Atrazine Triggers Mitochondrial Dysfunction and Oxidative Stress in Quail (Coturnix C. coturnix) Cerebrum via Activating Xenobiotic-Sensing Nuclear Receptors and Modulating Cytochrome P450 Systems

Abstract

The residues from the widely used broad-spectrum environmental herbicide, atrazine (ATR), result in the exposure of nontarget organisms and persist as a global major public health hazard. ATR is neurotoxic and may cause adverse health effects in mammals, birds, and fishes. Nevertheless, the molecular mechanism of ATR induced neurotoxicity remains unclear. To assess the molecular mechanisms of ATR-induced cerebral toxicity through potential oxidative damage, quail were treated with ATR by oral gavage administration at doses of 0, 50, 250, and 500 mg/kg body weight daily for 45 days. Markedly, increases in the amount of swelling of neuronal cells, the percentage of mean damaged mitochondria, mitochondrial malformation, and mitochondrial vacuolar degeneration as well as decreases in the mitochondrial cristae and mitochondrial volume density were observed by light and electron microscopy in the cerebrum of quail. ATR induced toxicities in the expression of mitochondrial function-related genes and promoted oxidative damage, as indicated by effects on oxidative stress indices. These results indicated that ATR exposure can cause neurological disorders and cerebral injury. ATR may initiate apoptosis by activating Bcl-2, Bax, and Caspase3 protein expression but failed to induce autophagy (LC3B has not cleaved to LC3BI/II). Furthermore, ATR induced CYP-related enzymes metabolism disorders by activating the nuclear xenobiotic receptors response (NXRs including AHR, CAR, and PXR) and increased expression of several CYP isoforms (including CYP1B1 and CYP2C18) and thereby producing mitochondrial dysfunction. In this study, we observed ATR exposure resulted in oxidative stress and mitochondrial dysfunction by activating the NXR response and interfering the CYP450s homeostasis in quail cerebrum that supported the molecular mechanism of ATR induced cerebrum toxicity. In conclusion, these results provided new evidence on molecular mechanism of ATR induced neurotoxicity.

The constitutive androstane receptor and pregnane X receptor in the brain

“…Similar findings have been reported in a study carried out in quail that evaluated the actions of atrazine, a NR1I2 ligand (Abass et al, 2012) and widely employed neurotoxic herbicide (Lin et al, 2018). Chronic exposure to increasing doses of atrazine resulted in mitochondrial dysfunction, elevated ROS production, induction of apoptosis in the cerebrum and cerebellar toxicity (Lin et al, 2018;Xia et al, 2017). Furthermore, atrazine increased the cerebral and cerebellar expression of NR1I2, NR1I3 and AhR, suggesting that activation of these NRs is responsible for the upregulation of expression of CYP450 isoforms (Lin et al, 2018;Xia et al, 2017).…”

“…Similar findings have been reported in a study carried out in quail that evaluated the actions of atrazine, a NR1I2 ligand (Abass et al, 2012) and widely employed neurotoxic herbicide (Lin et al, 2018). Chronic exposure to increasing doses of atrazine resulted in mitochondrial dysfunction, elevated ROS production, induction of apoptosis in the cerebrum and cerebellar toxicity (Lin et al, 2018;Xia et al, 2017).…”

“…Brain tissue a (mRNA) Brain tissue a (mRNA) (Chan et al, 2011;Lamba et al, 2004;Miki et al, 2005;Nishimura et al, 2004;Savkur et al, 2003 Lin et al, 2018; Porcine (Tripathi et al, 2017) PGP1 (Bauer et al, 2006), while humanised mice for hNR1I2 were responsive to the ligands rifampicin and hyperforin by increasing both P-gp expression and activity, findings that were reproduced in an in vivo model. The rodent NR1I2 ligand dexamethasone up-regulated the expression of P-gp in cortical brain capillaries but not in whole brain homogenates of mice (Chan et al, 2013).…”

“…Chronic exposure to increasing doses of atrazine resulted in mitochondrial dysfunction, elevated ROS production, induction of apoptosis in the cerebrum and cerebellar toxicity (Lin et al, 2018;Xia et al, 2017). Furthermore, atrazine increased the cerebral and cerebellar expression of NR1I2, NR1I3 and AhR, suggesting that activation of these NRs is responsible for the upregulation of expression of CYP450 isoforms (Lin et al, 2018;Xia et al, 2017). The authors of the above studies proposed that the NR1I3, NR1I2 and AhR-mediated changes in the expression of mitochondrial CYP450 enzymes are responsible for the mitochondrial dysfunction that leads to oxidative stress in the brain.…”

8:2 Fluorotelomer alcohol causes immunotoxicity and liver injury in adult male C57BL/6 mice

“…In agreement, the present study showed that 8:2 FTOH decreased the activities of SOD and CAT in both the liver and serum and reduced GSH content in serum (Figure ), indicating that 8:2 FTOH exposure caused oxidative stress in vivo. Oxidative stress damages biological molecules and thus mediates cellular and tissue injury caused by many xenobiotics . N ‐acetylcysteine, an antioxidant, reduced PFOA‐induced apoptosis in human hepatoma cells .…”