Malathion exposure modulates hypothalamic gene expression and induces dyslipedemia in Wistar rats

Exposure to organophosphate (OP) pesticides is virtually ubiquitous. These inevitable agents are neurotoxicants, but recent evidence also points to lasting effects on carbohydrate metabolism. The aim of this study was to investigate the effects of 32 repeated treatment days with malathion, an OP insecticide, on some molecular and metabolic parameters. Malathion at 100 mg/kg was administered by gavage in Wistar rats.     

Effect of Aldrin on Carbohydrate Metabolism in Indian Catfish*

Abstract: Exposure of the Indian catfish (Heteropneustes fossilis) to a sublethal concentration of 0.14 p.p.m. aldrin for 3, 6, 12, 48, and 96 hrs affected carbohydrate metabolism. Muscle glycogenolysis and glycogenesis were obtained at 3 and 12 hrs, respectively. Hepatic glycogenolysis occurred at 3, 48, and 96 hrs. The treatment caused hyperglycaemia at 3, 6, 48, and 96 hrs, and hypoglycaemia at 12 hrs. Blood pyruvate values increased significantly at 3, 6, and 96 hrs. Hyperlacticaemia was observed at 3 and 12 hrs but hypolacticaemia developed at 96 hrs. The results are discussed in relation to acute stress syndrome. Also, impairment of carbohydrate metabolism by aldrin may be involved in the biochemical mechanism for its toxic action. It is concluded that evaluation of carbohydrate metabolites in fish could prove useful as a rapid method for assessing acute toxicity of pesticides.     

Cellular metabolic,stress, and histological response on exposure to acute toxicity of endosulfan in Tilapia (Oreochromis mossambicus)

Endosulfan is one of the most hazardous organochlorines pesticides responsible for environmental pollution, as it is very persistent and shows bio‐magnification. This study evaluated the impact of acute endosulfan toxicity on metabolic enzymes, lysozyme activities, heat shock protein (Hsp) 70 expression, and histopathology in Tilapia (Oreochromis mossambicus). Among the indicators that were induced in dose dependent manner were the enzymes of amino acid metabolism (serum alanine aminotransferase and aspartate aminotransferase), carbohydrate metabolism (serum lactate dehydrogenase), pentose phosphate pathway (Glucose‐6‐phosphate dehydrogenase) as well as lysozyme and Hsp70 in liver and gill, while liver and gill Isocitrate dehydrogenase (TCA cycle enzyme) and marker of general energetics (Total adenosine triphosphatase) were inhibited. Histopathological alterations in gill were clubbing of secondary gill lamellae, marked hyperplasia, complete loss of secondary lamellae and atrophy of primary gill filaments. Whereas in liver, swollen hepatocyte, and degeneration with loss of cellular boundaries were distinctly noticed. Overall results clearly demonstrated the unbalanced metabolism and damage of the vital organs like liver and gill in Tilapia due to acute endosulfan exposure. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 106–115, 2016.     

Effects of Acute Exposure to Methyl Parathion on Carbohydrate Metabolism of Indian Catfish (Heteropneustes fossilis)

Abstract: Exposure of the Indian catfish (Heteropneustes fossilis) to a high sublethal concentration of 5.6 p.p.m. (0.8 of the 96 hr LC50) of methyl parathion for 3,6,12,48, and 96 hrs affected carbohydrate metabolism. Muscle glycogen levels decreased significantly at 3,6,12 and 96 hrs; liver glycogen content declined at 6 hrs but there was a resynthesis of hepatic glycogen stores at 12 hrs. Blood glucose levels in fish were elevated at 3 and 6 hrs. Mean values for blood pyruvate were elevated significantly at 6,12, and 96 hrs. Blood lactate level was elevated at 3 hrs but hypolactaemia resulted at 48 and 96 hrs in pesticide-treated fish. The observed effects of methyl parathion on carbohydrate metabolism in fish are discussed in relation to acute stress syndrome. Measurement of carbohydrate metabolites in fish for 3 hrs or longer could prove useful as a rapid method for evaluating toxicity of pesticides and other toxicants.     

