Arsenic Rats Research Articles

Unveiling the LncRNA-miRNA-mRNA Regulatory Network in Arsenic-Induced Nerve Injury in Rats through High-Throughput Sequencing.

Arsenic is a natural toxin which is widely distributed in the environment, incurring diverse toxicities and health problems. Previous studies have shown that long non-coding RNAs (LncRNAs) are also reported to contribute to As-induced adverse effects. LncRNAs are involved in the development of nerve injury, generally acting as sponges for microRNAs (miRNAs). This study aimed to investigate the competitive endogenous RNA (ceRNA) regulatory networks associated with arsenic-induced nerve damage. A total of 40 male Wistar rats were exposed to different doses of arsenic for 12 weeks, and samples were collected for pathological observation and high-throughput sequencing. The ceRNA network was constructed using Cytoscape, and key genes were identified through the PPI network and CytoHubba methods. A real-time quantitative PCR assay was performed to validate gene expression levels. The results showed that subchronic exposure to arsenic in drinking water resulted in pathological and ultrastructural damage to the hippocampal tissue, including changes in neuron morphology, mitochondria, and synapses. Exposure to arsenic results in the dysregulation of LncRNA and mRNA expression in the hippocampal tissues of rats. These molecules participated in multiple ceRNA axes and formed a network of ceRNAs associated with nerve injury. This study also verified key molecules within the ceRNA network and provided preliminary evidence implicating the ENRNOT-00000022622-miR-206-3p-Bdnf axis in the mechanism of neural damage induced by arsenic in rats. These findings provide novel insights into the underlying mechanism of nervous system damage induced by arsenic exposure.

Molecular mechanisms underlying ameliorative impact of melatonin against age-dependent chronic arsenic toxicity in rats' brains.

Accumulation of random molecular damage such as oxidative DNAdamage and inflammation is extremely found to be involved in the aging process. Due to extreme energy requirements and high lipid levels, the brain is more susceptible to oxidative damage during aging especially under exposure to toxic elements such as arsenic. Therefore, this study was aimed to evaluate the ameliorative effects of melatonin, as a neurohormone, on the arsenic-induced behavioral abnormalities, and the underlying mechanisms. Forty-eight rats, as young and old aged groups were exposed to 5.55 g/kg body weight arsenic for 4 weeks and then 10 mg/kg melatonin for 2weeks. Our results showed that arsenic led to anxiety-like behavioral abnormalities in rats. Increased oxidative stress-induced damage to DNA, lipids and proteins, decreased potential of antioxidant defense system, induced apoptosis, elevated inflammation, and alteration in the histology of cortical region of brains are observed in the rats exposed to arsenic. These effects were more prominent in aged rats in comparison to young rats. Melatonin successfully attenuates arsenic induced adverse effects on the brain in both age groups. In conclusion, our study shows that melatonin has significant ameliorative impact on age-dependent cytotoxicity of arsenic in rats' brains.

Maximum contaminant level of arsenic in drinking water potentiates quinalphos-induced renal damage on co-administration of both arsenic and quinalphos in Wistar rats.

This study was designed to determine alterations in renal biomarkers, antioxidant profile, and histomorphology of renal tissue following subacute exposure to quinalphos alone or in conjunction with arsenic in rats. A total of 54 adult Wistar rats were randomly divided into nine groups of six rats each and were administered sub-lethal concentrations of quinalphos (1/100th and 1/10th of LD50) orally daily and arsenic (50 and 100ppb) in drinking water for 28days. Significantly (p < 0.05) decreased levels of antioxidant biomarkers in renal tissue, viz., total thiols, catalase, superoxide dismutase, glutathione peroxidase, glutathione-s-transferase, and glutathione reductase along with increased (p < 0.05) thiobarbituric acid reacting substance (TBRAS) levels indicated that significant oxidative damage to renal tissue occurred following repeated administrations of quinalphos at either dose levels or arsenic at the concentration of 100ppb when compared with the control rats. The alterations in the antioxidant parameters were observed to be more pronounced in co-administered groups as compared with either toxicant administered group. Similarly, activity of renal acetylcholinesterase was decreased after repeated exposure to quinalphos or arsenic, but inhibition was higher (up to 48%) in rat renal tissue co-exposed with quinalphos and arsenic at the higher concentration. These findings corroborated with the histopathological alterations in renal tissue of toxicant exposed rats. The altered plasma and tissue antioxidant biomarkers along with histopathological changes in the kidney at higher dose level of either toxicant indicate that renal tissue is significantly impacted by these toxicants, and these effects become more pronounced after their co-administration.

