Prospective protective role of melatonin against arsenic-induced metabolic toxicity in Wistar rats

Pal, Sudipta; Chatterjee, Ankit

doi:10.1016/j.tox.2004.11.005

Cited by 34 publications

(26 citation statements)

References 49 publications

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“…Results of in vitro studies have consistently shown significant increases in basal (insulin-independent) glucose uptake by various types of cells or dissected tissues exposed to cytotoxic concentrations of a trivalent iAs, arsenite (iAs III ), or an aromatic derivative of As III , phenylarsine oxide (PAO) (Bazuine et al 2003, 2004; Brazy et al 1980; McDowell et al 1997; Pasternak et al 1991; Short 1965; Sviderskaya et al 1996; Widnell et al 1990). Consistent with these findings, some in vivo studies have reported moderate or severe hypoglycemia in animals chronically exposed to toxic, often lethal, concentrations of iAs III or arsenate (iAs V ), in drinking water (Hughes and Thompson 1996; Pal and Chatterjee 2004a, 2004b, 2005). Only limited information is available on the effects of arsenicals on glucose metabolism at low concentrations that are compatible with environmental or occupational exposures.…”

mentioning

confidence: 67%

Molecular Mechanisms of the Diabetogenic Effects of Arsenic: Inhibition of Insulin Signaling by Arsenite and Methylarsonous Acid

Paul¹,

Harmon²,

Devesa

et al. 2007

Environ Health Perspect

149

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BackgroundIncreased prevalences of diabetes mellitus have been reported among individuals chronically exposed to inorganic arsenic (iAs). However, the mechanisms underlying the diabetogenic effects of iAs have not been characterized. We have previously shown that trivalent metabolites of iAs, arsenite (iAsIII) and methylarsonous acid (MAsIII) inhibit insulin-stimulated glucose uptake (ISGU) in 3T3-L1 adipocytes by suppressing the insulin-dependent phosphorylation of protein kinase B (PKB/Akt).ObjectivesOur goal was to identify the molecular mechanisms responsible for the suppression of PKB/Akt phosphorylation by iAsIII and MAsIII.MethodsThe effects of iAsIII and MAsIII on components of the insulin-activated signal transduction pathway that regulate PKB/Akt phosphorylation were examined in 3T3-L1 adipocytes.ResultsSubtoxic concentrations of iAsIII or MAsIII had little or no effect on the activity of phosphatidylinositol 3-kinase (PI-3K), which synthesizes phosphatidylinositol-3,4,5-triphosphate (PIP3), or on phosphorylation of PTEN (phosphatase and tensin homolog deleted on chromosome ten), a PIP3 phosphatase. Neither iAsIII nor MAsIII interfered with the phosphorylation of 3-phosphoinositide-dependent kinase-1 (PDK-1) located downstream from PI-3K. However, PDK-1 activity was inhibited by both iAsIII and MAsIII. Consistent with these findings, PDK-1-catalyzed phosphorylation of PKB/Akt(Thr308) and PKB/Akt activity were suppressed in exposed cells. In addition, PKB/Akt(Ser473) phosphorylation, which is catalyzed by a putative PDK-2, was also suppressed. Notably, expression of constitutively active PKB/Akt restored the normal ISGU pattern in adipocytes treated with either iAsIII or MAsIII.ConclusionsThese results suggest that inhibition of the PDK-1/PKB/Akt-mediated transduction step is the key mechanism for the inhibition of ISGU in adipocytes exposed to iAsIII or MAsIII, and possibly for impaired glucose tolerance associated with human exposures to iAs.