三氯生对大鼠碳水化合物代谢的影响

目的　探讨三氯生对碳水化合物代谢以及糖尿病有无影响。方法　给SD大鼠三氯生按 5 0、15 0、2 5 0mg·kg- 1,ig ,每天 1次 ,连续 5周 ,测定血糖和乳酸浓度 ,并进行糖耐量实验。所得数据分别作单相关分析和多元逐步回归分析。结果　三氯生使大鼠血糖、乳酸浓度分别呈剂量依赖性地升高 ,糖耐量能力降低 ,说明大鼠的糖代谢受到了三氯生的干扰。结论　三氯生可影响大鼠糖代谢。     

Evidence for diabetogenic action of bumetanide in mice

The effect of bumetanide on carbohydrate metabolism was studied in mice. Intraperitoneal injection of 50 or 100 mg bumetanide/kg body weight resulted in an acute and transient hyperglycaemia. Pretreatment with 240 mg probenecid/kg body weight reduced the diuretic effect but potentiated the hyperglycaemic effect of bumetanide (50 mg/kg body weight). The glucose tolerance was impaired, and there was an elevated serum glucose and glucose/insulin ratio 2 h after a single injection of bumetanide (100 mg/kg body weight). It is suggested that bumetanide has an acute effect on carbohydrate metabolism in mice that is not secondary to diuresis and that the reduced glucose tolerance may, at least in part, be due to a reduced capacity to secrete insulin.     

Prior cadmium exposure improves glucoregulation in diabetic rats but exacerbates effects on metabolic dysregulation, oxidative stress, and hepatic and renal toxicity

The present study was taken up to assess the role of subchronic exposure to an environmentally relevant dosage of cadmium in type l diabetes. Female rats of the Wistar strain were treated with cadmium (5.12?mg/kg body weight) for 45 days. On day 46, rats were made diabetic by alloxan. After 7 days, diabetes (i.e., animals with serum glucose greater than 300?mg/dL) in the alloxanized animals was confirmed and further experiments were conducted for 15 days. Cadmium pretreatment showed disturbed glucose homeostasis with attendant changes in carbohydrate metabolism, coupled with decrease in food and water intake. Disturbance in carbohydrate metabolism was indicated by altered tissue metabolite load, as marked by a decrease in protein and glycogen contents and increased cholesterol store. Poor glucose clearance subsequent to a glucose challenge under the glucose tolerance test was observed in these animals (0.48/min in control vs. 0.13/min in Cd animals). There was a significantly lower glucose elevation rate in the insulin response test subsequent to an insulin-induced decrease in glucose level in Cd-exposed animals. Elevated oxidative stress was marked by increased lipid peroxidation, decreased antioxidant (both nonenzymatic and enzymatic) levels, and serum markers of hepatic and renal damage. Decreased corticosterone levels, together with increased E2 and reduced P4 levels, were some of the hallmark changes in the serum hormone profile of Cd-exposed animals. Overall, the present results are novel and interesting to open more investigations on animal models of type 1 diabetes with a history of previous Cd exposure.     

Hepatic injury and disturbed amino acid metabolism in mice following prolonged exposure to organophosphorus pesticides

Chronic occupational exposure to organophosphorus and carbamate-type pesticides significantly inhibits acetylcholinesterase activity and causes morbidity. This study on mice was designed to evaluate their amino profile and to identify signs of hepatic dysfunction following their chronic exposure to mixtures of organophosphorus pesticides. Laboratory mice were exposed to a formulated mixture of the six organophosphorus pesticides (Dimethoate, Chlorpyrifos, Profenofos, Pirimiphos methyl, Triazophos and Dimethoate) most commonly used in agriculture in this region of the Middle East. Doses (10% of LD50 of the mixture) were given once a week by gavage in corn oil for 7 weeks; the control group was given only corn oil. At the end of the exposure period, mice were culled and blood samples were collected to determine erythrocyte acetylcholinesterase activity, biochemical markers of liver function and concentrations of serum amino acids. Erythrocyte acetylcholinesterase activity and total serum proteins decreased significantly in the exposed group. Serum concentrations of alanine aminotransferase and aspartate aminotransferase, alanine, glutamic acid, glycine, isoleucine, leucine, methionine, ornithine, proline, serine, threonine and valine were significantly increased in the exposed mice, while serum levels of cystine were decreased significantly. There were also non-significant increases in serum alkaline phosphatase, gama-glutamyl transpeptidase and some of the other amino acids. Chronic exposure to mixtures of organophosphorus pesticides is associated with decreased acetylcholinesterase activity, hepatic dysfunction and disturbance of amino acids profile. Biochemical indices of hepatocellular injury and disturbed amino acid metabolism may be of value as markers of chronic exposure to such pesticides.     

