Bromoxynil induced hepatic toxicity via dysregulating TLR4/MyD88, JAK1/STAT3 and NF-κB signaling pathways: A dose-dependent investigation

Abstract

Bromoxynil (BML) is a toxic herbicide that is reported to cause various organ toxicities. However, there is not a single investigation conducted to elucidate the adverse impacts of BML on hepatic tissues at different dose concentrations. Therefore, the current investigation was planned to assess the deleterious effects of BML on liver against different dose concentrations. Thirty-six albino rats (Sprague Dawley) were divided into four groups including the control, BML (10 mg/kg), BML (20 mg/kg) and BML (40 mg/kg). Gene expressions were assessed by qRT-PCR while other biochemical parameters were evaluated through ELISA as well as standard assays. The histological procedure was conducted as per the standard protocols of histomorphology. It is revealed that BML intoxication at all tested doses showed notable elevation in the gene expression of tumor necrosis factor-alpha (TNF-α), toll-like receptors-4 (TLR-4), interleukin-1beta (IL-1β), myeloid differentiation primary response protein-88 (MyD88), interleukin-6 (IL-6), tumor necrosis factor receptor-associated factor-6 (TRAF-6), cyclooxygenase-2 (COX-2), nuclear factor kappa-B (NF-κB), Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) while reducing the gene expression of inhibitor of kappa-B (I-κB). Moreover, BML exposure (10 mg/kg, 20 mg/kg, 40 mg/kg) reduced the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione (GSH), glutathione S- transferase (GST), heme-oxygenase-1 (HO-1) and glutathione reductase (GSR) while upregulating the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). However, an elevation was observed in the levels of alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) while a reduction in the levels of total proteins and albumin was observed after high dose (20 mg/kg, 40 mg/kg) of BML. There was insignificant elevation among the values of these biomarkers at 10 mg/kg administration of BML. Besides, BML exposure at 10 mg/kg, 20 mg/kg and 40 mg/kg escalated the levels of Bcl-2–associated X protein (Bax), cysteine–aspartic acid protease-9 (Caspase-9) and cysteine–aspartic acid protease-3 (Caspase-3) while reducing the levels of B-cell lymphoma 2 (Bcl-2) in hepatic tissues. Similarly, BML at all tested concentrations showed adverse impacts on hepatic histology. These findings validated the deleterious impacts of BML on hepatic tissues owing to its pro-oxidative, pro-inflammatory and pro-apoptotic potential.