Phospholipids are biocompatible and versatile materials commonly used in the design of nanodelivery systems. However, the relationship between the structural characteristics of phospholipids and the physiological behavior of lipid-based nanoparticles remains inadequately understood. To explore the key structural features influencing efficient and targeted delivery, we created a library of phospholipid-coated gold nanoparticles (Lip@AuNPs), comprising 12 distinct formulations. These nanoparticles varied systematically in their headgroups (PA, PS, PC, and PE) and aliphatic chain lengths (6:0, 12:0, and 18:0). We investigated their effects on protein adsorption, cellular uptake, and in vivo delivery. Our findings showed that phospholipids with zwitterionic headgroups (PC and PE) reduced complement protein adsorption, enhanced selective uptake by nonphagocytic cells, and promoted increased accumulation in the spleen. Conversely, AuNPs coated with phospholipids containing shorter aliphatic chains exhibited higher serum protein adsorption, resulting in decreased and nonselective cellular uptake, which extended the circulation time of the nanoparticles in the bloodstream. This combinatorial approach provides valuable insights into the role of the phospholipid structure in nanoparticle design and offers practical guidance for developing lipid-based delivery systems with improved targeting and therapeutic efficacy.

Ubiquitination is a highly dynamic and reversible post-translational modification that is extensively involved in protein degradation,signal transduction,and functional regulation in eukaryotic cells.Through the coordinated action of the ubiquitin-activating enzyme(E1),ubiquitin-conjugating enzyme(E2),and ubiquitin-protein ligase(E3)cascade,ubiquitin molecules are conjugated to substrate proteins through distinct ubiquitin chain linkages,thereby determining proteasomal degradation,subcellular trafficking,or non-degradative scaffold functions of target proteins.In the immune system,E3 ligases and deubiquitinases(DUBs)precisely regulate T cell antigen recognition,receptor signaling,activation,proliferation,and effector differentiation by controlling substrate selection and ubiquitin chain editing.By modulating the stability of T cell receptors,co-stimulatory and cytokine signaling molecules,as well as key transcription factors and metabolic regulators,E3 ligases and DUBs influence T cell activation thresholds,anergic states,survival,and differentiation programs.Together,they constitute an essential regulatory network responsible for maintaining T cell homeostasis and peripheral immune tolerance.Dysregulation of this network can enhance pro-inflammatory T cell responses and impaired regulatory T cell function,thereby weakening peripheral immune tolerance and contributing to the development and progression of various autoimmune diseases,including systemic lupus erythematosus,rheumatoid arthritis,and type 1 diabetes mellitus.Systematic summarization of the molecular mechanisms and key signaling pathways through which E3 ligases and DUBs regulate T cell fate,together with elucidation of substrate landscapes,ubiquitin chain preferences,and their metabolic crosstalk among different T cell subsets,will deepen our understanding of how ubiquitination maintains T cell homeostasis and contributes to autoimmune disease pathogenesis.Furthermore,such insights may provide a theoretical foundation and translational directions for the development of chain-specific and cell-type-selective therapeutic strategies.

The rapid expansion of lithium-ion battery (LIBs) deployment has generated increasing volumes of spent batteries that are often improperly discarded, raising concerns about their environmental impact. Lithium nickel cobalt manganese oxides (NCM), the predominant cathode materials in modern LIBs, are of particular concern because of their high content of redox-active transition metals (TMs). Nevertheless, their dissolution behavior and underlying molecular mechanisms under environmentally relevant conditions are poorly understood. In this study, we systematically examined four commercial NCM compositions (NCM111, 523, 622, and 811) under environmentally relevant variables, including pH, temperature, salinity, and organic ligands. Lithium ions (Li+) exhibited high solubility across all conditions (>80%), whereas nickel ions (Ni2+), cobalt ions (Co2+), and manganese ions (Mn2+) demonstrated low but environmentally sensitive release (∼2%). Compared with temperature, salinity, and humic acid, metal dissolution was governed primarily by pH and citric acid. Density functional theory (DFT), combined with the computational hydrogen electrode (CHE) model, revealed that environmental factors influence the dissolution free energy (ΔG) through proton attack, ligand binding, ionic strength, and lattice destabilization. Experiments conducted in six representative waters further confirmed enhanced Ni2+ and Co2+ release in acidic, organic-rich leachates. Collectively, these findings provide mechanistic insights into NCM dissolution pathways and contribute to risk assessment and sustainable management strategies for spent LIBs.

