Sterigmatocystin (ST) is generally recognized as a potential carcinogen, mutagen and teratogen. Studies showed that ST could induce adenocarcinoma of lung in mice in vivo and DNA damage, cell cycle arrest in a human immortalized bronchial epithelial cell line (BEAS–2 B cells) and a human lung cancer cell line (A549 cells) in vitro. Besides, ST could induce G2 arrest (cell cycle arrest in G2 phase) in several other cells. Cell cycle arrest may be one of the common toxic effects of ST. As cells may undergo apoptosis or death due to cell cycle arrest, we wondered whether apoptosis is another common effect of ST in different cells in vitro. In the present study, we studied the effects of ST on proliferation and apoptosis in A549 cells and BEAS–2 B cells with 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis (FCM). The MTT results showed that proliferation inhibition following ST treatment for 24 h was observed in both A549 and BEAS–2 B cells in vitro. And increased apoptosis by FCM was also found after ST treatment. Down-regulation of Bcl-2, up-regulation of Bax and the activation of caspase-3 after ST treatment were detected by western blotting analyses. The results in the present study are consistent with our previous results, which indicated that inducing apoptosis may be a common effect of ST in different cells in vitro.
Oxidative stress is one of a critical pathogenic factor in the progression of aging and chronic diseases such as cancer, myocardial inflammation and diabetes. In the present scenario, peptides with short half life and more biological specificities are gaining much attention as prodrugs. Thus, the present investigation carried out to screen potential antioxidative peptide, VLPVPQK to cope with the cellular oxidative damage. Our results showed that treatment of rat fibroblast cells with 0.2mM H2O2 for 6h significantly declined different oxidative stress biomarkers such as SOD, CAT, GSH, and promoted LDH activity. In addition, ROS and TNF-α levels were also increased upon H2O2 exposure for 6h and thereby, it induced cell death. Amazingly, pretreatment of the peptide (VLPVPQK) significantly elevated cell survivability, by reversing all H2O2 induced alterations in fibroblast cells. Therefore, our results indicated that, the peptide (VLPVPQK) acted as a potential cytoprotective agent, who restored redox balance and cell homeostasis in cultured fibroblast cells, even after H2O2 exposure, suggesting that the peptide can be valuable as an effective remedy in treatment of oxidative stress related diseases and skin inflammation related disorders.
Deoxynivalenol (DON) and zearalenone (ZEA) are the two most common mycotoxins in animal feed. In this study, we examined oxidative injury and apoptosis of porcine splenic lymphocytes induced by DON or ZEA and their combination in vitro. Based on IC50 values, porcine splenic lymphocytes were treated with 0.06, 0.3, 1.5, and 7.5μg/mL DON, 0.08, 0.4, 2, and 10μg/mL ZEA, or both DON and ZEA at 0.06 and 0.08μg/mL, 0.3 and 0.4μg/mL, and 1.5 and 2μg/mL, respectively. After 48h of DON and/or ZEA exposure, the cells were analyzed for antioxidant functions, apoptosis, and mRNA and protein expression of apoptosis-related genes p53, Bcl-2, Bax, caspase-3, and caspase-8 to determine their apoptosis and oxidative damage effects and mechanisms. The results showed that, compared with the control group, SOD, CAT, GPx, GSH, and Bcl-2 mRNA and protein expression levels were significantly reduced in exposed groups (P<0.05 or P<0.01). Furthermore, MDA contents, apoptosis rates, and p53, Bax, caspase-3 and caspase-8 protein and mRNA expression levels were increased significantly (P<0.01). The effects of DON and ZEA were dose dependent and synergistic in combination. These data suggest that DON and ZEA induce oxidative damage and apoptosis of porcine splenic lymphocytes.