Chronic exposure of bisphenol A impairs carbohydrate and lipid metabolism by altering corresponding enzymatic and metabolic pathways

Bisphenol-A (BPA), a widespread endocrine-disrupting chemical, has been recognized as a risk factor for metabolic disorders. BPA is considered to be involved in the impairment of carbohydrate and lipid metabolism but the underlying mechanisms still need to be elucidated. Present study was aimed to investigate the impact of BPA exposure on enzymatic and metabolic pathways that are responsible to regulate the carbohydrate and lipid metabolism. Experimental rats were exposed to different doses of BPA (50, 500, 2500 and 5000 μg/kg/day orally) dissolved in 1.5% dimethyl sulfoxide for a period of 3 months. Serum level of key metabolic enzymes (α-amylase, α-glucosidase, hexokinase, glucose-6-phosphatase and HMG-CoA-reductase) was measured by ELISA method. BPA-exposure suppressed the mRNA expression of gene encoding insulin resulting in poor insulin production. While hexokinase, acetyl-CoA carboxylase and squalene epoxide were up-regulated upon BPA exposure that justified the increased lipid profile. Moreover, BPA exposure showed considerably decreased glucose uptake through insulin signaling via Akt/GLUT4 pathways. There was a significant (p < 0.001) reduction in tissue level of glucose transporters. BPA significantly (p < 0.001) decreased the serum levels of oxidative stress biomarkers (GSH, CAT, and SOD). Serum levels of leptin, TNF-α, and IL-6 were rapidly increased upon exposure to BPA (p < 0.001). It was clearly evident from this study that BPA disturbed the carbohydrate and lipid metabolism after chronic exposure. It also accelerated the inflammatory processes by increasing the oxidative stress which ultimately lead towards the insulin resistance and impaired carbohydrate and lipid metabolism.     

Serum Growth Hormone,Serum Immunoreactive Insulin and Blood Glucose Response to Intravenous Tolbutamide in Postmenopausal Women with and without Natural Oestrogen Therapy

Abstract The response of serum growth hormone, serum immunoreactive insulin and blood glucose to intravenously administered tolbutamide was studied in twenty non-obese and four obese healthy volunteer postmenopausal women with or without oestrogen therapy. Fasting blood glucose and the maximal fall in blood glucose during the test (44 % and 45 %) was normal in the non-obese control and oestrogen groups, and the two groups did not differ significantly from each other. Even the four obese women, two on oestrogen therapy and two without, showed a normal blood glucose response to tolbutamide. Moreover the response of serum immunoreactive insulin to tolbutamide was normal in subjects both with and without oestrogen therapy and there were no significant differences between the two groups. The response of serum growth hormone to tolbutamide was small in both groups, but slightly more pronounced in the non-obese women undergoing oestrogen therapy than in the controls. It is concluded that a postmenopausal period of five years leads to no impairment in carbohydrate metabolism in healthy women, and an oestrogen therapy for 3–7 years has no effects on glucose tolerance in healthy postmenopausal subjects.     

Influences of levodopa on adipose tissue and skeletal muscle metabolism in patients with idiopathic Parkinson’s disease