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mentioning

confidence: 67%

Molecular Mechanisms of the Diabetogenic Effects of Arsenic: Inhibition of Insulin Signaling by Arsenite and Methylarsonous Acid

Paul¹,

Harmon²,

Devesa

et al. 2007

Environ Health Perspect

149

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“…In fact, to sodium arsenite also change the weight testis does not cauda epididymis of rats (5.5 mg by 30 days) (Pal & Chatterjee, 2005).…”

Section: Discussionmentioning

confidence: 93%

Melatonin Protective Role in Mouse Cauda Epipidymal Spermatozoa Damage Induced by Sodium Arsenite

et al. 2013

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SUMMARY:We evaluated the sperm parameters such as cauda epididymis weight, sperm count, sperm morphology and sperm DNA stability of adult CF-1 male mice treated daily (oral exposure) with the toxic sodium arsenite (As, 7.0 mg/kg/body weight); Melatonin (Me, 10.0 mg/kg/bw), Me (10.0 mg/kg/bw) plus As (7.0 mg/kg/bw) and Negative Control (NaCl 0.9%) to assess acute (8.3 days), chronic (33.2 days) and recovery of testicular damage (66.4 days). Arsenic decreases the number of sperm from chronic treatment (33.2 days) and this effect continued until 66.4 days of treatment. The toxic effect of As also altered the morphology of spermatozoa in all treatment periods when compared to the negative control group. However, Metalonin induced protective effects in periods of 33.2 and 66.4 days of treatment. Additionally, the stability of DNA was significantly affected by arsenic in all periods, but the chronic treatment (33.2 days) in the AsMe revealed increased stability compared to the group treated with arsenic only. Melatonin partially protects sperm toxicity caused by Arsenic, especially during periods of 33.2 and 66.4 days. 1252In this work, we aim to determine the effects of acute, chronic and recovery of testicular exposure to sodium arsenite in epididymal sperm and assess the use of melatonin as a protective agent and antioxidant. MATERIAL AND METHODThree-month-old male mice (Mus musculus) strain CF-1, healthy and sexually mature, were obtained from the Faculty of Medicine, University of Chile. The animals were maintained in a room under controlled conditions of temperature (22±2°C), and a 12 h light/dark cycle, with ad libitum access to commercial pellets and tap water.Reproductive changes were studied as acute (8.3 days), chronic (33.2 days) and recovery of testicular damage (66.4 days) in 88 adult mice exposed every day to oral doses of Sodium Arsenite (As; 7.0 mg/kg/bw, Sigma Chemical Co., St. Louis, MO); Melatonin (Me; 10.0 mg/kg/bw, Arama Laboratorios SA, Santiago, Chile) (Gutelkin et al., 2001); Me (10.0 mg/kg/bw) plus As (7.0 mg/kg/bw), and Negative Control (NaCl 0.9%) delivered orally in a volume not greater than 0.05 mL.Before the beginning and after the end of treatment, all animals were weighted. Euthanasia was performed by cervical dislocation after anesthesia with ketamine (Laboratory Biosano SA, Santiago, Chile) according to the protocol of animal handling of the Bioethics Committee of the Faculty of Medicine, University of Chile. Sperm Parameters.Extraction, weighing and sperm count in epididymalcauda. After obtaining the cauda epididymis they were weighed. Then sperm suspension was obtained using the protocol by Fornés & Bustos-Obregón (1994). Sperm were counted at 200X in a microscope, equipped to use Makler® chamber, adding a drop of sperm suspension by capillary and counting in duplicate the sperm present in the 100 squares of the camera, expressing this result as a million sperm/mg epididymis. Sperm morphology analysis.From the sperm suspension obtained above it was obtained 200 µL of sample. Addit...

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“…Most of the studies treated animals with AsIII or arsenic trioxide, but other arsenicals have also been studied (Aguilar et al 1997; Arnold et al 2003; Hill et al 2009; Paul et al 2008). The studies also vary in experimental design and model systems used to assess end points relevant to diabetes as a health effect, ranging from urinary glucose in fasted animals (Pal and Chatterjee 2005), to blood glucose in nonfasted animals (Mitchell et al 2000), to glucose tolerance test (Cobo and Castineira 1997; Ghafghazi et al 1980; Hill et al 2009; Paul et al 2007b, 2008, 2011; Wang et al 2009). Glucose was a commonly reported end point but findings were inconsistent across studies, which may stem from differences in the biological compartment assessed (urine, serum, plasma, whole blood) and fasting status of the animal (fasted, nonfasted, fasting status not reported) in addition to the differences in experimental design noted above related to arsenical tested, species, route of administration, and dose levels (Aguilar et al 1997; Arnold et al 2003; Biswas et al 2000; Boquist et al 1988; Ghafghazi et al 1980; Hill et al 2009; Izquierdo-Vega et al 2006; Judd 1979; Mitchell et al 2000; Pal and Chatterjee 2004a, 2004b, 2005; Paul et al 2007b, 2008, 2011; Wang et al 2009).…”

