Newly synthesized chitosan-nanoparticles attenuate carbendazim hepatorenal toxicity in rats via activation of Nrf2/HO1 signalling pathway.

Widespread application of carbendazim (CBZ) is a major environmental impact because of its residues that caused multi-organ dysfunction. Recently, Chitosan nanoparticles (CS-NPs) are extensively used as nanocarriers due to their non-toxic and biodegradable nature. Therefore, the current study aimed to investigate the possible mechanistic pathway of modified CS-NPs to reduce the hepatic and nephrotoxicity of CBZ in rats. CS-NPs were synthesized by the ionic gelation method by using ascorbic acid instead of acetic acid to increase its antioxidant efficiency. Twenty-adult male Wistar rats were grouped (n = 5) as follows: Group (1) negative control, group (2) received CS-NPs, group (3) received CBZ, and group (4) co-administered CS-NPs with CBZ. Rats received the aforementioned materials daily by oral gavage for 28 days and weighed weekly. The results revealed that CBZ receiving group showed severe histopathological alterations in the liver and kidney sections including cellular necrosis and interstitial inflammation confirmed by immunostaining and showed marked immunopositivity of iNOS and caspase-3 protein. There were marked elevations in the serum levels of ALT, AST, urea, and creatinine with a significant increase in MDA levels and decrease in TAC levels. Upregulation of the Keap1 gene and down-regulation of Nrf2 and HO-1 genes were also observed. Co-treatment of rats by CS-NPs with CBZ markedly improved all the above-mentioned toxicological parameters and return liver and kidney tissues to normal histological architecture. We concluded that CBZ caused hepatorenal toxicity via oxidative stress and the Nrf2/HO-1 pathway and CS-NPs could reduce CBZ toxicity via their antioxidant, anti-apoptotic, and anti-inflammatory effects.

Insights overview on the possible protective effect of chitosan nanoparticles encapsulation against neurotoxicity induced by carbendazim in rats.

Carbendazim (CBZ) contamination of food and water is a principal factor in many negative impacts on public health. Nanoencapsulation of agrochemicals by nontoxic polymers as chitosan nanoparticles (CS-NPs) is one of the most applications of nanotechnology in agriculture. Despite its many advantages, such as it provides controlled release property, more stability and solubility of the active ingredient, it is not authorized to be used in the market because there are no adequate studies on the nano pesticides induced toxicity on experimental animals. So, we aim to study the possible impacts of CBZ-loading CS-NPs on the whole brain of rats and to explain its mechanism of action. 20 male Wistar rats were partitioned into 4 groups as follows: Group (1), normal saline; group (2), 5 mg/kg CS-NPs; group (3), 300 mg/kg CBZ; group (4) 300 mg/kg CS/CBZ-NCs. After 28 days, some neurobehavioral parameters were assessed to all rats then euthanization was done to collect the brain. Our results revealed that CBZ prompted neurotoxicity manifested by severe neurobehavioral changes and a significant increase of MDA with a decrease of GSH and CAT in brain tissue. In addition, there were severe neuropathological alterations confirmed by immunohistochemistry which showed strong bax, GFAP, and TNF-á½° protein expression in some brain areas. CBZ also induced apoptosis manifested by up-regulation of JNK and P53 with down-regulation of Bcl-2 in brain tissue. Otherwise, encapsulation of CBZ with CS-NPs could reduce CBZ-induced neurotoxicity and improve all studied toxicological parameters. We recommend using CBZ-loading CS-NPs as an alternative approach for fungicide application in agricultural and veterinary practices but further studies are needed to ensure its safety on other organs.

Novel insights into the potential mechanisms underlying carbendazim-induced hepatorenal toxicity in rats.

Carbendazim (CBZ) is a common environmental pollutant that can contaminate food and water and severely damage human health. Some studies revealed the adverse effect of CBZ on different organs, but its detailed toxicity mechanism has not been elucidated yet. Thus, the present study aims to clarify the mechanisms of CBZ-induced hepatorenal toxicity in rats. Therefore, we partitioned 40 male Wistar rats into four groups (n = 10): a negative control group and three treatment groups, which received 100, 300, and 600 mg/kg of CBZ. All rats received the treatment daily by oral gavage. We collected blood and organ samples (liver and kidney) at 14 and 28 days postdosing. CBZ caused extensive pathological alterations in both the liver and kidneys, such as cellular degeneration and necrosis accompanied by severe inflammatory reactions in a dose- and time-dependent manner. All the CBZ-treated groups displayed strong tumor necrosis factor-α and nuclear factor-κB (NF-κB) immunopositivity. Additionally, CBZ dose-dependently elevated the alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea, and creatinine serum levels and reduced the serum albumin levels. Furthermore, CBZ-induced apoptosis, as indicated by the observed Bax gene upregulation and Bcl-2 gene downregulation in both organs. All these changes may be related to oxidative stress, as indicated by the increase in malondialdehyde levels and the decrease in total antioxidant capacity. Our results demonstrate that CBZ-induced dose- and time-dependent hepatorenal damage through oxidative stress, which activated both the NF-κB signaling pathway and Bcl-based programmed cell death.

Neurobehavioral Toxicity Induced by Carbendazim in Rats and the Role of iNOS, Cox-2, and NF-κB Signalling Pathway.

Carbendazim (CBZ) is one of the most common fungicides used to fight plant fungal diseases, otherwise, it leaves residue on fruits, vegetables, and soil that contaminate the environment, water, animal, and human causing serious health problems. Several studies have reported the reproductive and endocrine pathological disorders induced by CBZ in several animal models, but little is known about its neurotoxicity. So that, the present study aimed to explain the possible mechanisms of CBZ induced neurotoxicity in rats. Sixty male Wistar rats were divided into 4 groups (n = 15). Group (1) received normal saline and was kept as the negative control group, whereas groups (2, 3, 4) received CBZ at 100, 300, 600 mg/kg b.wt respectively. All rats received the aforementioned materials daily via oral gavage. Brain tissue samples were collected at 7, 14, 28 days from the beginning of the experiment. CBZ induced oxidative stress damage manifested by increasing MDA levels and reducing the levels of TAC, GSH, CAT in some brain areas at 14 and 28 days. There were extensive neuropathological alterations in the cerebrum, hippocampus, and cerebellum with strong caspase-3, iNOS, Cox-2 protein expressions mainly in rats receiving 600 mg/kg CBZ at each time point. Moreover, upregulation of mRNA levels of NF-κB, TNF-α, IL-1B genes and downregulation of the transcript levels of both AchE and MAO genes were recorded in all CBZ receiving groups at 14 and 28 days especially those receiving 600 mg/kg CBZ. Our results concluded that CBZ induced dose- and time-dependent neurotoxicity via disturbance of oxidant/antioxidant balance and activation of NF-κB signaling pathway. We recommend reducing the uses of CBZ in agricultural and veterinary fields or finding other novel formulations to reduce its toxicity on non-target organisms and enhance its efficacy on the target organisms.