to neuronal degeneration. Thus, this study uncovers a hitherto unrecognized neuronal toxicity of PHCZ, which is partly attributed to their capacity to dysregulate LLPS and UPR ^ER , offering new insights into their potential health risks.

To date, Leucobacter species have been identified from diverse sources with various ecological and functional roles. However, the genomic features and pathogenic potential of antibiotic-resistant Leucobacter strains remain understudied. Here, we isolated the Leucobacter sp. HNU-1 from tropical Hainan Province, China, and found it can induce diapause in Caenorhabditis elegans following ingestion, while exhibiting no significant effects on the nematode’s lifespan, survival rate, locomotion, and intestinal epithelial cells. This bacterium demonstrates resistance to multiple antibiotics, including kanamycin, streptomycin, sulfonamides, and vancomycin. On LB medium, Leucobacter sp. HNU-1 forms yellow, opaque colonies with a smooth, moist surface, regular edges, a convex center, and no surrounding halo, with diameters ranging from 2 to 3 mm. Furthermore, we performed whole-genome sequencing using third-generation high-throughput sequencing technology. De novo assembly revealed a genome size of 3,375,033 bp, with a GC content of 70.37%. A total of 3270 functional genes, accounting for 88.98% of the genome, were annotated, along with six potential CRISPR sequences and other genetic elements. Genomic and bioinformatic analyses further identified antibiotics-related genes. This research provides a theoretical foundation for investigating antibiotic-resistant environmental bacteria in tropical environments and offers new insights into potential therapeutic strategies for microbial infections and host–microbe interactions.

The neurotoxicity of emerging contaminants, polyhalogenated carbazoles (PHCZs), is elusive. In this study, we investigated the potential toxicity of 13 prevalent PHCZs utilizing a network toxicology approach, which revealed shared molecular targets associated with Parkinson's disease (PD). Molecular docking simulations assessed the binding affinities of these PHCZs for eight key PD-related targets, identifying monoamine oxidase B (MAOB) as a critical target. Among the dihalogenated PHCZs, 2,7-dibromocarbazole (2,7-BCZ) exhibited the highest binding affinity to MAOB. Comparative molecular docking and dynamics simulations suggest that the inhibition of MAOB activity by 2,7-BCZ is a potential initiating event in PHCZ-induced neurological disorders. In vivo experiments confirmed that 2,7-BCZ exposure highly correlates with α-synuclein aggregation, a hallmark of PD pathology. Transcriptomic sequencing of 2,7-BCZ-exposed SH-SY5Y cells, combined with analysis of public PD microarray data, identified shared transcriptional alterations in genes including CLSTN2, CBLN1, AGTR1, DLK1, and DDC. By integrating pathways from PD-related targets of PHCZs, differentially expressed genes in 2,7-BCZ-exposed cells, and public PD data sets, we further elucidated key biological pathways through which 2,7-BCZ may contribute to PD pathogenesis, particularly dopaminergic synapse function and neurodevelopmental regulation. Collectively, this study not only highlights the potential role of PHCZs in PD, elucidating the potential biological mechanisms by which PHCZs may exacerbate PD, but also exemplifies an innovative, animal-sparing approach using New Approach Methodologies (NAMs) to assess environmental pollutants' risks in neurodegenerative adverse outcomes.

The dynamics of protein subcellular localization are intricately regulated, requiring new tools for controlling protein translocation to uncover the biological significance of post-translational regulation of protein localization. Here, we developed a new method, P rotein R erouting via IN tein-mediated T rans- S plicing (PRINTS), which enables precise control of protein translocation across diverse subcellular compartments. By reconstituting functional signaling peptides, PRINTS can efficiently relocalize fluorescent proteins to the 26S proteasome, nucleus, mitochondria, plasma membrane, endomembrane organelles, and liquid-liquid phase separation (LLPS) condensates. Furthermore, we incorporated the optically regulated dimerization domain CRY2clust into the PRINTS system, achieving light-mediated control of protein entry into the cell membrane and LLPS membraneless compartments. Strikingly, we observed that HNRNPA1 promiscuously recruit CRY2- or intein-containing proteins into LLPS condensate, whereas FXR1, another LLPS protein showed minimal non-specific activity. PRINTS also allow organelle relocalization, such as LLPS condensates or mitochondria to cell membrane in a light-controllable manner. Overall, PRINTS provides a versatile and robust platform for manipulating protein and organelle subcellular translocations, offering a powerful tool to investigate the regulatory coordination and crosstalk between membranous and membraneless compartments in response to physiological needs.