OBJECTIVE: The substantial weight loss in Parkinson's patients may be related to direct influences of levodopa treatment on fat mobilization/oxidation. We assessed systemic and local metabolic responses to levodopa/benserazide in patients with idiopathic Parkinson's disease. METHODS: We studied 10 Parkinson's disease patients and examined adipose tissue and skeletal muscle metabolism directly with microdialysis. We monitored dialysate concentrations of ethanol, glucose, lactate, pyruvate, and glycerol to assess tissue blood flow and metabolism before and after levodopa/benserazide intake. We also conducted in vitro studies on adipocytes from healthy women. RESULTS: Levodopa/benserazide increased serum levodopa, 3,4-dihydroxyphenylacetic acid (DOPAC), and norepinephrine (P < 0.01). Serum adipose tissue and skeletal muscle glycerol did not change or decreased. Adipose tissue glycerol was inversely correlated with serum levodopa concentrations (P < 0.05). In isolated adipocytes, levodopa attenuated isoproterenol-induced glycerol release (P < 0.05). CONCLUSION: Levodopa/benserazide elicits pronounced metabolic changes in both adipose tissue and skeletal muscle with a switch from lipid to carbohydrate metabolism. In adipose tissue, levodopa/benserazide failed to activate lipolysis. Therefore, we suggest that levodopa/benserazide does not induce fat wasting through direct and acute influences on adipose tissue metabolism.     

Studies on the protective effect of green tea against cisplatin induced nephrotoxicity

Cisplatin (CP) an anticancer drug is known to induce nephrotoxicity, which limits its long-term clinical use. Green tea (GT), consumed since ancient times is known for its numerous health benefits. It has been shown to improve kidney functions in animal models of acute renal failure. The present study was undertaken to see whether GT can prevent CP-induced nephrotoxic and other deleterious effects. A nephrotoxic dose of CP was co-administered to control and GT-fed male Wistar rats every fifth day for 25 days. The effect of GT was determined on CP-induced alterations in various serum parameters and on enzymes of carbohydrate metabolism, brush border membrane, and antioxidant defense system in renal cortex and medulla. CP nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. CP increased the activities of lactate dehydrogenase and acid phosphatase whereas, the activities of malate dehydrogenase, glucose-6-phosphatase, superoxide dismutase, catalase, and ³²Pi transport significantly decreased. GT consumption increased the activities of the enzymes of carbohydrate metabolism, brush border membrane, oxidative stress, and ³²Pi transport. GT ameliorated CP-induced nephrotoxic and other deleterious effects due to its intrinsic biochemical/antioxidant properties.     

The effect of pimobendan on myocardial mechanical function and metabolism in dogs: comparison with dobutamine.

The effect of pimobendan, a newly developed cardiotonic agent, on myocardial mechanical function and energy metabolism has been examined in the dog heart, and compared with that of dobutamine. Either saline, vehicle for pimobendan, dobutamine (0.3 and 1 microgram kg-1), or pimobendan (0.3 and 1 mg kg-1) was injected intravenously. Dobutamine and pimobendan both increased the first derivative of left ventricular pressure and percent segment shortening, indicating their positive inotropic action. After 2 min of dobutamine injection, or after 20 min of pimobendan injection, the myocardium was removed, and used for determination of the tissue levels of metabolites of energy and carbohydrate metabolism. In general, all metabolic parameters measured were not changed by either dobutamine or pimobendan injection. In animals with aortic constriction for 10 months, dobutamine and pimobendan injections did not alter the myocardial energy and carbohydrate metabolism. Although dobutamine and pimobendan increased the cardiac mechanical function, they did not disturb the myocardial energy and carbohydrate metabolism.     

EFFECTS OF THE PESTICIDES CARBOFURAN,CHLORPYRIFOS, DIMETHOATE,LINDANE, TRIALLATE,TRIFLURALIN, 2,4-D,AND PENTACHLOROPHENOL ON THE METABOLIC ENDOCRINE AND REPRODUCTIVE ENDOCRINE SYSTEM IN EWES