Inflammation response after the cessation of chronic arsenic exposure and post-treatment of natural astaxanthin in liver: potential role of cytokine-mediated cell-cell interactions.

Ongoing groundwater arsenic contamination throughout China was first recognized in the 1960s. Groundwater arsenic contamination is a high risk for human and animal health worldwide. Apart from drinking water, diet is the second pathway for arsenic to enter the human body and eventually cause liver injury. Natural astaxanthin extracted from the green algae Haematococcus pluvialis has dominated the nutraceutical market for potential health benefits. Nevertheless, the molecular mechanism underlying the protective effect post astaxanthin against arsenic-induced hepatotoxicity remains largely obscure. In this study, we investigate the effect of natural astaxanthin (derived from Haemotococcus pluvialis) on oxidative stress and liver inflammatory response in rats after the cessation of chronic arsenic exposure. Wistar rats were given astaxanthin (250 mg kg-1) daily for 2 weeks after the cessation of exposure to sodium arsenite (300 μg L-1, drinking water, 24 weeks) by intragastric administration. The results showed that post treatment with astaxanthin attenuated liver injury induced by long-term exposure to arsenic in rats. Most importantly, post treatment with astaxanthin decreased the increasing of inflammatory cytokine NF-κB, tumor necrosis factor-α, interleukin-1β, oxidative stress level, and total arsenic content in livers of rats exposed to arsenic. In addition, post treatment with astaxanthin reversed the increasing of protein levels of alpha-smooth muscle actin and collagen Iα1, which are the activation markers of hepatic stellate cells (HSCs). Collectively, these data demonstrate that post astaxanthin treatment attenuates inflammation response in the liver after the cessation of chronic arsenic exposure via inhibition of cytokine-mediated cell-cell interactions. Daily ingestion of natural astaxanthin might be a potential and beneficial candidate for the treatment of liver damage after the cessation of chronic exposure to sodium arsenite.

Protective effect of Mucuna pruriens against arsenic-induced liver and kidney dysfunction and neurobehavioral alterations in rats

Background and Aim:Intoxication of arsenic in rats is known to result in neurological effects as well as liver and kidney dysfunction. Mucuna pruriens has been identified for its medicinal properties. The aim of the study was to investigate the protective effect of aqueous seed extract of M. pruriens on sodium arsenite-induced memory impairment, liver, and kidney functions in rats.Materials and Methods:The experiment was divided into short-term treatment (45 days) and long-term treatment (90 days), with each group divided into nine sub-groups consisting of six animals each. Sub-groups 1 and 2 served as normal, and N-acetylcysteine (NAC) controls, respectively. Sub-groups 3-9 received sodium arsenite in drinking water (50 mg/L). In addition, sub-group 4 received NAC (210 mg/kg b.wt) orally once daily, sub-groups 5-7 received aqueous seed extract of M. pruriens (350 mg/kg b.wt, 530 mg/kg b.wt, and 700 mg/kg b.wt) orally once daily and sub-groups 8 and 9 received a combination of NAC and aqueous seed extract of M. pruriens (350 mg/kg b.wt and 530 mg/kg b.wt) orally once daily. Following the treatment, the blood was drawn retro-orbitally to assess the liver (serum alanine transaminase [ALT], serum aspartate transaminase, and serum alkaline phosphatase) and kidney (serum urea and serum creatinine) functions. Learning and memory were assessed by passive avoidance test. Animals were sacrificed by an overdose of ketamine, and their Nissl stained hippocampal sections were analyzed for alterations in neural cell numbers in CA1 and CA3 regions.Results:In the short-term treatment, groups administered with M. pruriens 530 mg/kg b.wt alone and combination of NAC + M. pruriens 350 mg/kg b.wt exhibited a significant improvement in memory retention, less severe neurodegeneration, and decrease in serum ALT levels. In long-term treatment, groups administered with M. pruriens 700 mg/kg b.wt alone and combination of NAC+M. pruriens 350 mg/kg b.wt, respectively, showed better memory retention, decreased neural deficits, and reduced levels of kidney and liver enzymes.Conclusion:The seed extract of M. pruriens showed significant enhancement in memory and learning. The number of surviving neurons in the CA1 and CA3 regions also increased on treatment with M. pruriens. Serum ALT, serum urea, and serum creatinine levels showed significant improvement on long-term treatment with M. pruriens.