Dysregulation of thymic T cell development compromises immune homeostasis and can lead to leukemic transformation, but the molecular mechanisms linking developmental signals, proliferative cues, and leukemogenesis remain incompletely understood. Here, we integrate deubiquitinase library screening and publicly available single-cell RNA sequencing to analyze mouse and human thymocytes. We find the deubiquitinase USP10 to be expressed in thymocytes, and also elevated in peripheral blood from patients with T-cell acute lymphoblastic leukemia (T-ALL) compared to healthy controls; by contrast, T cell-specific USP10 deficiency blocks mouse thymocyte proliferation and differentiation. Mechanistically, USP10 interacts with SOX4, de-ubiquitinating and protecting SOX4 from degradation to promote thymocyte proliferation, with SOX4 overexpression restoring thymocyte differentiation in USP10-deficient mice. Lastly, MYC induces Usp10 expression, and pharmacologic inhibition of USP10 delays MYC-driven leukemogenesis in a mouse leukemia model. Our results thus identify USP10 as coordinator of developmental signals and oncogenic processes in thymocytes, and implicate USP10 as a potential target for T-ALL therapy.

In the treatment of atopic dermatitis (AD), synergistic activation of the aryl hydrocarbon receptor (AHR)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways represents a promising strategy. However, known dual agonists are limited, and traditional screening methods are inefficient. Therefore, this study developed machine learning models to predict AHR/NRF2 dual agonists using molecular descriptors and fingerprints. All models achieved area under the receiver operating characteristic curve (AUC) values above 0.86, indicating good classification performance. The optimal AHR model showed an accuracy (ACC) of 0.811 and an AUC of 0.878, while the best NRF2 model yielded an ACC of 0.839 and an AUC of 0.907. Based on this model, compounds with a low fraction of sp3-hybridized carbons, moderate hydrophobicity, limited alkyl chains, and highly conjugated structures tend to act as AHR/NRF2 dual agonists. Finally, this study screened 1011 potential natural AHR/NRF2 dual agonists suitable for drug development. Among these, 2-arylbenzofurans, alkaloids, phenanthrenes, flavones, and furocoumarins demonstrated particular advantages. For validation, Indirubin, imperatorin and 3 '-O-Methylbutastatin III were first discovered as AHR/NRF2 dual agonists in HaCaT cells. This work provides a robust predictive tool, clarifies key molecular features of dual agonists, and may support the discovery of anti-AD agents.

The aryl hydrocarbon receptor (AHR) has expanded beyond its classical role and is increasingly recognized for its involvement in mediating the biological effects of cosmetic bioactives. Increasing evidence indicates that key cosmetic compounds, including resveratrol, ferulic acid, and curcumin, exert part of their effects through AHR activation, rather than solely via classical nuclear factor erythroid 2related factor 2 (NRF2) and nuclear factor kappa B (NF-κB)mediated pathways. Based on a comprehensive review of existing studies, AHR regulates multiple pathways relevant to skin function, including collagen synthesis, melanogenesis, barrier integrity, and metabolic signaling, highlighting its role as an integrative hub coordinating complex skin responses. This review frames AHR not merely as a xenobiotic sensor but as a transcription factor integrating multiple signals from environmental and bioactive inputs. Finally, we discuss how emerging tools, including AI-driven modeling and synthetic biology, may expand opportunities for future AHR-focused research and help inform more tailored skincare strategies.

