Melatonin protects against endosulfan-induced oxidative tissue damage in rats

Abstract:  Endosulfan is a chlorinated cyclodiene insecticide which induces oxidative stress. In this study, we investigated the possible protective effect of melatonin, an antioxidant agent, against endosulfan (Endo)-induced toxicity in rats. Wistar albino rats (n = 8) were administered endosulfan (22 mg/kg/day orally) followed by either saline (Endo group) or melatonin (10 mg/kg/day, Endo + Mel group) for 5 days. In other rats, saline (control group) or melatonin (10 mg/kg/day, Mel group) was injected for 5 days, following corn oil administration (vehicle of endosulfan). Measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were performed in liver and kidney. Furthermore, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine levels, lactate dehydrogenase (LDH) activity were measured in the serum samples, while tumor necrosis factor-α (TNF-α), interleukin-β (IL-β) and total antioxidant capacity (AOC) were assayed in plasma samples. Endosulfan administration caused a significant decrease in tissue GSH and plasma AOC, which was accompanied with significant rises in tissue MDA and collagen levels and MPO activity. Moreover, the proinflammatory mediators (TNF-α and IL-β), LDH activity, AST, ALT, creatinine and BUN levels were significantly elevated in the endosulfan-treated rats. On the other hand, melatonin treatment reversed all these biochemical alterations induced by endosulfan. Our results suggest that oxidative mechanisms play an important role in endosulfan-induced tissue damage and melatonin, by inhibiting neutrophil infiltration, balancing oxidant–antioxidant status and regulating the generation of inflammatory mediators, ameliorates oxidative organ injury as a result of endosulfan toxicity.     

Endosulfan poisoning with intravascular hemolysis

We describe a 26-year-old female patient, who had attempted suicide with Endosulfan, and who presented to the Emergency Department with status epilepticus. She subsequently developed hypotension refractory to inotropes, intravascular hemolysis, disseminated intravascular coagulation (DIC), metabolic acidosis and, finally, cardiac arrest and death. Endosulfan is a chlorinated insecticide that causes central nervous system hyperstimulation. It is absorbed from the gastrointestinal tract, skin, and respiratory tract, and leads to nausea, vomiting, paraesthesia, giddiness, convulsion, coma, respiratory failure, and congestive cardiac failure. Hepatic, renal and myocardial toxicity, agranulocytosis, aplastic anemia, cerebral edema, DIC, thrombocytopenia, and skin reaction also have been reported. Management includes decontamination of skin and gastrointestinal tract, supportive care including treatment of status epilepticus, dysrhythmias, and mechanical ventilation. Mortality and morbidity rates are very high and there is no specific antidote. Atropine and catecholamines should be avoided.     

A physiologically based pharmacokinetic model for endosulfan in the male Sprague-Dawley rats

Endosulfan, an organochlorine (OC) insecticide belonging to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. To date, no physiologically based pharmacokinetic (PBPK) model has been located for endosulfan in animal species and humans. The estimation by a mathematical model is essential since information on humans can scarcely be obtained experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of (14)C-Endosulfan to male Sprague-Dawley rats. The model was parameterized by using reference physiological parameter values and partition coefficients that were determined in the experiment and optimized by manual adjustment until the best visual fit of the simulations with the experimental data were observed. The model was verified by simulating the disposition of (14)C-Endosulfan in vivo after single and multiple oral dosages and comparing simulated results with experimental results. The model was further verified by using experimental data retrieved from the literature. The present model could reasonably predict target tissue dosimetries in rats. Simulation with three-time repeated administration of (14)C-Endosulfan and experimental data retrieved from the literature by the constructed model fitted fairly well with the experimental results; thus suggesting that the newly developed PBPK model was developed. Sensitivity analyses were used to determine those input parameters with the greatest influence on endosulfan tissue concentrations.     

Chronic exposure to endosulfan induces inflammation in murine colon via β-catenin expression and IL-6 production

Endosulfan (ENDO) is a widely used organochlorine (OC) pesticide and persistent organo-pollutant. Epidemiological studies have shown that high levels of OC exposure were related to colorectal cancer (CRC) incidence. The objectives of the present study were to evaluate histological changes in the colon, as well as in in situ expression of β-catenin and P-selectin, and serum levels of select pro-inflammatory cytokines in mice administered ENDO; there is a relationship between increased serum IL-6 and P-selectin levels in CRC patients and aberrant β-catenin signaling is important in initiation/maintenance of most CRCs. Mice were exposed to ENDO (at dose?50) orally once a week for up to 24 weeks, and monitored (inclusive) for a total of 42 weeks. The experiment was comprised of three groups, one that did not receive ENDO (olive oil vehicle), one administered 2?mg ENDO/kg/week and a positive control (for induction of CRC) given a weekly 20?mg 1,2-dimethylhydrazine (DMH)/kg injection. The results indicated that oral administration of ENDO provoked moderate inflammation starting at six weeks, and severe colonic inflammation with an appearance of dysplastic formations (aberrant crypts) in mice treated with ENDO (or DMH) for 12 weeks or longer. Serum IL-6 levels significantly increased starting at six weeks and rose to a peak of 15-fold higher than in controls at 42 weeks; TNFα levels likewise significantly increased, with a later peak (≈four-fold higher than controls) at 30–42 weeks. Immunohistochemical analysis of the colon also showed that expression of β-catenin and P-selectin increased with length of exposure to ENDO. Taken together, the results indicate that continued repeated oral exposure to ENDO induces increased expression of β-catenin and P-selectin, inflammation in the colon, and, ultimately, local tissue dysplasia.     