The PKCδ-Nrf2-ARE signalling pathway may be involved in oxidative stress in arsenic-induced liver damage in rats

Arsenic poisoning is a worldwide endemic disease that affects thousands of people. Growing evidence from animal, cell, and human studies indicates that arsenic has deleterious effects on the liver. Oxidative stress is considered the primary mechanism for arsenic toxicity in liver damage. However, the mechanisms remain unclear. In light of this fact, the main objective of this study was to investigate the effects of the protein kinase C delta-nuclear factor E2-related factor 2-antioxidant response element (PKCδ-Nrf2-ARE) signalling pathway on oxidative stress in liver damage. In the present study, we used a model of liver damage induced by coal-burning arsenic in rats, which was set up by our research group. The oxidative stress index and the transcription and protein expression levels of PKCδ, Nrf2, Keap1, SOD1, and GPx1 were detected, and then their correlation analyses were carried out. The results demonstrated that coal-burning arsenic can cause oxidative stress liver damage in rats, which may be related to the PKCδ-Nrf2-ARE signalling pathway. This study may provide a new pathway for studies of the mechanisms of arsenism.

Protective effects of thymoquinone against apoptosis and oxidative stress by arsenic in rat kidney

We aimed to investigate the protective role of thymoquinone (TQ) by targeting its antiapoptotic and antioxidant properties against kidney damage induced by arsenic in rats. We have used the 24 male Sprague-Dawley rats. Rats were divided into three groups. Physiological serum in 10 mL/kg dose as intragastric was given to the control group. Sodium arsenite (10 mg/kg, intragastric by gavage for fifteen days) was given to the arsenic group. Sodium arsenite (10 mg/kg, intragastric by gavage for fifteen days) and TQ (10 mg/kg, intragastric by gavage for 15 days) was given to the arsenic + TQ group. After 15 days, the animals’ kidneys were taken theirs, then we have performed histological and apoptotic assessment. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) enzyme activities and malondialdehyde (MDA) levels have examined as the oxidative stress parameters. We have determined the levels of arsenic. Increased renal injury and apoptotic cells have been detected in the arsenic group. Degenerative changes in the arsenic + TQ group were diminished. Although the MDA levels were augmented in the arsenic group, SOD, CAT and GSH-Px enzyme activities were lessened than the other groups. Our findings suggest that TQ may impede the oxidative stress, the cells have been damaged and also the generation of apoptotic cells arisen from arsenic. TQ plays a protective role against arsenic-induced toxicity in kidney and may potentially be used as a remedial agent.

Rutin, a flavonoid phytochemical, ameliorates certain behavioral and electrophysiological alterations and general toxicity of oral arsenic in rats.