The extensive use of lithium (Li) in green energy generation and storage poses a growing risk of human Li+ exposure. Therefore, advancing bioimaging and safety evaluation approaches for Li+ is crucial. This study introduces a new stratagem to reveal the toxicity effects of Li+ by developing a reversible lithium-sensitive probe (LSP). This probe, designed by conjugating spiropyran and azacrown ethers, enables highly selective imaging of Li+ within living cells at environmentally relevant concentrations, both extracellularly and in vitro. Utilizing this advanced probe, we conducted noninvasive monitoring to observe Li+ permeation through Aquaporin-1 (AQP1) channels in human embryonic kidney cells (HEK293) and its subsequent accumulation in the mitochondria. This mitochondrial accumulation led to decreased mitochondrial membrane potential, increased Cytochrome C (Cyto C) release, disruption of mitochondrial respiratory chain complex activity, and heightened cellular oxidative stress. These findings underscore LSP's utility in delineating spatial distributions and concentrations of Li+ in biological systems and monitor the Li+-involved nephrotoxicity caused by mitochondrial damage.

BACKGROUND:Type 1 diabetes (T1D) is characterised by the autoimmune-mediated destruction of pancreatic β-cells. Although traditionally viewed as a disease dominated by T cells, recent studies have emphasised the crucial role of B cells in the development of T1D. Genome-wide association studies (GWAS) have revealed that CD226 is related to susceptibility to several autoimmune diseases, including T1D. Our recent work identified a pathogenic role of CD226+ CD8+ T cells in T1D. However, the involvement of CD226+ B cells in T1D development remains unclear. METHODS:The expression and functional characteristics of CD226+ B cells in T1D patients and non-obese diabetic (NOD) mice were detected by flow cytometry. RNA sequencing and molecular biology experiments were performed to reveal regulatory mechanisms. In addition, in vivo interventions were conducted to explore potential preventive and therapeutic targets for T1D. FINDINGS:The percentage of CD226+ B cells is increased and positively correlated with disease severity in T1D. CD226+ B cells from T1D patients and NOD mice exhibit increased capability for activation, proliferation, and production of pro-inflammatory cytokines along with heightened glycolytic metabolism. Mechanistic studies have revealed that interleukin-15 (IL-15) secreted by monocytes or macrophages promotes the inflammatory response of CD226+ B cells. Importantly, the use of an anti-CD132 monoclonal antibody (anti-CD132) or an anti-IL-15 monoclonal antibody (anti-IL-15), which blocks IL-15 signalling, effectively prevented the disease onset of T1D. Furthermore, combination therapy with anti-CD3 monoclonal antibody (anti-CD3) and anti-CD132 synergistically reversed hyperglycemia in cyclophosphamide-accelerated NOD mice. INTERPRETATION:Our study demonstrates a novel role of the monocyte/macrophage-IL-15-CD226+ B cell axis in T1D immunopathogenesis and provides potential targets for T1D immunotherapy. FUNDING:This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507300, 2023ZD0507303, 2023ZD0508200, and 2023ZD0508201), the Natural Science Foundation of China (82570973, 82170795, 82470814, 82100949, and 82470931), the Scientific Research Program of FuRong Laboratory (2024PT5105) and the Central South University Research Programme of Advanced Interdisciplinary Studies (2023QYJC008).

BP-3 is the most widely used ultraviolet absorber, but its toxic effects and mechanisms far from being elucidated. This study evaluated the male developmental reproductive toxicities and mechanism of low-doses of BP-3. The results indicated that BP-3 (2.28 and 228 μg/L) led to a decrease in sperm quantity, quality and testosterone level, impaired blood-testis barrier (BTB) integrity and cytoskeleton, accompanied by aggravated oxidative stress in testes of mice on postnatal day 56 (PND 56). Notably, chemokine CCL27, a driver of oxidative stress, was significantly upregulated induced by BP-3. Similar disrupted effects were detected in testes of mice on PND14, which could be antagonized by ICI 182780 (estrogen receptor antagonist). Mechanistically, BP-3 directly interacted with ER, which boosted CCL27 expression, reactive oxygen species (ROS) accumulation, and BTB and cytoskeleton impairment. In vitro, si-CCL27 and/or ROS scavenger treatment significantly antagonized BP-3-induced oxidative stress and the decrease of BTB and cytoskeleton related genes in TM4 cells. These findings demonstrate that prolonged exposure to low-doses of BP-3 resulted in detrimental effects on testicular development through activation of the ER/CCL27/ROS axis. This study provides a novel perspective understanding the male reproductive toxicity risk caused by BPs exposure at low-doses.