Many pesticides are used in the agricultural environment, and some may have the potential to disrupt reproductive or endocrine function. Ewes, in separate groups of 6, received orally into their rumen either empty gelatin capsules or capsules containing chlorpyrifos (12.5 mg/ kg), trifluralin (17.5 mg/ kg), lindane (2.5 mg/ kg), or pentachlorophenol (2 mg/kg) 2 times per week for 43 d. Dimethoate (0.2 mg/kg), carbofuran (0.30 mg/kg), 2,4-dichlorophenoxyacetic acid (10 mg/kg), or triallate (5 mg/kg) was given 3 times per week. After 36 d of treatment, blood samples were taken every 12 min for 6 h for hormone analysis. Ewes were euthanized at the end of the study for necropsy and histopathology. No overt signs of toxicity were seen, and body weight was not affected by treatment. Carbofuran caused a significant increase in serum concentrations of thyroxine compared to control ewes, but all other pesticides, except trifluralin, resulted in a marked decrease in thyroxine concentrations. Serum concentrations of cortisol were significantly increased by trifluralin and chlorpyrifos. Concentrations of insulin in serum were markedly increased in ewes given dimethoate, lindane, trifluralin, triallate, and pentachlorophenol, and concentrations of estradiol were also significantly increased in ewes given lindane and trifluralin. Mean serum concentrations of LH were markedly decreased by trifluralin, and basal LH concentrations were significantly decreased by lindane, dimethoate, and trifluralin but increased by triallate. Both pentachlorophenol and triallate caused a significant increase in severity of oviductal intraepithelial cysts in ewes. Data suggest that several currently used pesticides could influence serum concentrations of reproductive and metabolic hormones, particularly thyroxine, the major secretory product of the thyroid and a principal regulator of metabolism.     

Application of an enantioselective LC-ESI MS/MS procedure to determine R- and S-hyoscyamine following intravenous atropine administration in swine

S-hyoscyamine (S-hyo) is a natural plant tropane alkaloid acting as a muscarinic receptor (MR) antagonist. Its racemic mixture (atropine) is clinically used in pre-anaesthesia, ophthalmology and for the antidotal treatment of organophosphorus (OP) poisoning with nerve agents or pesticides even though R-hyo exhibits no effects on MR. Further investigative research is required to optimize treatment of OP poisoning. Swine are often the animal model utilized due to similarities in physiology and antidote response to humans. However, no studies have been reported that elucidated differences in the kinetics of R- and S-hyo. Therefore, the concentration-time profiles of total hyo as well as both enantiomers were analyzed in plasma after intravenous administration of atropine sulfate (Atr(2) SO(4) , 100?μg/kg) to anaesthetized swine. For quantification plasma samples were incubated separately with human serum (procedure A) and rabbit serum (procedure B). The rabbit serum used contained atropinesterase, which is suitable for stereoselective hydrolysis of S-hyo, while human serum does not hydrolyze either enantiomer. After incubation samples were precipitated and the supernatant was analyzed by RP-HPLC-ESI MS/MS. Procedure A allowed determination of total hyo and procedure B remaining R-hyo concentrations. S-hyo was calculated as the difference of the two procedures. Concentration data were regressed by a two-phase decay according to a two-compartment open model revealing similar kinetics for both enantiomers thus indicating distribution, metabolism and elimination without obvious stereoselective preference in tested swine.     

A theoretical approach to the mechanism of biological oxidation of organophosphorus pesticides

Organophosphorus pesticides are the most common classes involved in poisonings related to pesticides. We used enzymatic activity of chloroperoxidase on the metabolism of some phosphorothioate pesticides published previously and molecular mechanics methods to perform a theoretical approach of the mechanism of biological oxidation of this class of pesticides. The molecular structure of eight pesticides were optimized by molecular mechanics methods using the CAChe program package for biomolecules, ver. 3.11 (Oxford Molecular Ltd., Campbell, CA). Total energy resulted from the structure optimization process and the partial charges of both phosphorus and sulfur were computed for every pesticide. Phosphorus partial charge and enzymatic activity were significantly related by linear regression analysis (r=0.82, P<0.05). Analyzing our results and using previously reported enzymatic activity of chloroperoxidase on these pesticides, we deduced chemical events involved in activation of the active site of chloroperoxidase and proposed a novel mechanism of oxidation for this class of pesticides. This mechanism will also help to understand the oxidation process of pesticides by cytochrome P450, and production of toxic metabolites.     

The metabolic effects of isradipine, ramipril, Ednit and beta-adrenoblockers in patients with non-insulin-dependent diabetes mellitus and arterial hypertension]

The effect of isradepin, ramipril, ednyt, and beta-adrenoblockers on carbohydrate and lipid metabolism and free-radical oxidation in patients with insulin-independent diabetes mellitus was studied. Isradepin caused an increase in high-density lipoproteins (HDLP) in the blood serum and the content of esterified cholesterol in HDLP, and reduced the arterogenicity coefficient. Rampiril reduced the basal level of glycemia and insulin. Treatment with ednyt lead to increase in the content of HDLP and the content of free cholesterol in them. In the course of treatment isradepin normalized chemoluminescence of the serum and urine, rampiril that of serum, and beta-adrenoblockers the chemoluminescence of the blood. The favorable changes induced by the drugs under study allow them to be recommended for the treatment of arterial hypertension in patients with insulin-independent diabetes mellitus.     