Arsenic affects large populations and attacks, among others, the nervous system. Waterborne or occupational exposure causes electrophysiological alterations and motor disturbances in humans, and analogous effects were found in animals. Certain phytochemicals may be protective against As-caused damages. In the present study it was investigated whether the flavonoid rutin, applied via the drinking water (2 g/L), ameliorates the effects of arsenic given by gavage (10 mg/kg b.w., in form of NaAsO2) on open field motility, evoked cortical and peripheral electrophysiological activity, and body weight gain in adult male Wistar rats. Body weight gain was significantly reduced from the 4th week of the 6 weeks arsenic treatment and this effect was largely abolished by rutin in the combination treatment group. Rats treated by arsenic alone showed decreased open field motility; latency of the cortical evoked potentials increased and peripheral nerve conduction velocity decreased. These functional alterations were also counteracted by co-administration of rutin, and both the antioxidant and the chelating activity of rutin might have contributed to the ameliorative effect. These results are apparently novel and support the potential role of natural agents in preserving human health in a contaminated environment.

The effects of evening primrose oil on arsenic-induced oxidative stress in rats†

Forty-eight male Wistar albino rats were allocated to the four groups such that each comprised 12 animals. The first group was maintained as the control. In group 2, evening primrose oil was administered at a dose of 0.1 mL rat−1 day−1 (∼500 mg kg−1 bw) into the stomach via gavage, whilst in group 3 sodium arsenide was administered at a concentration of 100 mg L−1 in ad-libitum drinking water for 30 days. The fourth group was given 0.1 mL rat−1 day−1 evening primrose oil into the stomach via gavage plus 100 mg L−1 of sodium arsenide in ad-libitum drinking water for 30 days. At the end of the 30th day, tissue (liver, lung, kidney, brain, heart, spleen, and testis) and blood samples were collected from each group. Malondialdehyde (MDA) and nitric oxide (NO) levels and superoxide dismutase, catalase and glutathione peroxidase activities were measured in the samples. Exposure to arsenic in rats causes oxidative stress by increasing lipid peroxidation (increase of MDA and NO levels) and altering the activity of antioxidant enzymes. Evening primrose oil did not have any adverse effects. Furthermore, it was ascertained that the administration of arsenic with evening primrose oil reduced the severity of oxidative stress.

Hematological effects of arsenic in rats after subchronical exposure during pregnancy and lactation: The protective role of antioxidants

Free radicals production is involved in the toxicity of arsenic. The aim of this study was to determine whether biochemical changes occurred in the blood of arsenic-exposed pups during gestation and lactation, and additionally to investigate the potential beneficial role of the administration of certain antioxidants against arsenic exposure damage. Pregnant wistar rats received the following treatments as drinking water: (1) distilled water; (2) arsenic (50 mg/L); (3) antioxidants: zinc (20 mg/L)+vitamin C (2 g/L)+vitamin E (500 mg/L); (4) arsenic (50 mg/L)+antioxidants: zinc (20 mg/L)+vitamin C (2 g/L)+vitamin E (500 mg/L). We found a normocytic and normochromic anemia as well as a significant increase in hemolysis, TBARS production and catalase activity in the blood of arsenic intoxicated pups. Moreover, this metalloid produced a significant increase of serum cholesterol, triglicerids and urea levels whereas the proteins diminished. These effects were palliated in some extent by the coadministration of vitamins and zinc. Our findings suggest that administration of antioxidants during gestation and lactation could prevent some of the negative effects of arsenic.

Metabolic adaptations to arsenic‐induced oxidative stress in male wistar rats

The present study was planned to investigate the effect of arsenic in rats on several biochemical indices of oxidative stress. Rats were exposed to arsenite in drinking water for upto 12 weeks. Chronic exposure to arsenic for a period of 12 weeks significantly (p < 0.05) increased arsenic burden in blood, liver, and kidney. Several intrinsic antioxidant defenses were activated after a 4-week exposure to arsenic. Some remained elevated, but others became depressed over a longer exposure period. Alterations in most of the biochemical variables reached statistical significant (p < 0.05). Arsenic significantly (p < 0.01) reduced mRNA expression of the superoxide dismutase 2 (SOD2) gene with respect to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. These observations indicated that prolong exposure to arsenic causes induction of oxidative stress and biochemical alterations.