Ultraviolet (UV) filters are emerging contaminants of great concern that are widely used in personal care products (PCPs). In this study, the concentrations of 15 UV filters in six types of PCP marketed in China were analyzed and the health risks posed by their internal and external exposure were evaluated. 2-ethylhexyl-4-methoxycinnamate (EHMC) presented the highest median concentration of 3150 ng/g in PCPs, followed by 2-ethylhexyl salicylate (109 ng/g) and octocrylene (OC, 95.1 ng/g). The total UV filter concentrations were considerably higher in sunscreens than other PCPs. Total external dermal exposure to UV filters in sunscreen was higher than the total estimated daily dietary intake of UV filters. A physiologically based toxicokinetic model to predict internal UV filter concentrations after sunscreen application for 1 d showed that EHMC had the highest predicted maximum concentration in venous blood at 0.0770 ng/mL, only one order of magnitude lower than the reference dose. The predicted maximum UV filter concentrations were higher for high-lipid-content tissues than venous blood, consistent with UV filters being lipophilic. OC, EHMC and homosalate made large contributions to the toxic activity assay results, and thus should receive more attention than other UV filters.

Human exposure to organic ultraviolet (UV) filters may pose health risks, but the distribution of UV filters in PM2.5 of four seasons is currently unknown. In this study, PM2.5 samples were collected during 2021-2022 in Beijing, and 15 organic UV filters were analyzed. The concentrations of Sigma UV filter ranged from 260 to 1859 pg/m(3). The highest Sigma UV filter concentrations were observed during summer, with temperature showing a significant positive correlation (p < 0.01) on the concentrations of homosalate (HMS), 2-ethylhexyl salicylate (EHS) and Ethylhexyl-4-methoxycinnamate (EHMC). The dominant compounds were HMS, EHS, and EHMC, which accounted for 93.5% of the median contributions. The median concentration of 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328) was 0.58 pg/m(3), which was lower than that in other studies. It was noteworthy that 2,4-Di-tert-butyl-6-(5-chloro-2H-benzotriazol-2-yl) phenol (UV-327) and 2-(2H-Benzotriazol-2-yl)-6-(butan-2-yl)-4-tert-butylphenol (UV-350) were firstly detected in ambient PM2.5. In vivo predicted biological toxicity and absorption, distribution, metabolism, and excretion characteristics were assessed, EHMC was prioritized due to its high concentration and high potential to be absorbed by human body. The risks of Sigma UV filters through inhalation and dermal contact were negligible for both toddlers and adults, and inhalation exposure exceeded dermal contact by 2-3 orders of magnitude. This is the first study of the occurrence, profiles and risk assessment of 15 UV filters in PM2.5, and more attention should be paid for prioritized UV filters especially EHMC.

The increasing usage of bisphenol S (BPS) analogs as novel alternatives to bisphenol A (BPA) or BPS results in widespread exposure risks. In contrast to BPS, BPS analog-induced perturbations in lipid metabolism are largely unknown. Our study aimed to investigate the interactions of nine novel BPS analogs with peroxisome proliferator-activated receptor γ (PPARγ) and their impacts on 3T3-L1 adipogenesis. BPS and its analogs were found to have varying binding affinities to the PPARγ ligand-binding domain, and five of the BPS analogs were identified as novel PPARγ agonists as evidenced by increased expressions of the PPARγ mediated luciferase reporter gene. Interestingly, seven BPS analogs, including five BPS analogs with PPARγ agonistic potency and two BPS analogs with negligible binding affinity, exhibited comparable or even greater adipogenic effects than BPS, which were demonstrated by increased triglyceride accumulation and enhanced expressions of the adipogenic biomarkers in 3T3-L1 cells. Further comparison revealed that a phenoxy group may be a potential structural regulator for the adipogenic capacities of the test BPS analogs. The findings provided the first evidence that seven novel BPS analogs exerted adipogenic potentials through PPARγ or other signaling pathways, revealing a hidden environmental factor in the development of obesity and other lipid metabolism disorders.

