Indoxacarb induces hepatotoxicity in rats via dysregulation of <i>AMPK/SIRT1/NRF-2/ERRα</i> , redox balance and apoptosis

Indoxacarb (IND) is a toxic pesticide that can cause several organ damages in non-target organisms. However, to date no study has investigated the impacts of IND on hepatic tissues at various concentrations. Therefore, this investigation was executed to evaluate the dose-dependent effect of IND on hepatic tissue. Albino rats (<i>Rattus norvegicus</i>) (n = 36) were divided into four groups: control and three IND concentrations (30, 60, and 90 mg/kg). IND exposure showed a notable reduction in the gene expression of Estrogen-Related Receptor Alpha (ERRα), nuclear respiratory factor-1 (NRF-1), mitochondrial transcription factor-A (TFAM), peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), nuclear respiratory factor-2 (Nrf-2), and silent information regulator sirtuin-1 (SIRT1) while increasing the expression of adenosine monophosphate-activated protein kinase (AMPK). Moreover, IND exposure decreased the activities of catalase (CAT), heme-oxygenase-1 (HO-1), glutathione peroxidase (GP<i>x</i>), superoxide dismutase (SOD), and glutathione reductase (GSR) while increasing the levels of ROS and MDA. However, an increase was recorded in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), Gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) whereas the levels of albumin and total proteins were decreased after high dose (90 mg/kg) of IND. IND concentration (30, 60, and 90 mg/kg) induced apoptosis by increasing the levels of Bax, Caspase-9 and Caspase-3 while diminishing the levels of Bcl-2 and displayed adverse impacts on hepatic histological profile. In conclusion, the IND administration at all the tested doses cause severe hepatic damage via dysregulation of AMPK/SIRT1/NRF-2/ERRα, increasing oxidative stress, decreasing antioxidant defense, leading to inflammation, apoptosis and changes in the hepatic histology.