Pleurotus florida lectin normalizes duration dependent hepatic oxidative stress responses caused by arsenic in rat

Natural contamination of arsenic in ground water is a major health problem throughout the World. It is one of the most hazardous substances in the environment known to cause toxicity in multiple organs via oxidative stress. The molecular basis for arsenic toxicity involves direct or indirect damage to protein, lipid and DNA. Various studies have focused on the possible toxic effects of arsenic on membrane components and its correlation with oxidative damage. The present study was aimed to mitigation of arsenic induced hepatic oxidative stress by dietary modulation using of mushroom lectin in rats. Animals were divided into four groups; the first group was used as control. Groups 2, 3 and 4 were arsenic (20 ppm) exposed through drinking water, arsenic exposed plus oral ascorbic acid (25 mg/kg body weight) and arsenic exposed plus oral mushroom lectin (150 mg/kg body weight) respectively for a period of 12 weeks. We observed significant alterations in the antioxidant enzymes, oxidative stress intermediates and SOD(2) gene expression profile on arsenic exposure. These alterations were restored by co-administration of Pleurotus florida lectin which was as potent as standard antioxidant viz. ascorbic acid. The findings of the experiment suggested that P. florida lectin has capability of modulating arsenic mediated toxic effects and could be helpful in ameliorating them.

Pathological, immunological and biochemical markers of subchronic arsenic toxicity in rats

Subchronic exposure to arsenic in rats was investigated to identify sensitive indicators of subclinical toxicity in rats. Immunological, pathological, and biochemical bioindicators were examined in rats exposed to arsenic in their drinking water. Juvenile male Wistar rats were allocated to four treatment groups receiving 0, 0.4, 4, and 40 ppm of arsenite in drinking water for 18 wks. Besides daily monitoring for clinical signs of adverse health effects, clinical biochemistry, B-cell-mediated and innate immune responses, plus gross, and histopathology were examined. In vitro tests of oxidative damage to basic cellular constituents, lipids, proteins, and nucleic acids, were measured using thiobarbituric acid reacting substances (TBARS) assays, protein carbonyl formation, and 8-hydroxydeoxyguanosine (8-OHdG), respectively. Clinical changes in the rats were limited to decreased feed and water intake in the high- (40 ppm) dose group (P < 0.05), however, growth rate was not affected. Serum biochemical changes occurred in blood urea nitrogen, K(+) , Cl(-) , and alanine aminotransferase (ALT) from arsenic exposure. Immunotoxicity was evident through a dose-dependent suppression of the secondary antibody-mediated response to a T-cell-dependent antigen, keyhole limpet hemocyanin (KLH). Histopathology of the liver revealed marked fatty infiltration and vacuolization particularly evident in periacinar hepatocytes. This pattern of toxicopathology in the high-exposure group may be related to the significantly higher (P < 0.05) oxidative stress, demonstrated through lipid peroxidation (TBARS assay) in the rats exposed to 40 ppm arsenite. The present study revealed that young, growing rats exposed to arsenic for 18 wks tolerated exposures up to 4 ppm. At higher doses, there was evidence of hepatotoxicity, humoral immunity was compromised, and an adverse effect on hepatic organelle and cell membranes was evident through a dose dependent increased in oxidative stress.

Reduced cellular redox status induces 4-hydroxynonenal-mediated caspase 3 activation leading to erythrocyte death during chronic arsenic exposure in rats

Chronic exposure to arsenic in rats led to gradual accumulation of the toxicant in erythrocytes causing oxidative stress in these cells. 4-Hydroxynonenal (4-HNE), a major aldehyde product of lipid peroxidation, contributed significantly to the cytopathological events observed during oxidative stress in the erythrocytes of exposed rats. 4-HNE triggered death signal cascade that was initiated with the formation of HNE–protein adducts in cytosol. HNE–protein adduct formation resulted in depletion of cytosolic antioxidants followed by increased generation of ROS. Results showed accumulation of hydrogen peroxide (H 2O 2) from the early stages of arsenic exposure, while superoxide (O 2 •−) and hydroxyl radical ( •OH) also contributed to the oxidative stress during longer period of exposure. Suppression of antioxidant system coupled with increased generation of ROS eventually led to activation of caspase 3 during arsenic exposure. Attenuation of HNE-mediated activation of caspase 3 in presence of N-acetylcysteine (NAC) indicated the involvement of GSH in the process. Prevention of HNE-mediated degradation of membrane proteins in presence of Z-DEVD-FMK identified caspase 3 as the principal mediator of HNE-induced cellular damage during arsenic exposure. Degradation of band 3 followed by its aggregation on the red cell surface promoted immunologic recognition of redistributed band 3 by autologous IgG with subsequent attachment of C3b. Finally, the formation of C3b–IgG–band 3 immune complex accelerated the elimination of affected cells from circulation and led to the decline of erythrocyte life span during chronic arsenic toxicity.