The aryl hydrocarbon receptor (AhR) signaling pathway mediates nephrotoxic compound effects on the kidney, although its mechanisms are incompletely understood. Given that renal tubulointerstitial fibrosis is a central pathological feature of progressive kidney diseases, we investigated AhR-induced profibrotic events at the molecular and cellular levels in human renal tubular epithelial cells (HKC). We found that the AhR activation by the potent agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) promoted epithelial-mesenchymal transition (EMT) and inflammatory responses. This was evidenced by a 56.19% decrease in E-cadherin; 1.87-, 2.39-, and 8.27-fold increases in fibronectin, MMP9, and IL-6, respectively; and a 37.77% enhancement in cell migration. Transcriptome analysis and experimental validations confirmed the consistent dysregulation of these markers. Moreover, we found the profibrotic effects of the known nephrotoxic phytochemical aristolactam I (AL-I) also involving activation of AhR and consistent regulation of the above marker genes, primarily via the AhR. In addition, the transcriptome data further suggested that AhR activation may indirectly induce the profibrotic epidermal growth factor receptor (EGFR) pathway by upregulating AREG, EREG, and TGF-α, indicating crosstalk between AhR and EGFR. Given the wide variety of AhR-active chemicals, these AhR-EMT/inflammation-related markers could be used to screen nephrotoxicity of emerging dioxin-like pollutants and toxic phytochemicals.

The problem of soil polycyclic aromatic hydrocarbon (PAH) pollution in coking plant sites has been widely studied in recent years, but there is a lack of research on the correlation between soil microorganisms, soil metabolomics, and soil properties. Thus, in this study, the long-term impact of coke combustion on soil microbial community structure, enzyme activities, and metabolic pathways within a former coking plant site was investigated. Soil samples were collected from both the coking production area (CA group) and office area (OLA group), approximately 0 to 20 cm in depth. Compared with OLA group, elevated levels of 16 PAHs in the list of US EPA were detected by gas chromatography-mass spectrometry in the CA group. Several dominant microorganisms, such as Altererythrobacter, Lysobacter, and Sulfurifustis, were identified by 16 s ribosomal DNA sequencing in the CA group. The fatty acid biosynthesis pathway exhibited specific inhibition, while the phenylalanine metabolic pathway was promoted in response to PAH stress. Long-term PAH exposure led to the inhibition of soil urease activity. The co-occurrence network of microorganisms revealed intricate patterns of co-metabolism and co-adaptation within complex bacterial communities, facilitating their adaptation to and decomposition of soil-borne PAHs. This research could provide valuable insights into the community characteristics and metabolic mechanisms of microorganisms inhabiting PAH-polluted soil within coking plant sites. The findings enhance our understanding of the indigenous soil microbiome and its intricate network dynamics under the persistent stress of PAHs, contributing to a more comprehensive knowledge of soil ecosystems in such environments.

