RESUMEN
The benzotriazole UV stabilizer UV-328 is well known for its potent antioxidative properties; however, there are concerns about how it may affect signaling nodes and lead to negative consequences. This study identified the key signaling cascades involved in oxidative stress in zebrafish (Danio rerio) larvae and evaluated the cell cycle arrests and associated developmental alternations. Exposure to UV-328 at 0.25, 0.50, 1.00, 2.00, and 4.00 µg/L downregulated gene expression associated with oxidative stress (cat, gpx, gst, and sod) and apoptosis (caspase-3, caspase-6, caspase-8, and caspase-9) at 3 days postfertilization (dpf). The transcriptome aberration in zebrafish with disrupted p38 mitogen-activated protein kinase (MAPK) cascades was validated based on decreased mRNA expressions of p38 MAPK (0.36-fold), p53 (0.33-fold), and growth arrest and DNA damage-inducible protein 45 α (Gadd45a) (0.52-fold) after a 3- and 14-day exposure alongside a correspondingly decreased protein expression. The percentage of cells in the Gap 1 (G1) phase increased from 69.60% to a maximum of 77.07% (p < 0.05) in the 3 dpf embryos. UV-328 inhibited the p38 MAPK/p53/Gadd45a regulatory circuit but promoted G1 phase cell cycle arrest, abnormally accelerating the embryo hatching and heart rate. This study provided mechanistic insights that enrich the risk profiles of UV-328.
Asunto(s)
Pez Cebra , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ciclo Celular/fisiología , Transducción de Señal , Apoptosis , Estrés OxidativoRESUMEN
2-Mercaptobenzothiazole (MBT) is an industrial chemical widely used for rubber products, corrosion inhibitors, and polymer materials with multiple environmental and exposure pathways. A growing body of evidence suggests its potential bladder cancer (BC) risk as a public health concern; however, the molecular mechanism remains poorly understood. Herein, we demonstrate the activation of the aryl hydrocarbon receptor (AhR) by MBT and reveal key events in carcinogenesis associated with BC. MBT alters conformational changes of AhR ligand binding domain (LBD) as revealed by 500 ns molecular dynamics simulations and activates AhR transcription with upregulation of AhR-target genes CYP1A1 and CYP1B1 to approximately 1.5-fold. MBT upregulates the expression of MMP1, the cancer cell metastasis biomarker, to 3.2-fold and promotes BC cell invasion through an AhR-mediated manner. MBT is further revealed to induce differentially expressed genes (DEGs) most enriched in cancer pathways by transcriptome profiling. The exposure of MBT at environmentally relevant concentrations induces BC risk via AhR signaling disruption, transcriptome aberration, and malignant cell metastasis. A machine learning-based model with an AUC value of 0.881 is constructed to successfully predict 31 MBT analogues. Overall, we provide molecular insight into the BC risk of MBT and develop an effective tool for rapid screening of AhR agonists.
Asunto(s)
Receptores de Hidrocarburo de Aril , Neoplasias de la Vejiga Urinaria , Benzotiazoles , Biomarcadores , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Humanos , Ligandos , Aprendizaje Automático , Metaloproteinasa 1 de la Matriz/metabolismo , Simulación de Dinámica Molecular , Receptores de Hidrocarburo de Aril/metabolismo , GomaRESUMEN
3,3',5,5'-Tetrabromobiphenyl (BB-80) was once used as additive flame retardants. Whether its early exposure and discontinued exposure alter thyroid function remains unknown. We investigate adverse effects after early-life exposure and discontinued exposure to BB-80 and hydroxylated BB-80 (OH-BB-80) on thyroid hormone (TH) levels, thyroid tissue, and transcriptome profiles in zebrafish larvae. BB-80 at 10 µg/L induces pathological changes of thyroid with reduced thyroid follicles in larvae (P < 0.05), whereas OH-BB-80 significantly increases T4 and T3 contents (1.8 and 2.5 times of the control, P < 0.05) at 14 days postfertilization (dpf) without morphological thyroid alterations. BB-80 and OH-BB-80 cause transcriptome aberrations with key differentially expressed genes involved in the disruption of TH synthesis and signal transduction (BB-80 at 14 dpf) or TH pathway activation (OH-BB-80 at 21 dpf). After 7 days of discontinued exposure, thyroglobulin (tg) and thyroid peroxidase (tpo) genes are downregulated (P < 0.05) by 52 and 48% for BB-80 and by 49 and 39% for OH-BB-80, respectively; however, the whole-body TH levels fail to fully recover, and the locomotor activity is impaired more by BB-80. Our results indicate significant adverse impacts of BB-80 and OH-BB-80 on TH homeostasis and thyroid function of zebrafish.