The pesticide rotenone has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of dopamine neurons along the nigrostriatal pathway, as observed in Parkinson’s disease (PD). Recently, intracranial infusion of rotenone was found to increase the protein levels of the Lewy body constituents, α-synuclein and small ubiquitin-related modifier-1(SUMO-1), in the lesioned hemisphere of the mouse brain. These findings are supportive of a mouse model of PD, but information about the dopamine-synthesizing enzyme, tyrosine hydroxylase (TH), an essential marker of dopaminergic status, was not reported. Clarification of this issue is important because an intracranial rotenone mouse model of Parkinson's disease has not been established. Towards this end, the present study examined the effects of intracranial rotenone treatment on TH and α-synuclein immunohistochemistry in addition to forelimb motor function. Mice were unilaterally infused with either vehicle or rotenone (2μg/site) in both the medial forebrain bundle and the substantia nigra. The forelimb asymmetry (cylinder) test indicated a significant decrease in use of the contralateral forelimb in lesioned animals as compared to the sham group. Densitometric analysis revealed a significant depletion of TH immunofluorescence within the ipsilateral striatum and substantia nigra of lesioned animals. Moreover, a significant bilateral increase in α-synuclein immunofluorescence was found in the substantia nigra of lesioned mice, as compared to control animals. These findings indicate that this intracranial rotenone mouse model will be useful for studies of neurodegenerative disorders such as PD.
This study investigates the cytotoxicity and the genotoxicity induced by arsenic trioxide As2O3in human laryngeal SQ20B carcinoma cell line. SQ20B cells were exposed to graded concentrations of arsenic trioxide (2 and 5μM) for 48h. Comet assay and γ-H2AX foci formation were used for measuring DNA damages, flow cytometry was used to identify cell cycle alterations and apoptosis, while cell morphology was visualized using transmission electron microscopy. The results show a dose-dependent induction of DNA damages and double strand breaks, alterations in cell cycle and morphologic alterations of cells. These results prove that As2O3 is highly cytotoxic and genotoxic at the micromolar range ina human laryngeal carcinoma cell line.
Developing effective treatments and preventing inflammatory bowel disease (IBD) are urgent challenges in improving patients' health. It has been suggested that platelet activation and reactive oxidative species generation are involved in the pathogenesis of IBD. We examined the inhibitory effects of a selective phosphodiesterase-3 inhibitor, cilostazol (CZ), and two antioxidants, enzymatically modified isoquercitrin (EMIQ) and α-lipoic acid (ALA), against dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were treated with 0.3% CZ, 1.5% EMIQ, and 0.2% ALA in their feed. Colitis was induced by administering 5% DSS in drinking water for 8days. The inhibitory effects of these substances were evaluated by measuring relevant clinical symptoms (faecal blood, diarrhoea, and body weight loss), colon length, plasma cytokine and chemokine levels, whole genome gene expression, and histopathology. Diarrhoea was suppressed by each treatment, while CZ prevented shortening of the colon length. All treatment groups exhibited decreased plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α compared with the DSS group. Microarray analysis showed that cell adhesion, cytoskeleton regulation, cell proliferation, and apoptosis, which might be related to inflammatory cell infiltration and mucosal healing, were affected in all the groups. DSS-induced mucosal injuries such as mucosal loss, submucosal oedema, and inflammatory cell infiltration in the distal colon were prevented by CZ or antioxidant treatment. These results suggest that anti-inflammatory effects of these agents reduced DSS-induced mucosal injuries in mice and, therefore, may provide therapeutic benefits in IBD.
There are two types of bronchiolo-alveolar hyperplasia (hyperplasia) in rodent lungs. The first is "inflammatory hyperplasia" that retains its ability to revert to normal epithelia upon removal of the stimulating insult. The second is "latent tumorigenic hyperplasia", which is irreversible and causes independent preneoplastic lesions that can progress to bronchiolo-alveolar adenocarcinoma. Previously, lung samples with hyperplastic lesions were obtained from rats exposed to N-bis (2-hydroxypropyl) nitrosamine (DHPN) and fine particles (e.g. quartz), and 19 specific markers were examined immunohistochemically to identify latent tumorigenic hyperplasia. In the cytoplasm of the cells that make up the alveolar wall, we found that napsin A was weakly expressed in the inflammatory hyperplastic lesions, and was strongly expressed in the latent tumorigenic hyperplastic lesions induced by DHPN. To validate the possibility that napsin A may serve as a tumorigenic hyperplastic marker, additional experiments were performed with rats and mice. Latent tumorigenic hyperplasia induced by various carcinogens were positive for napsin A, similar to hyperplasia induced by DHPN. Thus, high expression of napsin A in alveolar walls may serve as a useful marker for detecting the tumorigenic potential of lung hyperplasia in rodents.