Environmental contaminants, such as pesticides, can inhibit the enzymatic activity of acetylcholinesterase (AChE), an enzyme necessary for neurotransmission. The inhibitory effects of structurally diverse pesticides on AChE may result from either reversible or covalent interactions. Therefore, assessing their potency typically requires different assay design to determine either dissociation constants or rate constants, respectively. To avoid complex kinetic experiments and enable comparison of potencies across structurally diverse pesticides, we optimized an AChE inhibitor detection system using an endpoint Ellman assay in 96-well plates. Given the significant interspecies variability in sensitivity to inhibitors, we investigated AChE inhibition using both electric eel AChE (eeAChE) and human AChE (hAChE). After confirming the repeatability, reproducibility, and solvent compatibility of the detection system using the reversible inhibitor BW284c51, we determined the inhibition potency of selected organophosphorus (OP) pesticides based on IC50 values. We found that chlorpyrifos, fenamiphos and ethoprophos were more potent inhibitors of hAChE than eeAChE. In contrast, phosalone and methamidophos showed similar inhibitory effects on both enzymes. The potencies aligned well with previously reported inhibitory rate constants. In conclusion, since OPs acts as progressive inhibitors of AChE, our optimized assay offers a simplified yet effective method for assessing their inhibitory potency. It also allows for comparative evaluation of various environmental pollutants based solely on IC50 values, eliminating the need for complex kinetic studies.

Dioxins and dioxin-like compounds (DLCs) exert toxicity through the aryl hydrocarbon receptor (AHR), but species variations in AHR lead to differing sensitivities. Investigating the variation in AHR homolog diversity, expression levels, predominant forms, and AHR sensitivity across species-particularly in fish sensitive to dioxins-is essential for enhancing ecological risk assessment. This study focuses on the tiger puffer (Takifugu rubripes), identifying five AHRs and two ARNTs, with truAHR2a showing the highest expression and the truAHR1 subfamily displaying lower levels. All truAHRs are functional and can be activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with truARNT1 cooperating more efficiently with truAHRs than truARNT2. We determined EC50 values for truAHR1a (0.30 ± 0.10 nM), truAHR1b (0.32 ± 0.20 nM), truAHR2a (0.98 ± 0.63 nM), truAHR2b (2.62 ± 2.48 nM), and truAHR2c (0.43 ± 0.22 nM), with truAHR1a showing the highest sensitivity. The truAHR1 subfamily displayed greater sensitivity than the truAHR2 subfamily, contrasting with medaka and zebrafish, where AHR2 is similar to or more sensitive than AHR1. Comparisons highlighted species- and subform-specific sensitivities in AHRs, differing by one to two orders of magnitude. Ligand-binding assays showed that all truAHRs bound [3H]TCDD specifically. Molecular docking indicated that although TCDD binds AHRs with similar affinities and conserved residues, other subform-specific factors likely contribute to their differential sensitivities. This study provides valuable data on AHR diversity and ligand-sensitivity, contributing to ecological toxicity assessment of dioxin-like compounds.

PAH contamination from coking plants have received widespread attention. However, the microbial diversity, co-occurrence patterns, and functional genes of bacteria in aged coking contaminated soils by PAHs are still not clear. In our study, we used a macro-genetic approach to detect PAH-contaminated soils from both a coking production area (CA group) and an office zone (OA group) in an abandoned coking plant, and analyzed the characteristic bacteria and function genes, microbial network interaction patterns, and soil P-cycling in long-term PAH-contaminated soils. The results revealed that Proteobacteria were significantly positively correlated with PAHs and Betaprobacteria bacterium rifcsplowo2 12 full 6514, candidatus Muproteobacteria bacterium RBG16609, and Sulfurifustis variabilis, which belong to Proteobacteria, were characteristic bacteria in PAH-contaminated soils. The phn, which is the PAH degradation gene, was abundantly expressed in the PAH-contaminated soil. The phn gene cluster genes (phnE, phnC, and phnD) were significantly expressed in the CA group of PAH-contaminated soils (p < 0.05). By integrating microbial diversity, network structure, and functional genes, it offers a comprehensive understanding of soil ecosystem response indicators to prolonged PAH stress. The results of this study will provide new ideas for constructing an assessment index system for soil health and screening biomarkers for PAH-contaminated soils.

