Human and Experimental Toxicology

Adedara, Isaac A ;Farombi, Ebenezer O

doi: 10.1177/0960327109360115pmid: 20172899

The effects of ethylene glycol monoethyl ether (EGEE) on the antioxidant systems of the testes and epididymal spermatozoa were investigated in rats at dose levels of 0, 100, 200 and 400 mg kg-1 body weight (bw) administered orally by gavage for 14 consecutive days. The bw gain of the EGEE-treated rats decreased significantly at 200 and 400 mg kg- 1 bw compared with the control group. There were no significant changes in the weights of the testes, epididymis, seminal vesicles and prostate glands of the EGEE-treated rats. In the testes, while EGEE treatment resulted in significant decrease in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities, it markedly increased the malondialdehyde (MDA) level, glutathione-S-transferase (GST) and lactate dehydrogenase (LDH) activities at 200 and 400 mg kg-1 dose levels but vitamin C content remained unaffected in all the groups. In the spermatozoa, administration of EGEE caused significant decrease in the activities of CAT, GST and LDH as well as in the levels of vitamin C and GSH but significantly increased the MDA level and SOD activity compared with the control rats. Histopathological examination showed severe degeneration of the testes, such as generalized erosion and necrosis of the germinal epithelium of the testes, but mildly affected the epididymis at 400 mg kg-1 dose only. Data on spermatozoa analysis of EGEE-treated rats revealed significant decrease in the epididymal spermatozoa number, testicular spermatozoa number, daily spermatozoa production and spermatozoa motility but significantly increased the total spermatozoa abnormalities without affecting the spermatozoa live-dead ratio at all dose levels when compared with the control group. Results of haematological examination showed that white blood cells (WBC), platelets neutrophils and mean corpuscular haemoglobin concentration (MCHC) were significantly lower whereas lymphocytes were increased in 200 and 400 mg/kg EGEE-exposed rats than in the controls. EGEE at 100 mg/kg bw produced minor effect on haematological parameters but adversely affected testes and spermatozoa. In summary, short term administration of EGEE is hematotoxic and gonadotoxic and its effects on male reproduction could be due to the induction of oxidative stress in testes and spermatozoa.

Bartel, Laura Cecilia ;de Mecca, María Montalto;de Castro, Carmen Rodríguez;Bietto, Florencia Matilde ;Castro, José Alberto

doi: 10.1177/0960327110361756pmid: 20150355

Two nitroheterocyclic drugs, nifurtimox (NFX) and benznidazole (BZ), used in the treatment of Chagas’ disease have serious side effects attributed to their nitroreduction to reactive metabolites. Here, we report that these drugs reach the mammary tissue and there they could undergo in situ bioactivation. Both were detected in mammary tissue from female Sprague-Dawley rats after their intragastric administration. Only NFX was biotransformed by pure xanthine-oxidoreductase and from tissue cytosol. These activities were purine dependent and were inhibited by allopurinol. Also, only NFX was biotransformed by microsomes in the presence of β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), and was inhibited by carbon monoxide and partially by diphenyleneiodonium. NFX treatment produced significant decrease in protein sulfhydryl content after 1, 3 and 6 hours; no increases in protein carbonyl content at any time tested and significantly higher levels of lipid hydroperoxides at 3 and 6 hours; besides, ultrastructural observations after 24 hours showed significant differences in epithelial cells compared to control. These findings indicate that NFX might be more deleterious to mammary tissue than BZ and could correlate with early reports on its ability to promote rat mammary tissue toxicity.

Sorodoc, Laurentiu ;Lionte, Catalina ;Sorodoc, Victorita ;Petris, Ovidiu ;Jaba, Irina

doi: 10.1177/0960327110363327pmid: 20179021

Patients with Amanita phalloides-induced liver failure (LF) have a high mortality, despite significant advances in intensive care managemet. Our study evaluated the effect of Molecular Absorbents Recirculating System (MARS) comparative with optimal intensive care (OIC) in adults with this condition, in the absence of liver transplantation (LT). Six consecutive patients (women, range 16—61 years) affected by A.phalloides-induced LF were treated with OIC (3 patients) and MARS (3 patients). Laboratory parameters and hepeatic encephalopaty were evaluated 15 min before and 24 hours following each MARS treatment. Three 6-hour sessions per patient were performed in MARS group, with a statistically significant decrease in ammonia (p value 0.011), alaninaminotransferase (ALT) and prothrombin time (PT) (p value 0.004). Two patients had a significant rebound in bilirubin (+116%; p value 0. 04) 24 hours following MARS. Mortality in MARS group was 66.7%. Survival rate in OIC was 0%. Negative prognostic markers: lack of PT and hepatic encephalopaty improvement, rebound in bilirubin, and delay of MARS therapy initiation. No significant adverse reactions occurred during MARS. MARS is an effective depurative therapy in adults with A.phalloides-induced LF, but alone is not enough. Survival is predicted by the results of the initial MARS, amount of mushroom consumed, and time from toxin exposure.