Effects of Inorganic Arsenic on the Rat and Mouse Urinary Bladder

Inorganic arsenic (arsenate and arsenite) is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. Understanding the mechanism of inorganic arsenic carcinogenesis has been hampered by a lack of animal models. To define the urothelial effects of inorganic arsenic, we administered arsenate and arsenite in the diet or drinking water to rats and mice in several short-term experiments (2-10 weeks). Treatment with arsenate or arsenite in the drinking water or diet induced cytotoxicity and necrosis of the urothelial superficial layer and hyperplasia in rats and mice. Arsenate-induced changes occurred later in mice compared with arsenite-induced changes, but not in the rat. Hyperplasia in rats was evident by light microscopy at an earlier time point (2 weeks) than previously observed after treatment with dimethylarsinic acid (DMA(V)). The bromodeoxyuridine labeling index was increased in treated rats. We were unable to determine the bromodeoxyuridine labeling index in mice. The effects of inorganic arsenicals on the bladder were greater when administered in the drinking water than in the diet in rats and mice, but so was the overall toxicity to the animal. The female rat appeared more sensitive to the effects of inorganic arsenic than the male rat, but effects were similar in female and male mice. The mode of action of inorganic arsenic in rats and mice appears to involve urothelial cytotoxicity, increased cell proliferation and ultimately tumors. Cytotoxicity is likely due to the generation of reactive trivalent arsenicals excreted in the urine.

Supplementation of ascorbic acid and α-tocopherol prevents arsenic-induced protein oxidation and DNA damage induced by arsenic in rats

Contamination of arsenic in drinking water is associated with several human diseases including cancer. It has been reported that oxidative stress plays a vital role in arsenic-induced biochemical and molecular alterations. The aim of the present study was to improve the understanding of arsenic-induced oxidative damage to proteins and to DNA and the role of antioxidants such as ascorbic acid and alpha-tocopherol in alleviating arsenic-induced damages in experimental rats. A significant increase in the levels of protein oxidation, DNA strand breaks, and DNA-protein cross-links was observed in blood, liver, and kidney of rats exposed to arsenic (100 ppm in drinking water) for 30 days. Co-administration of ascorbic acid and alpha-tocopherol to arsenic-exposed rats showed a substantial reduction in the levels of arsenic-induced oxidative products of protein and DNA. The results of this study support that free radical-mediated toxic manifestations of arsenic and also suggest that ascorbic acid and alpha-tocopherol supplementation can improve the arsenic-induced molecular alterations.

Studies on the neurotoxicity of arsenic in rats in different exposure timing schemes

Studies on the neurotoxicity of arsenic in rats in different exposure timing schemes

Oxidative stress indices and plasma biochemical parameters during oral exposure to arsenic in rats