The evaluation of toxicity related to polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) is crucial for a comprehensive risk assessment in real-world exposure scenarios. This study employed a controlled feeding experiment to investigate the metabolic effects of dioxin-like compounds (DLCs) on laying hens via feed exposure. Diets enriched with two concentrations (1.17 and 5.13 pg toxic equivalents (TEQ) /g dry weight (dw)) were administered over 14 days, followed by 28 days of clean feed. Metabolomics analyses of blood samples revealed significant metabolic variations between PCDD/Fs and DL-PCBs exposed groups and controls, reflecting the induced metabolic disruption. Distinct changes were observed in sphingosine, palmitoleic acid, linoleate, linolenic acid, taurocholic acid, indole acrylic acid, and dibutyl phthalate levels, implying possible connections between PCDD/Fs and DL-PCBs toxic effects and energy-neuronal imbalances, along with lipid accumulation and anomalous amino acid metabolism, impacting taurine metabolism. Moreover, we identified three differential endogenous metabolites—L-tryptophan, indole-3-acetaldehyde, and indole acrylic acid—as potential ligands for the aryl hydrocarbon receptor (AhR), suggesting their role in mediating PCDD/Fs and DL-PCBs toxicity. This comprehensive investigation provides novel insights into the metabolic alterations induced by PCDD/Fs and DL-PCBs in laying hens, thereby enhancing our ability to assess risks associated with their exposure in human populations.

Astrocytes play an important role in the nervous system's response to external stimulation. Environmental pollutants could activate astrocytes into A1 (toxic) or A2 (protective) types and induce different effects. Meanwhile, the aryl hydrocarbon receptor (AhR) is an environmental molecule sensor in the body and has various ligands. But the difference between exogenous and endogenous AhR ligands on the astrocytic activation is unclear; in this study, we employed rat primary cultured cortical astrocytes to reveal the effects and mechanisms of AhR ligands on astrocytic activation. We found that, after treatment with exogenous AhR ligand (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) ranging from 0.01 to 0.1 nmol/L, astrocytes mainly exhibited A2 type activation. The specific manifestation includes the increase in the expression of A2 marker genes, the enhancement of cellular autonomous movement, the expression and secretion of chemokines, such as Cxcl10, Cxcl2, and Ccl7. And TCDD-induced A2 type astrocytes show a positive impact on neuronal synaptic formation. Although both TCDD and endogenous AhR ligand (6-formylindolo[3,2-b] carbazole, FICZ) could activate AhR pathway in astrocytes, FICZ (50 nmol/L) neither induces activation of A2 type astrocytes nor upregulation of chemokines. Therefore, our findings suggest that AhR is crucial for astrocytes to recognize environmental pollutants and protect the nervous system.

1,3,6,8-Tetrabromocarbazole (1368-BCZ) has been proposed as an emerging environmental contaminant which has aryl hydrocarbon receptor (AhR) activating properties analogous to those of dioxins. Skeletal muscle development is a critical target of dioxin toxicity. However, the impact of 1368-BCZ on muscle development is inadequately understood. The C2C12 mouse myoblast cell is extensively utilized as an in vitro model for studying myogenesis. In the present study, we observed that treatment with 1368-BCZ inhibited myogenic myoblast differentiation in a concentration-dependent manner, without inducing cytotoxicity. Using flow cytometry analysis and a wound healing assay, we found that the cell cycle exit and migratory activity were blocked in 1368-BCZ-treated cells at the early stage of C2C12 differentiation. In line with this alteration, 1368-BCZ significantly upregulated the expression of cell cycle regulators and migration-related genes, whereas it suppressed the expression of myogenic regulatory factors (MRFs) and skeletal muscle myosin isoforms (MYH3 and MYH4), marker genes for myogenesis. Furthermore, treatment with 1368-BCZ activated the AhR signaling pathway, leading to the transcriptional upregulation of AhR-target genes, CYP1A1 and CYP1B1. Silencing AhR mitigated the inhibitory effects of 1368-BCZ on C2C12 differentiation and significantly enhanced the formation of multi-nucleated myotubes through the upregulation of MRFs expression. Taken together, our study suggests that 1368-BCZ exerts an inhibitory effect on myogenesis in C2C12 cells through an AhR-dependent regulatory mechanism, which is highly similar to the observed dioxin effect.