Upreti, Raj K ;Kannan, A. ;Pant, AB

doi: 10.1177/0960327110363333pmid: 20167629

Aspirin, a commonly used therapeutic non-steroidal anti-inflammatory drug (NSAID) is known to cause gastric mucosal damage. Intestinal bacteria having a regulatory effect on intestinal homeostasis play significant role in NSAID-induced intestinal injury. Bacteria and specific cell lines are considered to be suitable for toxicity screening and testing of chemicals. Therefore, to evaluate and compare in vitro toxicity, cultures of rat intestinal epithelial cells (IEC), isolated bacteria and IEC-6 cell line were assessed for viability, morphometric analysis, membrane transport enzymes and structural constituents for membrane damage, dehydrogenase activity test for respiratory and energy producing processes and esterase activity test for intra- and extra-cellular degradation, following the post exposure to aspirin (0—50 µg mL- 1). Similar pattern of dose-dependent changes in these parameters were observed in three types of cells. Similar in situ effects on IEC validated the in vitro findings. These findings indicate that higher aspirin concentrations may alter cellular functions of IEC and gut bacteria. Furthermore, results suggest that gut bacteria and IEC-6 cell line can be used for the initial screening of gastrointestinal cellular toxicity caused by NSAIDs.

Sunmonu, TO ;Oloyede, OB

doi: 10.1177/0960327110363441pmid: 20194576

Monocrotophos is an organophosphate pesticide used in agriculture to control insect pests. Changes in performance and haematological parameters (such as packed cell volume, white blood cells, neutrophils, eosinophils and lymphocytes) were used to assess the effect of the pesticide on rats chronically exposed to 12.5 parts per million (ppm), 25 ppm, 50 ppm, 100 ppm and 200 ppm for 10 days, while the control rats were placed on borehole water. Administration of the pesticide to the animals resulted in several physical deteriorations including appearance and agility. A significant reduction (p < .05) was observed in the weight gained by rats while the liver-to-body weight ratio increased significantly (p < .05) as the level of exposure to monocrotophos increased. Whereas packed cell volume, white blood cells and lymphocytes increased significantly (p < .05), neutrophils and eosinophils counts reduced significantly (p < .05) as the concentration of monocrotophos in the drinking water increased. Overall, the data indicated that exposure to monocrotophos portends serious consequences on the performance and haematological parameters of rats.

Ranjbar, Akram ;Ghahremani, Mohammad Hossein ;Sharifzadeh, Mohammad ;Golestani, Abolfazl ;Ghazi-Khansari, Mahmood ;Baeeri, Maryam ;Abdollahi, Mohammad

doi: 10.1177/0960327110363836pmid: 20194575

Objective: The objective of this study was to investigate the possible protective effects of pentoxifylline as a phosphodiesterase-5 inhibitor on malathion-induced oxidative damage to rat brain mitochondria. Methods: Rats received malathion (200 mg/kg/day) and pentoxifylline (PTX, 50 mg/kg/day) in combination or alone. Alpha-tocopherol (AT, 15 mg/kg/day) was used as a positive standard. After 1 week of treatment, blood, whole brain tissue, and brain mitochondria were isolated. The activity of enzymatic scavengers such as glutathione peroxidase (GPx), catalase (CAT), copper-zinc superoxide dismutase (Cu/ZnSOD), and manganese superoxide dismutase (MnSOD) were measured. The extents of cellular lipid peroxidation (LPO), nitrotyrosine (NOx), and the ratio of reduced versus oxidized glutathione (GSH/GSSG) were determined. The protein expression of MnSOD was determined in brain mitochondria. Results: Malathion stimulated activities of CAT, Cu/ZnSOD, GPx, and increased LPO and NOx, and decreased GSH/GSSG in whole brain homogenate. The changes in CAT, LPO, GPx, and GSH/GSSG were restored by PTX and AT. In plasma samples, malathion increased CAT, Cu/ZnSOD, and GPx activities, increased LPO, and decreased GSH/GSSG, while PTX and AT attenuated malathion-induced changes in GPx, Cu/ZnSOD, LPO, and GSH/GSSG. In brain mitochondria, malathion enhanced LPO, NOx, CAT, GPx, and MnSOD and decreased GSH/GSSG as compared to controls, whereas PTX and AT restored malathion-induced changes in GSH/GSSG, NOx, GPx, and CAT. Malathion noticeably enhanced expression of MnSOD protein as compared to controls. Malathion decreased viability of mitochondria that was recovered by AT. It is concluded that oxidative damage is at least in part the mechanism of toxicity of malathion in the mitochondria that can be recovered by PTX comparable to AT.