We demonstrate the expression patterns of A-kinase anchor protein 13 (AKAP13), a scaffold protein that acts upstream of Rho signaling, and Rho-associated coiled-coil containing protein kinase (ROCK) 1/2 in mouse colorectal cancer and during the healing stage of mouse colitis. BALB/c mice received an intraperitoneal injection of azoxymethane at 10mg/kg, followed by two 7-day cycles of 3% dextran sulfate sodium (DSS) administered through their drinking water to induce colon cancer, or a 7-day administration of 4% DSS to induce colitis. The colorectal tissue was then analyzed for gene expression, histopathology, and immunohistochemistry. In the colorectal cancer, AKAP13 and ROCK1/2 were highly expressed in adenocarcinoma compared to the control tissue and low-grade dysplasia. In colitis, AKAP13 and ROCK1 were highly expressed in the restituted and regenerated mucosa but were only moderately expressed in the injured mucosal epithelium, compared to the normal epithelium that exhibited weak expression levels. ROCK2 was weakly expressed in these cells, consistent with the expression of AKAP13 and ROCK1. Furthermore, we found several clumps of epithelial cells expressing AKAP13 and ROCK1/2 in the lamina propria during the mucosal healing process, and these cells also expressed interleukin-6, which is a multipotential cytokine for both inflammation and healing. These data suggest that AKAP13 was expressed in relation with ROCK1/2, which probably play an overall role in both mucosal healing and tumorigenesis.
Cigarette smoking is one of highly risk factors of cervical cancer. Recently nicotine has been reported to increase proliferation and invasion in some smoking related cancers, like non-small cell lung cancer and esophageal squamous cell cancer. However, the effects and mechanisms of nicotine stimulation on cervical cancer cells are not clear. Here, we investigated the effects and mechanisms of nicotine stimulation on HeLa cells in vitro. In our study, we found that nicotine could accelerate HeLa cells migration and invasion, activate PI3K/Akt and NF-κB pathways and increase the expression of Vimentin in vitro. Moreover, we demonstrated that the specific PI3K inhibitor LY294002 could reverse nicotine-induced cell migration and invasion, NF-κB activation and up-regulation of Vimentin. Inhibition of NF-κB by Pyrrolidine dithiocarbamate (PDTC) also antagonized nicotine-induced cell migration, invasion and up-regulation of Vimentin. Simply put, these findings suggest that nicotine promotes cervical carcinoma cell line HeLa migration and invasion by activating PI3k/Akt/NF-κB pathway in vitro.
Background: Cerium oxide nanoparticles have gained much more attention especially in the field of nanomedicine. This work represents cerium oxide nanoparticles as a new prophylactic model for heart failure progression. Objective: To investigate the potential protective effect of cerium oxide nanoparticles on Isoproterenol (150)-induced cardiac toxicity in rats. Methods: Cerium oxide nanoparticles (5 +/- 1 nm) were synthesized by reverse micelle method and characterized using High Resolution Transmission Electron Microscopy, X-Ray Diffraction and particle size analyzer. The experiments were performed on 96 male Wistar rats. The rats were randomly allocated into eight groups. Namely; two Negative and positive control groups, captopril administered group, Nano-ceria (low dose) group, Nano-ceria (high dose) group, Captopril-Isoproterenol group, Nano-ceria (low dose)-Isoproterenol group and Nano-ceria (high dose)-Isoproterenol group. Cardio toxic rat model was induced by subcutaneous administration of Isoproterenol (ISO) (30 mg/kg) for two consecutive days in adult male rats. Two doses (0.5 and 5 mu g/kg/week) of cerium oxide nanoparticles were applied for five weeks and 50 mg/kg/day of Captopril was used as a reference drug. Cardiac marker enzymes, Cortisol and Aldosterone hormones were assessed in serum. Oxidant-antioxidant parameters and histopathological examination in heart tissues were also determined. Results: These dose of nano-ceria, showed a promising ameliorative and prophylactic effect against cardiac toxicity compared to Captopril reference drug. Serum cardiac markers were decreased by noticeable percentage, CK-MB (50% and 57%), LDH (47% and 57.7%), AST (38% and 36.5%) and ALT (33.5% and 30.6%) for both doses respectively, while increased tissues level of the antioxidant enzymes, catalase (48% - 26%) and superoxide dismutase (64%, 143%). Conclusion: These consistent biochemical and histopathological results suggest that, nano-ceria could be used as effective antioxidant in prophylactic protocols for management of cardiac disorders associated with oxidative stress. (C) 2017 Elsevier GmbH. All rights reserved.