Section: Experimental Animal Studiesmentioning

confidence: 99%

“…Measures of insulin regulation [i.e., HOMA-IR (homeostasis model assessment of insulin resistance), insulin sensitivity (Paul et al 2011)], as well as pancreatic effects [including indicators of oxidative stress, degenerative changes in β-cells, and pancreatitis (Arnold et al 2003; Boquist et al 1988; Izquierdo-Vega et al 2006; Mukherjee et al 2006; Yen et al 2007)], have also been reported to be affected. Results from several animal studies suggest that cotreatment with methyl donors or antioxidants (e.g., folic acid, vitamin B 12 , methionine, N -acetyl cysteine) may attenuate the effects of arsenic toxicity, including reductions in the degree of arsenic-induced pancreatic toxicity (Mukherjee et al 2006) and arsenic-induced hyperglycemia (Pal and Chatterjee 2004a, 2004b, 2005). Although not directly assessing the potential diabetogenic effects of arsenic, Reichl et al (1990) reported that cotreatment with glucose increased the survival rate in NMRI mice treated with a dose of AsIII oxide that resulted in 100% mortality when administered without the glucose (12.9 mg/kg by subcutaneous injection).…”

Section: Experimental Animal Studiesmentioning

confidence: 99%

Evaluation of the Association between Arsenic and Diabetes: A National Toxicology Program Workshop Review

Maull

Ahsan

Edwards

et al. 2012

Environ Health Perspect

306

264

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Background: Diabetes affects an estimated 346 million persons globally, and total deaths from diabetes are projected to increase > 50% in the next decade. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. In 2011, the National Toxicology Program (NTP) organized a workshop to assess the literature for evidence of associations between certain chemicals, including inorganic arsenic, and diabetes and/or obesity to help develop a focused research agenda. This review is derived from discussions at that workshop.Objectives: Our objectives were to assess the consistency, strength/weaknesses, and biological plausibility of findings in the scientific literature regarding arsenic and diabetes and to identify data gaps and areas for future evaluation or research. The extent of the existing literature was insufficient to consider obesity as an outcome.Data Sources, Extraction, and Synthesis: Studies related to arsenic and diabetes or obesity were identified through PubMed and supplemented with relevant studies identified by reviewing the reference lists in the primary literature or review articles.Conclusions: Existing human data provide limited to sufficient support for an association between arsenic and diabetes in populations with relatively high exposure levels (≥ 150 µg arsenic/L in drinking water). The evidence is insufficient to conclude that arsenic is associated with diabetes in lower exposure (< 150 µg arsenic/L drinking water), although recent studies with better measures of outcome and exposure support an association. The animal literature as a whole was inconclusive; however, studies using better measures of diabetes-relevant end points support a link between arsenic and diabetes.

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Prospective protective role of melatonin against arsenic-induced metabolic toxicity in Wistar rats

Cited by 34 publications

References 49 publications

Molecular Mechanisms of the Diabetogenic Effects of Arsenic: Inhibition of Insulin Signaling by Arsenite and Methylarsonous Acid

Molecular Mechanisms of the Diabetogenic Effects of Arsenic: Inhibition of Insulin Signaling by Arsenite and Methylarsonous Acid

Melatonin Protective Role in Mouse Cauda Epipidymal Spermatozoa Damage Induced by Sodium Arsenite

Evaluation of the Association between Arsenic and Diabetes: A National Toxicology Program Workshop Review

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