Bnouham, Mohamed ;Merhfour, Fatima Zahra ;Ziyyat, Abderrahim ;Aziz, Mohamed ;Legssyer, Abdelkhaleq ;Mekhfi, Hassane

doi: 10.1177/0960327110362704pmid: 20154101

The goal of the present study is to test the effect of water extract (WE) of four medicinal plants used as antidiabetics in Eastern Morocco (Arbutus unedo: Au, Ammoïdes pusilla: Ap, Thymelaea hirsuta: Th, and Urtica dioïca: Ud). These plants are used in cooking to bring out the flavor in a dish or to complement it. The first experiment was realized in order to determine the antidiabetic effect of the WE of these plants during 5 weeks’ treatment. Seven groups of Wistar rats were used: Healthy controls, neonatal streptozotocin (n-stz) induced-diabetic rats (90 mg/kg; intraperitoneally [i.p.]), n-stz + tolbutamide (400 mg/l), and 4 groups n-stz + WE of plants (400 mg/l, drink water). The percentages of Plasma glucose lowering effect were, respectively for Au, Ap, Th, Ud and tolbutamide: 31.6 % p<0.01, 27.4 % p<0.05, 38.2 % p<0.01, 13 % and 33.9 % p<0.05 when compared with untreated diabetic controls. In a second experiment, oral glucose tolerance tests were carried out in n-stz induced-diabetic rats. The i.p. administration of the water extract (WE) of Ap and Ud (150 mg/kg) 30 minutes before the glucose overload (2 g/kg) showed a significant reduction glycemia, respectively of 36 % at 60 min (p<0.05) and 50 % at 180 min (p<0.05) after glucose overload compared with controls. In contrast, the effect of WE of Au and Th (150 mg/kg, i.p.) was not significant. The in vitro study of glucose utilization by isolated rat hemidiaphragm suggests that these extracts in combination with insulin potentiate its activity and enhance the utilization of glucose. In conclusion, it seems that these plants possess antidiabetic activity.

Miler, Eliana A ;Nudler, Silvana I ;Quinteros, Fernanda A ;Cabilla, Jimena P ;Ronchetti, Sonia A ;Duvilanski, Beatriz H

doi: 10.1177/0960327110362703pmid: 20197452

Cadmium (Cd2+) is one of the most important environmental contaminants and acts as an endocrine disruptor. Previously, we have demonstrated that the simultaneous administration of Cd2+ and melatonin (Mel) in drinking water impaired metal-induced oxidative stress in rat anterior pituitary gland. The aim of this study was to investigate if a treatment started after the toxic manifestations of Cd 2+ became evident could reverse the effects of the metal. Animals exposed to Cd2+ (5 parts per million [ppm], 30 days) were treated with Mel or without the metal during the next 1 or 2 months. Cd2+ exposure increased the expression of heme oxygenase-1 (HO-1), a biomarker of oxidative stress, and an a posteriori Mel treatment reversed oxidative stress induced by Cd2+. This effect was also observed 1 month after metal removal. The Cd2+-induced increase in metallothionein-1 (MT-1) and nitric oxide synthase 1 (NOS1) expression were also reversed by metal removal. In addition, serum prolactin and luteinizing hormone levels affected by Cd 2+ exposure were normalized. Considering that the manifestations of Cd2+ intoxication become evident only after a certain period of metal accumulation, these results show that metal removal is enough to reverse Cd2+ effects in anterior pituitary gland and bring to light the relevance of moving away the individual from the contamination source.

Mahmood, Danish ;Akhtar, M. ;Vohora, Divya ;Khanam, Razia

doi: 10.1177/0960327110364152pmid: 20194573

Antidepressants (ADs) are frequently used for the treatment of persistent pain associated with diabetic neuropathy. The aim of this study is to investigate the antinociceptive effects of sertraline (Ser) and amitriptyline (Ami) in diabetic rats, and additionally monitoring their effects on grip strength, blood glucose and percentage glycosylated hemoglobin (GHb%) levels. Streptozotocin (STZ; 55 mg/kg, intraperitoneal [ip]) was injected in rats to induce diabetes. After 7 days, Ser (30 mg/kg) or Ami (15 mg/kg) was administered in diabetic rats orally. After 28 days drug treatment, the antinociceptive effects were evaluated using hot plate test both in diabetic and non-diabetic rats. The effects of these drugs on grip strength, blood glucose and GHb% were also measured. Ser and Ami showed antinociceptive effects in diabetic and non-diabetic rats. Both the drugs increased the grip strength reduction in STZ-induced diabetic rats. Ser reduces and Ami increases the serum glucose levels in diabetic and normal rats. Administration of Ami per se increased GHb% levels, while Ser per se has no effects. The effects of Ser (30 mg/kg, per os [po]) on glucose, GHb% and antinociceptive action on hot plate test showed an association between improved blood glucose levels and analgesia. However, the results of Ami treatment are controversial and needs further studies.

Koseoglu, Zikret ;Kara, Banu ;Satar, Salim

doi: 10.1177/0960327110364639pmid: 20203131

Cardiotoxicity is an important adverse effect of tricyclic antidepressants. But cardiac side effects after intoxication with the tetracyclic mianserin are rare. In this paper, we describe a case in which bradycardia and hypotension occured due to mianserin overdose. A 37-year-old woman was admitted to the medical intensive care unit for self-poisoning with 30 tablets of 10 mg mianserin 2 hours before her admission. The patient denied taking any other drugs. Four hours after her admission, bradycardia and hypotension occurred and she began to suffer from giddiness. Atropine and theophylline were given. On the second and third day, her heart rate and blood pressure were normal. Based on this case, we estimate the probability of bradycardia and hypotension in mianserin intoxication and the significance of closely monitoring the patient.