Sodium arsenite is an environmental pollutant with the ability to generate free radicals and curcumin acts as a potent antioxidant. This study investigates the effect of curcumin on kidney histopathology, lipid peroxidation and antioxidant capacity of serum in the mice treated with sodium arsenite. Adult male mice were divided into four groups: control, sodium arsenite, curcumin and curcumin+sodium arsenite. The treatments were delivered for 5 weeks. After the treatment period, blood samples were collected and the concentrations of malondialdehyde (MDA) and total antioxidant capacity of serum were determined. Left kidney was dissected, weighed and used for histopathological and histomorphometrical studies. Sodium arsenite-treated mice showed a significant decrease in the diameter of glomerulus and proximal tubule, glomerular area, total antioxidant capacity of serum as well as a significant increase in serum concentration of MDA compared to the control group. However, no significant difference was found in kidney weight, area and diameter of Bowman's capsule as well as the diameter of distal tubule in mice treated with sodium arsenite compared to the control. In curcumin+sodium arsenite group, curcumin significantly reversed the adverse effects of sodium arsenite on the diameter of glomerulus and proximal tubule, glomerular area, total antioxidant capacity of serum and serum concentration of MDA compared to the sodium arsenite group. The application of curcumin alone significantly increased the total antioxidant capacity of serum compared to the control. Curcumin compensated the adverse effects of sodium arsenite on kidney tissue, lipid peroxidation and total antioxidant capacity of serum.
INTRODUCTION:The usage of Titanium dioxide nanoparticles (TiO2-NPs) covers a vast area in different fields ranging from cosmetics and food to the production of drugs. Maternal exposure to TiO2-NPs during developmental period has been associated with hippocampal injury and with a decrease in learning and memory status of the offspring. However, little is known about its injury mechanism. This paper describes the in vivo neurotoxic effects of TiO2-NPs on rat offspring hippocampus during developmental period. MATERIAL AND METHODS:Pregnant and lactating Wistar rats received intragastric TiO2-NPs (100mg/kg body weight) daily from gestational day (GD) 2 to (GD) 21 and postnatal day (PD) 2 to (PD) 21 respectively. Animals in the control groups received an equal volume of distilled water via gavage. At the end of the treatment process, offspring were deeply anesthetized and sacrificed. Then brains of each group were collected and sections of the rat offspring's brains were stained using TUNEL staining (for detection of apoptotic cells) and immunostaining (for neurogenesis). Moreover, the right hippocampus (n=6 per each group) were removed from the right hemisphere for evaluating the expression of Bax and Bcl-2 level. RESULTS:Results of histopatological examination by TUNEL staining showed that maternal exposure to TiO2-NPs during pregnancy and lactation periods increased apoptotic cells significantly (P<0.01) in the offspring hippocampus. The immunolabeling of double cortin (DCX) protein as neurogenesis marker also showed that TiO2-NPs reduced neurogenesis in the hippocampus of the offspring (P<0.05). Moreover, in comparison with the control group, the mRNA levels of Bax and Bcl-2 in the TiO2-NPs group significantly increased and decreased, respectively (P<0.01). CONCLUSION:These findings provide strong evidence that maternal exposure to TiO2-NPs significantly impact hippocampal neurogenesis and apoptosis in the offspring. The potential impact of nanoparticle exposure for millions of pregnant mothers and their offspring across the world is potentially devastating.
Aminoglutethimide is a steroidogenesis inhibitor and inhibits a cholesterol side-chain cleavage enzyme (CYP11A1) that converts cholesterol to pregnenolone in mitochondria. We investigated histopathological changes induced by 5-day administration of AG in mice. Cytoplasmic vacuoles of various sizes and single cell necrosis were found in zona fasciculata cells in AG-treated mice. Some vacuoles were positive for adipophilin, whereas others were positive for lysosome-associated membrane protein-2 on immunohistochemical staining, indicating they were enlarged lipid droplets and lysosomes, respectively. Electron microscopy revealed enlarged lysosomes containing damaged mitochondria and lamellar bodies in zona fasciculata cells, and they were considered to reflect the intracellular protein degradation processes, mitophagy and lipophagy. From these results, we showed that AG induces excessive lipid accumulation and mitochondrial damage in zona fasciculata cells, which leads to an accelerated lysosomal degradation in mice.