The action of cyclodiene pesticides on oxidative phosphorylation in rat liver mitochondria.

The effects of a number of chlorinated hydrocarbon pesticides have been studied on isolated rat liver mitochondria. Inhibition of mitochondrial function was found to be dependent upon the ratio of pesticide to protein, and to some extent upon the type of pesticide. Most of the pesticides tested exerted more than one effect depending upon the concentration. At low concentrations (less than 20–25 nmoles/mg protein). State 3 respiration, DNP-activated respiration and valinomycin-induced swelling were inhibited by certain cyclodienes. These results cannot be explained by inhibition of the electron transport chain or uncoupling. They appear to be associated with restrictions of ion movements across the membrane (DNP, valinomycin-K⁺ complex, ADP). On increasing the concentration of pesticide, lysis of the membranes and uncoupling can be induced. The electron transport chain can also be inhibited, but only with 5–10 times greater concentrations of pesticide than required for uncoupling. In general, the cyclodiene pesticides are slightly more effective inhibitors than the non-cyclodienes tested.2 The effectiveness of the cyclodienes is, however, dependent upon its stereochemical properties. These findings suggest that the cyclodienes may inhibit mitochondria in a common, and, perhaps, specific manner. The specificity and mode of action of cyclodienes was found to be similar to that described earlier (B.D. Nelson and C. Williams, Agric. fd Chem.19, 339 (1971)), using growing yeast cells as the test system.     

Acute toxicity of endosulfan 35EC to two freshwater bivalve molluscs from Godavari river at Maharashtra State, India

Static bioassay tests were conducted using commercial grade endosulfan 35EC to study its toxicity during different seasons to two species of Lamellidens from the Godavari river at Paithan (Maharashtra State). Acute toxicity studies for 96 h showed that both species of Lamellidens were more sensitive to endosulfan 35EC in summer, at times of high temperature, pH and total carbonate content of the water used, than in monsoon and winter. LC0 and LC50 values were determined for L. corrianus and L. marginalis, during summer, monsoon and winter. Statistical analyses showed that both species were more sensitive during summer (P less than 0.001) than in monsoon and winter and that L. marginalis was more sensitive to endosulfan 35EC than L. corrianus in summer (P less than 0.001). Behavioural changes and mortality of the bivalves were dose-related. Regression equations and 95% confidence limits for each species were established in different studies. The results are discussed in the light of possible effects of endosulfan on these species of bivalve molluscs.     

Experimentally induced citrinin and endosulfan toxicity in pregnant Wistar rats: histopathological alterations in liver and kidneys of fetuses

In the present investigation, citrinin (CIT) (10 mg kg(-1) feed) and endosulfan (1 mg kg(-1) body weight) were administered orally alone and in combination to pregnant Wistar rats from gestational day 6 to 20 and their fetuses were collected to evaluate the histopathological alterations in hepatic and renal tissues. In CIT-fed group fetal liver, the changes were less marked, showing only sinusoidal dilation and mild vacuolar degeneration, whereas the consistent changes in the fetal kidney included tubular degeneration, medullary tubular necrosis, cystic dilatation of tubules, distortion of glomerulur capillary tuft and interstitial fibroblastic proliferation which separated clusters of tubules. In the endosulfan group, the liver was predominantly affected, showing vacuolar degeneration, karyomegaly and severe sinusoidal dilation, whereas the renal changes were mainly confined to tubular degeneration and varying degree of interstitial fibrosis. In the combination group, the hepatic and renal histopathological alterations in the fetus, though of similar nature to those of the individual groups, were more severe.     

番茄表层硫丹残留的近红外快速检测方法

选择经Rubberband 64点基线校正和二阶导数(平滑窗口为17,拟合阶数为2)预处理的近红外漫反射光谱,采用Boosting偏最小二乘法(PLS),利用5个子模型建立了番茄表层硫丹残留量预测模型,并对模型的预测性能进行验证。模型的定标系数为0.992,预测残留量范围为5.1~134.1 ng,预测均方根误差（RMSEP）和校正均方误差（RMSECV）分别为2.79 和2.82,训练集和预测集的回收率范围分别为（100.1±1.4）%和（98.9±2.6）%。结果表明：本法快速、准确,有望成为新的蔬菜表层农药残留监测方法。