Specific Metabolic Fingerprint of a Dietary Exposure to a Very Low Dose of Endosulfan

Canlet, Cécile; Tremblay-Franco, Marie; Gautier, Roselyne; Molina, Jérôme; Metais, B; Estrada, Florence Blas-Y; Gamet-Payrastre, Laurence

doi:10.1155/2013/545802

Cited by 15 publications

(9 citation statements)

References 43 publications

(46 reference statements)

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“…A recent comprehensive review showed that exposure to pesticides mixtures may induce metabolic modifications potentially linked with physiopathological disturbances [ 24 ]. Endosulfan, atrazine, and chlorpyrifos in combination can potentially induce changes in amino-acid metabolism, the citrate cycle, the urea cycle, and glucose metabolism through an oxidative disturbance in mice [ 25 , 26 ]. Exposure to organophosphorus mixtures (chlorpyrifos and carbaryl, or dichlorvos, dimethoate, acephate, phorate) induces disturbances in energy and lipid metabolism in rats [ 27 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolome disruption of pregnant rats and their offspring resulting from repeated exposure to a pesticide mixture representative of environmental contamination in Brittany

et al. 2018

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The use of pesticides exposes humans to numerous harmful molecules. Exposure in early-life may be responsible for adverse effects in later life. This study aimed to assess the metabolic modifications induced in pregnant rats and their offspring by a pesticide mixture representative of human exposure. Ten pregnant rats were exposed to a mixture of eight pesticides: acetochlor (246 μg/kg bw/d) + bromoxynil (12 μg/kg bw/d) + carbofuran (22.5 μg/kg bw/d) + chlormequat (35 μg/kg bw/d) + ethephon (22.5 μg/kg bw/d) + fenpropimorph (15.5 μg/kg bw/d) + glyphosate (12 μg/kg bw/d) + imidacloprid (12.5 μg/kg bw/d) representing the main environmental pesticide exposure in Brittany (France) in 2004. Another group of 10 pregnant rats served as controls. Females were fed ad libitum from early pregnancy, which is from gestational day (GD) 4 to GD 21. Urine samples were collected at GD 15. At the end of the exposure, mothers and pups were euthanized and blood, liver, and brain samples collected. 1H NMR-based metabolomics and GC-FID analyses were performed and PCA and PLS-DA used to discriminate between control and exposed groups. Metabolites for which the levels were significantly modified were then identified using the Kruskal-Wallis test, and p-values were adjusted for multiple testing correction using the False Discovery Rate. The metabolomics analysis revealed many differences between dams of the two groups, especially in the plasma, liver and brain. The modified metabolites are involved in TCA cycle, energy production and storage, lipid and carbohydrate metabolism, and amino-acid metabolism. These modifications suggest that the pesticide mixture may induce oxidative stress associated with mitochondrial dysfunction and the impairment of glucose and lipid metabolism. These observations may reflect liver dysfunction with increased relative liver weight and total lipid content. Similar findings were observed for glucose and energy metabolism in the liver of the offspring, and oxidative stress was also suggested in the brains of male offspring.

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Section: Introductionmentioning

confidence: 99%

Metabolome disruption of pregnant rats and their offspring resulting from repeated exposure to a pesticide mixture representative of environmental contamination in Brittany

et al. 2018

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“…Runoff from agricultural fields and/or discharge during the manufacture of the pesticide is responsible for the majority of ENDO contamination of air, water and soil environments . ENDO residues have also been detected in various fruits, vegetables, nuts, grains and fish (Canlet et al 2013) with concentrations ranging from 0.0005 to 0.013 ppm, and in various sea foods from 0.2 ppt to 1.7 ppb.…”

Section: Introductionmentioning

confidence: 99%

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

Téllez‐Bañuelos

Haramati

Franco-Topete

et al. 2016

Journal of Immunotoxicology

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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 b-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 b-catenin signaling is important in initiation/maintenance of most CRCs. Mice were exposed to ENDO (at dose < LD 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; TNFa 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 b-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 b-catenin and P-selectin, inflammation in the colon, and, ultimately, local tissue dysplasia. ARTICLE HISTORY

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“…In fact, there are data implicating several potential Cyp2b inhibitors such as PCB, nonylphenol, bisphenol A, chlorpyrifos, diazinon, and parathion in increased fat deposition, prediabetic states, and obesity (Lassiter et al, 2008;Masuno et al, 2003;Slotkin, 2011;Wada et al, 2007;Wahlang et al, 2013). Furthermore, metabolic changes in the livers of endosulfan-treated mice are consistent with diabetes and insulin resistance (Canlet et al, 2013).…”

Section: Femalesmentioning

confidence: 99%

Cyp2b‐Knockdown Mice Poorly Metabolize Corn Oil and Are Age‐Dependent Obese

Damiri

Baldwin

2018

Lipids

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We previously made a RNAi-based Cyp2b-knockdown (Cyp2b-KD) mouse to determine the in vivo role of the Cyp2b subfamily in xenobiotic detoxification. Further studies reported here indicate a role for Cyp2b in unsaturated fatty acid (UFA) metabolism and in turn obesity. Mice were treated i.p. with 100 μl corn oil as a carrier or the potent Cyp2b-inducer TCPOBOP (TC) dissolved in corn oil. Surprisingly, female Cyp2b-KD mice but not male mice showed increased liver lipid accumulation. Male Cyp2b-KD mice had higher serum triacylglycerols, cholesterol, VLDL, LDL, and HDL than wildtype (WT) mice; females had higher cholesterol, LDL, and HDL. Thus, Cyp2b-KD mice are unable to clear a high bolus dose of corn oil, potentially because the Cyp2b-KD mice were unable to metabolize the UFA in the corn oil. Therefore, WT and Cyp2b-KD mice were housed for 35 weeks and necropsies performed to test whether Cyp2b-KD mice develop age onset obesity. Cyp2b-KD mice exhibited a significant increase in body weight caused by an increase in white adipose tissue deposition relative to WT mice. Serum cholesterol, triacylglycerol, LDL, and VLDL were significantly greater in 35-week old Cyp2b-KD males compared to WT males; only serum triacylglycerol and LDL were higher in females. In conclusion, changes in Cyp2b expression led to perturbation in lipid metabolism and depuration in Cyp2b-KD mice. This suggests that Cyp2b is more than a detoxification enzyme, but also involved in the metabolism of UFA, as Cyp2b-KD mice have increased body weight, fat deposition and serum lipids.

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Specific Metabolic Fingerprint of a Dietary Exposure to a Very Low Dose of Endosulfan

Cited by 15 publications

References 43 publications

Metabolome disruption of pregnant rats and their offspring resulting from repeated exposure to a pesticide mixture representative of environmental contamination in Brittany

Metabolome disruption of pregnant rats and their offspring resulting from repeated exposure to a pesticide mixture representative of environmental contamination in Brittany

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

Cyp2b‐Knockdown Mice Poorly Metabolize Corn Oil and Are Age‐Dependent Obese

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