Glyphosate based-herbicide disrupts energy metabolism and activates inflammatory response through oxidative stress in mice liver.
Chemosphere
Glyphosate, the most widely used herbicide worldwide, has been reported to cause hepatotoxicity. However, these systematic mechanisms remain poorly understood. Here, we investigated the effects of glyphosate-based herbicides (GBH) on liver toxicity in mice exposed to 0, 50, 250, and 500 mg/kg/day GBH for 30 d. Pathological and ultrastructural changes, serum biochemical indicators, oxidative stress state, and transcriptome and key protein alterations were performed to describe the hepatic responses to GBH. GBH induced hepatocytes structural alterations, vacuolation, and inflammatory, mitochondrial swelling and vacuolization; damaged liver function and aggravated oxidative stress; blocked the respiratory chain, promoted gluconeogenesis, fatty acid synthesis and elongation, and activated complement and coagulation cascades system (CCCS) in the liver. Moreover, SOD, HO, and MDA were negatively correlated with the CxI and CxIV genes, but positively correlated with the genes in glucolipid metabolism and CCCS pathways; however, the opposite results were observed for CAT, GSH-Px, and T-AOC. Overall, this study revealed the systematic mechanism underlying hepatotoxicity caused by GBH, providing new insights into understanding the hepatotoxicity of organophosphorus pesticide.
10.1016/j.chemosphere.2023.137751
Ameliorative effect of N-acetylcysteine against glyphosate-induced hepatotoxicity in adult male albino rats: histopathological, biochemical, and molecular studies.
Environmental science and pollution research international
Glyphosate (GLP) is the most commonly used herbicide that presents many hazards to the environment and living organisms. The present study aimed to explore hepatotoxic properties of GLP on adult albino rats, and the ability of N-acetylcysteine (NAC) to ameliorate these toxic effects. Thirty mature male albino rats were distributed into 3 groups (10 rats/group): Group I (C) a negative control, Group II (GLP) orally administered Roundup 0.8503 ml/kg/day which contain GLP (375 mg/kg) (1/10 of LD) by gavage needle, and Group III (NAC+ GLP) received NAC (160 mg/kg, 1h before Roundup) by gavage needle and Roundup (0.8503 ml/kg) orally for 6 weeks. Blood and liver samples were collected and processed for biochemical, histopathological, ultrastructural, and immunohistochemical investigations. Group II displayed a significant elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) levels, as well as overexpression of apoptotic markers. The total antioxidant capacity "TAC" and mRNA expression of NRF2 were significantly decreased. Concerning the histopathological findings, there were various degenerative changes as the hepatocytes showed hydropic swelling with nuclear pyknosis. These alterations were confirmed ultrastructurally as most of the cytoplasmic organelles were lost and the mitochondria appeared to deteriorate. Immunohistochemical results showed intense immunoreactivity against proliferating cell nuclear antigen (PCNA) and caspase-3. NAC administration before GLP partially ameliorates these alterations. ALT, AST, and MDA levels as well as expression of apoptotic markers were significantly reduced. TAC and mRNA expression of NRF2 were significantly increased. Histopathological alterations were partially improved as the hepatocytes returned normal and ultrastructurally they showed nearly normal cytoplasmic organelles. Additionally, the intense expression of PCNA and caspase-3 was significantly reduced. We concluded that NAC can ameliorate most of the adverse effects of GLP exposure through its antioxidant property and free radicals scavenging capacity.
10.1007/s11356-021-13659-2
Single-cell transcriptome analysis reveals liver injury induced by glyphosate in mice.
Cellular & molecular biology letters
BACKGROUND:Glyphosate (GLY), as the active ingredient of the most widely used herbicide worldwide, is commonly detected in the environment and living organisms, including humans. Its toxicity and carcinogenicity in mammals remain controversial. Several studies have demonstrated the hepatotoxicity of GLY; however, the underlying cellular and molecular mechanisms are still largely unknown. METHODS:Using single-cell RNA sequencing (scRNA-seq), immunofluorescent staining, and in vivo animal studies, we analyzed the liver tissues from untreated and GLY-treated mice. RESULTS:We generated the first scRNA-seq atlas of GLY-exposed mouse liver. GLY induced varied cell composition, shared or cell-type-specific transcriptional alterations, and dysregulated cell-cell communication and thus exerted hepatotoxicity effects. The oxidative stress and inflammatory response were commonly upregulated in several cell types. We also observed activation and upregulated phagocytosis in macrophages, as well as proliferation and extracellular matrix overproduction in hepatic stellate cells. CONCLUSIONS:Our study provides a comprehensive single-cell transcriptional picture of the toxic effect of GLY in the liver, which offers novel insights into the molecular mechanisms of the GLY-associated hepatotoxicity.