The purpose of this study is to identify the potential of a two-dimensional preantral follicle culture as an in vitro model of predicting premature ovarian failure. The two-dimensional preantral follicles culture method was established by cultivating preantral follicles collected from ICR F1 hybrids (aged 12-14 days) for 12 days. The preantral follicles were incubated with 0.54 mg/ml cyclophosphamide, 0.5 mg/ml busulfan, 0.12 mg/ml cisplatin, 3.12 mg/ml 4-vinylcyclohexene diepoxide, 5 mg/ml D (+) galactose, and 0.5 mg/ml hydrocortisone for 24 h at culture days 2, 6 and 11. The diameter of follicles, the cumulus-oocyte complex number and the maturity of oocytes were recorded as the parameters to detect follicular maturation induced by the culture agents. The results indicated that, except for busulfan, D (+) galactose, and hydrocortisone, such test articles could significantly decrease follicular growth (p < 0.05 or p < 0.01), and induce oocyte degeneration and follicle atresia when the follicles were treated at day 2. With the exception of hydrocortisone, such agents also gradually decreased follicular development (p < 0.05 orp < 0.01) when the follicles were treated at day 6. All of the test articles but hydrocortisone can interfere with the ovulation, the cumulus-oocyte complex discharge and oocyte maturation of follicles when treated at days 2, 6 and 11. It is suggested that two-dimensional preantral follicle culture could be utilized as a potential in vitro system to mimic the POF model. It may also be employed in screening potential ovarian toxic agents, reducing laboratory animal use and promoting animal welfare.
Biliary fibrosis is a complex process in which macrophages and myofibroblasts may play central roles. We investigated biliary fibrosis lesions induced in the Glisson's sheath in rats by alpha-naphthylisothiocyanate (ANIT) administration under macrophage depletion. Hepatic macrophages were depleted in F344 rats with liposome-encapsulated clodronate (CLD) (10mL/kg body weight, i.v) followed by bile duct injury with ANIT (75mg/kg body weight, i.p) (ANIT+CLD group). Rats received empty-liposomes (Lipo) followed by ANIT, and served as control (ANIT+Lipo group). In both ANIT+Lipo and ANIT+CLD groups, ANIT-induced bile duct injury with inflammatory cell infiltration was seen on days 1-3, and subsequently reparative fibrosis occurred on days 5 and 7. In comparisons between the two groups, macrophages reacting to CD68, CD163, MHC class II and CD204 were less in numbers in ANIT+CLD group; the most sensitive immunophenotype was of CD163-positive. Furthermore, in ANIT+CLD group interstitial mesenchymal cells/myofibroblasts reacting to vimentin, desmin and α-smooth muscle actin were also less in grades and tended to be delayed in appearance. Interestingly, MCP-1, IFN-γ, IL-10, and TGF-β1 mRNAs were significantly increased mainly on day 2 in ANIT+Lipo group, while the levels of these factors were prominently lower in ANIT+CLD group. Collectively, depletion of hepatic macrophages plays roles in attenuating biliary fibrogenesis by production of inflammatory factors. The present results indicated clearly importance of macrophage functions in the pathogenesis of biliary fibrosis.
Developmental exposure to glycidol of rats causes axonal injury targeting axon terminals in dams and transient disruption of late-stage differentiation of hippocampal neurogenesis, accompanying sustained increase in the number of reelin-producing or calretinin-expressing interneurons in offspring. The molecular mechanism of disruptive neurogenesis probably targets the newly generating nerve terminals. We previously found differences between mice and rats in the effects on hippocampal neurogenesis after developmental exposure to the same neurotoxic substances. In the present study, we examined the effects and underlying mechanisms of developmental exposure to glycidol on hippocampal neurogenesis in mice. Glycidol (800 or 1600ppm) was administered in drinking water to mated female mice from gestational day 6 to postnatal day 21. Compared to mice drinking water without glycidol (control), the exposed dams showed axon terminal injury at both concentrations of glycidol. The offspring of the dams that had received 1600ppm glycidol had fewer parvalbumin (PVALB)+ γ-aminobutyric acid (GABA)-ergic interneurons and neuron-specific nuclear protein+ postmitotic neurons in the hilus of the hippocampal dentate gyrus. Thus, exposure of glycidol to adult mice induced axonal degeneration equivalent to that seen in the rat; however, the target mechanism for the disruption of hippocampal neurogenesis by developmental exposure was different from that in rats, with the hilar neuronal population not affected until adulthood. Considering the role of PVALB+ GABAergic interneurons in the brain, developmental glycidol exposure in mice may cause a decline in cognitive function in later life, and involve a different mechanism from that targeting axon terminals in rats.