Impairment of insulin secretion in man by nifedipine

Summary The effect of nifedipine, a calcium antagonist, on carbohydrate metabolism and insulin secretion was evaluated in patients who required treatment with this drug. 20 subjects underwent two oral glucose tolerance tests (100 g), one under basal conditions, and the other after ten days of treatment with nifedipine 30 mg/day by mouth, in three divided doses. 10 subjects had normal glucose tolerance; in them nifedipine administration reduced the insulin response to oral glucose in the first 60 min, but improved glucose tolerance. The other 10 subjects had impaired glucose tolerance and nifedipine treatment resulted in a further reduction both of insulin secretion and glucose tolerance. No such effects were seen in the placebo (weight- and disease-matched) group. The mechanism by which nifedipine influences carbohydrate metabolism and insulin secretion is discussed.     

Association between organophosphate pesticides exposure and thyroid hormones in floriculture workers

The ability of organophosphate pesticides to disturb thyroid gland function has been demonstrated by experimental studies on animal, but evidence of such effects on human remains scarce. The aim of this study was to assess the association between exposure to organophosphate compounds and serum levels of thyroid hormones in floriculture workers. A longitudinal study was conducted on 136 male subjects from the State of Mexico and Morelos, Mexico, occupationally exposed to organophosphate pesticides, during agricultural periods of high (rainy season) and low (dry season) levels of pesticide application. Using a structured questionnaire, a survey was carried out on sociodemographic characteristics, anthropometry, clinical history, alcohol and tobacco consumption, residential chemical exposure, and occupational history. Urine and blood samples were taken the day after pesticide application to determine urine dialkylphosphate (DAP) levels, serum levels of TSH, total T₃, total T₄, serum PON1 activity, and serum p,p′-DEE levels. The analysis of the association between DAP levels and thyroid hormonal profile was carried out using multivariate generalized estimating equation (GEE) models. Our results showed an increase in both TSH and T₄ hormones in serum associated with a increase in total dimethylphosphate levels (ΣDMP) in urine (p-trend < 0.001) and a decrease in total T₃ serum levels with an increase of ΣDMP levels in the urine (p-trend = 0.053). These results suggest that exposure to organophosphate pesticides may be responsible of increasing TSH and T₄ serum hormone levels and decreasing T₃ serum hormone levels, therefore supporting the hypothesis that organophosphate pesticides act as endocrine disruptors in humans.     

Rapid simultaneous determination for organophosphorus pesticides in human serum by LC-MS

A simple and rapid method was developed for measuring 10 organophosphorus pesticides (acephate, methidathion, dichlorvos, fenthion, EPN, diazinon, phenthoate, malathion, fenitrothion, and cyanophos) in the serum of acute poisoning patients by LC/MS. Following deproteinization by acetonitrile, an aliquot of the biological sample was injected into a C(18) column using 10mM ammonium formate-methanol as the mobile phase. Extraction recoveries were satisfactory and ranged between 60.0 and 108.1% in serum. The limits of detection (LODs) in serum ranged from 0.125 to 1 microg/ml, and the limits of quantitation (LOQs) ranged from 0.25 to 1.25 microg/ml. An excellent linearity was observed for these LOQs up to 8 microg/ml. Intra- and interassay precision and accuracy were satisfactory for most of the pesticides analyzed. In terms of temperature stability, of all the organophosphorus compounds analyzed, dichlorvos and malathion exhibited the most rapid degradations over 24h at room temperature. Methidathion and diazinon remained relatively stable at all temperatures during the entire 4-week testing period. The present method was successfully applied to one actual case of acute poisoning. In conclusion, this method is simple, accurate, and useful for the determination of organophosphorus pesticides and should benefit both clinical and forensic toxicology.