An experiment was conducted to study the response of rat tissues to low level exposure of arsenic (III) for different time periods. Rats were exposed to 0 (Gr. I, healthy control, n = 18) or 10 ppm arsenic (Gr. II, positive control, n = 18) through drinking water ad lib for a maximum period of 12 weeks. Six rats were sacrificed from each group under light chloroform anesthesia at the end of 4, 8 and 12 weeks of arsenic exposure for collection of blood, liver and kidneys. Samples were processed for estimation of oxidative stress indices and biochemical variables indicative of hepatic and renal functions. Tissue arsenic burden was measured at the end of 12 weeks of exposure. Arsenic treated rats (Gr. II) had comparatively poor body weight gain over time, and the mean body weights of these rats were significantly ( P < 0.05) lower from 10th weeks onwards. Oral exposure to arsenic for a period of 12 weeks significantly ( P < 0.05) increased arsenic burden in blood, liver and kidney from arsenic treated rats. This was associated with exposure duration-dependent rise ( P < 0.05) in lipid peroxidation in these tissues. Superoxide dismutase (SOD) and catalase (CAT) activities increased initially ( P < 0.05) in all the tissues followed by a declining trend and at the end of 12 weeks, the activities were non-significantly ( P > 0.05) lower than respective controls. Alterations in most of the biochemical parameters did not reach statistical significance ( P > 0.05). It was concluded from the present study that low dose arsenic exposure for a shorter period caused activation of intrinsic antioxidant defense whereas a prolonged insult suppressed it. However, biochemical parameters indicative of hepatic and renal dysfunction remained well within the normal range.

Influence of thyroxine and n-propylthiouracil on nephro-toxicity of inorganic arsenic in rat

The effect of hyper or hypoactive thyroid on the renal toxicity of arsenic trioxide has been studied in rats. It was observed that pre-treatment of rats with thyroxine stimulates arsenic excretion in urine. The anti-thyroid drug n-propylthiouracil (PTU), inhibits the accumulation of arsenic in renal tissue. Both treatments affect the renal pathology. Histopathological lesions are less severe in PTU and arsenic-treated rats in comparison to thyroxine and arsenic-treated rats. Ultrastructural studies support light microscopical observations. An adaptive response was noticed against arsenic in PTU pre-treated rats. We attribute this response to decreased glutathione-S-transferase (GSH) activity and increased GSH synthesis in the kidney. A relationship between thyroidal activity and arsenic toxicity is suggested by present observations.

Role of glutathione in reduction of arsenate and of γ-glutamyltranspeptidase in disposition of arsenite in rats

Arsenate (AsV), the environmentally prevalent form of arsenic, is converted sequentially in the body to arsenite (AsIII), monomethylarsonic acid (MMAsV), monomethylarsonous acid (MMAsIII), and dimethylarsinic acid (DMAsV) and some trimethylated metabolites. Although the biliary excretion of arsenic in rats is known to be glutathione (GSH)-dependent, involving transport of arsenic-GSH conjugates, the role of GSH in the reduction of AsV to the more toxic AsIII in vivo has not been defined. Therefore, we studied how the fate of AsV is influenced by buthionine sulfoximine (BSO), which depletes GSH in tissues. Control and BSO-treated rats were given AsV (50 micromol/kg, i.v.) and arsenic metabolites in bile, urine, blood and tissues were analysed by HPLC-HG-AFS. BSO increased retention of AsV in blood and tissues and decreased appearance of AsIII in blood, bile (by 96%) and urine (by 63%). The biliary excretion of MMAsIII was also nearly abolished, the appearance of MMAsIII and MMAsV in the blood was delayed and the renal concentrations of these monomethylated arsenicals were decreased by BSO. Interestingly, appearance of DMAsV in blood and urine remained unchanged and the concentrations of this metabolite in the kidneys and muscle were even increased in response to BSO. To test the role of gamma-glutamyltranspeptidase (GGT) in arsenic disposition, the effect of the of the GGT inhibitor acivicin was investigated in rats injected with AsIII (50 micromol/kg, i.v.). Acivicin lowered the hepatic and renal GGT activities and increased the biliary as well as urinary excretion of GSH, but failed to alter the disposition (i.e. blood and tissue concentrations, biliary and urinary excretion) of AsIII and its metabolites. In conclusion, shortage of GSH decreases not only the hepatobiliary transport of arsenic, but also reduction of AsV and the formation of monomethylated arsenic, while not hindering the production of dimethylated arsenic. While GSH plays an important role in the disposition and toxicity of arsenic, GGT, which hydrolyses GSH and GSH conjugates, apparently does not influence the fate of the GSH-reactive trivalent arsenicals in rats.