The pathological changes of parasympathetic nerve are considered as an independent prognostic factor of the survival rate of patients with chronic liver disease. The non-selective muscarinic acetylcholine receptors (mAchR) agonists and antagonists can affect the proliferation of hepatocytes and hepatic stellate cells, but the subtypes of mAchR expressions in HCs are still uncertain. Here, we investigate the expression of mAchR in hepatic fibrosis on rats. 3ml/kg 40% carbon tetrachloride (CCL4) was given to induce hepatic fibrosis on rats and the hepatocytes were isolated. Compared to the normal state, the expression levels of m1, 3, 5 in fibrotic liver tissues or hepatocytes were obviously increased, while m2, 4 decreased. 10μM pilocarpine or 10μM acetylcholine could increase the alanine aminotransferase (ALT), hydroxyproline (Hyp), collagen I, III in the hepatocytes, and decreased albumin (ALB). They also changed the expressions of mAchR similarly as the fibrotic hepatocytes and livers. However, atropine could ameliorate the state of fibrotic hepatocytes. These data indicate that mAchR played an important role in the regulation of hepatic fibrosis process. Targeting mAchR would have therapeutic potential for hepatic fibrosis.
Graphene and graphene-related materials have broadly applied in biomedical purposes due to their unique properties, thus safety evaluation of them is crucial. This study was performed to explore the genotoxic and pulmonary toxic potential of different doses of graphene oxide nanosheets' (GOs) in mice.A total of 90 male mature mice were randomly divided into six groups of fifteen mice per each, five groups were intraperitoneally injected by GO at doses of 10, 50, 100, 250 and 500μg/kg b.w once weekly in addition to the control group that was injected intraperitoneally with 0.2ml saline solution. Five animals from each group were euthanized after 7, 28 and 56days post treatment. Evaluation of genotoxicity was performed through detection of chromosomal aberrations in bone marrow while assessment of lung injury was made by determination of DNA fragmentation in lung specimens using the alkali Comet assay, pulmonary oxidative markers estimation and finally histopathological investigations. Results revealed that GOs induced variable structural chromosomal aberrations (SCA) in bone marrow and DNA damage of lung cells that were time and dose dependent and represented by increase in%DNA in comet tail, tail moment and tail length and decrease in% head DNA in nuclei of lung of GOs-treated mice versus control groups in addition, GOs induced various changes in pulmonary oxidative stress parameters that were affected by dose and duration of treatment compared with the control as well as various pulmonary histopathological alterations were detected indicating lung injury.CONCLUSION:GO potentiate the induction of genotoxicity and pulmonary injury in mice in time and dose dependent manner.
Glycosaminoglycans (GAGs) in the urine of Wistar rats, and on the surface of the epithelium and lamina propria of the bladder, were quantitatively assessed before and after acute intoxication with paraoxon or cyclophosphamide. Paraoxon was administered subcutaneously (s.c.) twice with an interval of 1h to a final dose of 275mg/kg; cyclophosphamide was administered intraperitoneally (i.p.) with a single dose of 100mg/kg or to a final dose of 240mg/kg (three times per 80mg/kg every 12h). GAGs on the surface of the epithelium and lamina propria of the urinary bladder of rats were quantitatively determined by Alcian blue dye staining. GAGs in the urine were determined spectrophotometrically with 1-9-dimethyl methylene blue. By 48–96h after intoxication with either paraoxon or cyclophosphamide, statistically significant increases in the concentration of GAGs were obtained both for the tissues of the bladder and the urine of rats. Cyclophosphamide, in contrast to paraoxon, caused the development of hemorrhagic cystitis in the animals. The synthesis of GAGs is considered to be compensatory response to the toxic xenobiotics.