10.1186/s11658-023-00426-z
Glyphosate-triggered hepatocyte ferroptosis via suppressing Nrf2/GSH/GPX4 axis exacerbates hepatotoxicity.
The Science of the total environment
Glyphosate (GLY) exposure has been reported to damage organs in animals, in particular the liver, due to increased reactive oxygen species (ROS). Ferroptosis is defined as a new type of cell death that is characterized by the increase of ROS. The purpose of this study was to elucidate whether the relationship between ferroptosis and GLY-induced hepatotoxicity is of significance to enlarge the knowledge about GLY toxicity and consequences for human and animal health. To this end, in this study, we investigated the role of ferroptosis in GLY-induced hepatotoxicity both in vivo and in vitro. The results showed that GLY exposure triggered ferroptosis in L02 cells, but pretreatment with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, thereby indicating that ferroptosis plays a key role in GLY-induced hepatotoxicity. Moreover, N-acetylcysteine, a glutathione (GSH) synthesis precursor, reversed GLY-triggered ferroptosis damage, thus indicating that GSH exhaustion may be a prerequisite for GLY-triggered hepatotoxicity. Mechanistically, GLY inhibited GSH biosynthesis via blocking the phosphorylation and nuclear translocation of Nrf2, which resulted in GSH depletion-induced hepatocyte ferroptosis. In a mouse model, GLY exposure triggered ferroptosis-induced liver damage, which can be rescued by pretreatment with Fer-1 or tBHQ (a specific agonist of Nrf2). To our knowledge, this is the first study to reveal that GLY-triggered hepatocyte ferroptosis via suppressing Nrf2/GSH/GPX4 axis exacerbates hepatotoxicity, which expands our knowledge about GLY toxicity in animal and human health.
10.1016/j.scitotenv.2022.160839
Organophosphorus pesticide chlorpyrifos intake promotes obesity and insulin resistance through impacting gut and gut microbiota.
Microbiome
BACKGROUND:Disruption of the gut microbiota homeostasis may induce low-grade inflammation leading to obesity-associated diseases. A major protective mechanism is to use the multi-layered mucus structures to keep a safe distance between gut epithelial cells and microbiota. To investigate whether pesticides would induce insulin resistance/obesity through interfering with mucus-bacterial interactions, we conducted a study to determine how long-term exposure to chlorpyrifos affected C57Bl/6 and CD-1 (ICR) mice fed high- or normal-fat diets. To further investigate the effects of chlorpyrifos-altered microbiota, antibiotic treatment and microbiota transplantation experiments were conducted. RESULTS:The results showed that chlorpyrifos caused broken integrity of the gut barrier, leading to increased lipopolysaccharide entry into the body and finally low-grade inflammation, while genetic background and diet pattern have limited influence on the chlorpyrifos-induced results. Moreover, the mice given chlorpyrifos-altered microbiota had gained more fat and lower insulin sensitivity. CONCLUSIONS:Our results suggest that widespread use of pesticides may contribute to the worldwide epidemic of inflammation-related diseases.
10.1186/s40168-019-0635-4
A simple and highly effective catalytic nanozyme scavenger for organophosphorus neurotoxins.
Journal of controlled release : official journal of the Controlled Release Society
A simple and highly efficient catalytic scavenger of poisonous organophosphorus compounds, based on organophosphorus hydrolase (OPH, EC 3.1.8.1), is produced in aqueous solution by electrostatic coupling of the hexahistidine tagged OPH (His-OPH) and poly(ethylene glycol)-b-poly(l-glutamic acid) diblock copolymer. The resulting polyion complex, termed nano-OPH, has a spherical morphology and a diameter from 25nm to 100nm. Incorporation of His-OPH in nano-OPH preserves catalytic activity and increases stability of the enzyme allowing its storage in aqueous solution for over a year. It also decreases the immune and inflammatory responses to His-OPH in vivo as determined by anti-OPH IgG and cytokines formation in Sprague Dawley rats and Balb/c mice, respectively. The nano-OPH pharmacokinetic parameters are improved compared to the naked enzyme suggesting longer blood circulation after intravenous (iv) administrations in rats. Moreover, nano-OPH is bioavailable after intramuscular (im), intraperitoneal (ip) and even transbuccal (tb) administration, and has shown ability to protect animals from exposure to a pesticide, paraoxon and a warfare agent, VX. In particular, a complete protection against the lethal doses of paraoxon was observed with nano-OPH administered iv and ip as much as 17h, im 5.5h and tb 2h before the intoxication. Further evaluation of nano-OPH as a catalytic bioscavenger countermeasure against organophosphorus chemical warfare agents and pesticides is warranted.
10.1016/j.jconrel.2016.12.037