Effects of a glyphosate-based herbicide on systemic metabolic alterations and histologic hepatic changes present in an animal model of insulin resistance
DOI:
https://doi.org/10.47196/diab.v50i1.72Keywords:
glyphosate, insulin resistance, sucrose, oxidative stress, hepatic steatosis, inflammation, fibrosisAbstract
Introduction: oxidative stress and inflammation associated with insulin resistance (IR) contribute to the generation of non-alcoholic steatohepatitis. Also, exposure to glyphosate, a widely used herbicide, increases hepatic lipid peroxidation with increased free radicals of O2.
Objectives: to evaluate the effects of the prolonged administration of a herbicide based on glyphosate on the generation of IR, oxidative stress and hepatic histological changes in animals treated with a sucrose rich diet (DRS).
Methodology: male Wistar rats weighing ~300 g received the herbicide (Credit®) injected intraperitoneally (i.p.) 3 times/week at a dose of 50 mg/kg glyphosate (group G, n=6), 30% sucrose in the drinking water (group S, n=6), both treatments (n=8, group G+S) or vehicle injections and tap water (n=7, controls or group C). Serum insulin and glucose levels (basal and after an i.p.
glucose load) were measured during weeks 8-10 after initiating these treatments. During week 13, animals were slaughtered, and liver tissue samples were taken for histologic evaluations and for oxidative stress/lipidic peroxidation estimation (TBARS).
Results: no significant changes in glycemic levels were found. IR (as estimated by HOMA-IR) was slightly increased versus controls in animals receiving G or S, and significantly augmented in G+S rats. These animals also showed marked elevations in hepatic TBARS content. Histologic evaluations showed signs of steatosis and fibrosis in the G and G+S groups, and inflammatory infiltrates in all treated groups.
Conclusions: the administration of glyphosate to animals receiving a sucrose-rich diet results in increased metabolic disturbances. Hepatic oxidative stress is also augmented, thus showing
an additive effect of glyphosate on metabolic and hepatic changes observed in sucrose-treated animals.
References
Clark JM. The epidemiology of nonalcoholic fatty liver disease. J. Clin. Gastroenterology 2006; 40 (3) Suppl 1:S5-10.
Angulo P. GI Epidemiology: nonalcoholic fatty liver disease. Aliment. Phamacol. Ther. 2007, 25; 883-889.
Rafiq N, Bai Ch, et al. Long-term follow up of patients with nonalcoholic fatty liver. Clinical Gastroenterology and Hepatology 2009; 7; 234-238.
El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-8.
Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol. Rev. 2008; 60:311-357.
Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am. J. Clin. Nutr. 2004; 79:537-43.
Angelico F, Del Ben M, Conti R, et al. Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 2005; 90:1578-1582.
Pengue W. Producción agroexportadora e inseguridad alimentaria: el caso de la soja argentina. Rev. Iber. Econ. Ecol. 2004; Vol. 1: 46-55.
Trigo E, Cap E. Diez años de cultivos genéticamente modificados en la agricultura argentina; 2006. http://www.argenbio.org/h/biblioteca/index.php (Acceso: 24/03/2016)
Monroy C, Cortez A, Sicard D, Restrepo H. Cytotoxicity and genotoxicity of human cells exposed in vitro to glyphosate. Biomedica 2005; 25:335-345.
Adam A, Marzuki A, Arman H, Asís M. The oral and intratracheal toxicities of Roundup and its components to rats. Vet. Hum. Toxicology. 1997; 39 (3):147-151.
Sawada Y, Nagai Y, Ueyama M. Probable toxicity of the surface active agent in commercial herbicide containing glyphosate. Lancet 1988; 6(1):299-303.
Hietanen E, Linnainmaa K, Vainio H. Effects of phenoxy-herbicides and glyphosate on the hepatic and intestinal biotransformation activities in the rat. Acta Pharmacol. Toxicol (Copenh). 1983; 53:103-112.
Peluso M, Munnia A, Bolognesi C, Parodi S. 32P-Postlabeling detection of DNA adducts in mice treated with the herbicide Roundup. Environ. Mol. Mutagen. 1998; 31:55-59.
Beuret C, Zirulnik F, Gimenez S. Effect of the herbicide glyphosate on liver lipoperoxidation in pregnant rats and their fetuses. Reproduct. Toxicol. 2005; 19:501-504.
Benedetti A, Vituri L, Trentin A, Domingues M, Alvarez-Silva M. The effects of sub-chronic exposure of Wistar rats to the herbicide Glyphosate-Biocarb. Toxicol. Lett 2004; 153:227-32.
Food and Agriculture Organization/World Health Organization (FAO/WHO). Pesticide residues in food 1986. Joint Meeting on Pesticide Residues (JMPR), Rome, Italy. FAO Plant Production and Protection Paper 78/2, p. 63 (1987).
Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid. Redox. Signal. 2005; 7:1040-52.
Sakai K, Matsumoto K, Nishikawa T, Suefuji, et al. Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. Biochem Biophys Res. Commun. 2003; 300:216-22.
Lapertosa S, González C, Benítez J, Céspedes MS, Bordón C, de Loredo L, Santoro S, de Sereday M. Prevalencia de Diabetes Mellitus tipo 2 en población adulta de Gobernador Virasoro, Provincia de Corrientes. Revista ALAD 2009; 17: 1-18.
Ministerio de Salud de la Nación. Tercera Encuesta Nacional de Factores de Riesgo para Enfermedades No Transmisibles. http://www.msal.gob.ar/images/stories/ bes/graficos/0000000544cnt-2015_09_04_encuestanacional_factores_riesgo.pdf (acceso 24/03/2016).
Lúquez H, De Loredo L, Madoery RJ, Luquez H (h), Senestrari D. Síndrome metabólico: prevalencia en dos comunidades de Córdoba, Argentina, de acuerdo con definiciones ATP-III y OMS. Rev. Fed. Arg. de Cardiología 2005; 34: 80-95.
Ferreira M del R, Lombardo YB, Chicco A. β-Cell adaptation/dysfunction in an animal model of dyslipidemia and insulin resistance induced by the chronic administration of a sucrose-rich diet. Islets 2010; 2:367-73.
Zago V, Lucero D, Macri EV, et al. Circulating very-low-density lipoprotein characteristics resulting from fatty liver in an insulin resistance rat model. Ann Nutr. Metab. 2010; 56(3):198-206.
Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-9.
Trujillo E, Vásquez B, del Sol M. Características estereológicas del hígado de rata (Rattus norvergicus) sometidas a menopausia inducida por ovariectomía. International Journal of Morphology. Dic. 2011. Vol. 29 Nº 4.
Carrara Moreti DL, Lopes RA, Vinha D. Efectos del albendazol en el hígado de feto de rata. Estudios morfológicos y morfométricos. Int. J. Morphol. 2005. 23(2):111-120.
Pomeraniec Y, Grion N, Gadda L, Pannunzio V, Podesta EJ, Cymeryng CB. Adrenocorticotropin induces heme oxygenase-1 expression in adrenal cells. J Endocrinol (2004) 180: 113-24.
Williams GM, Kroes R, Munro IC. Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans. Regul. Toxicol. Pharmacol. 2000 Apr; 31(2 Pt 1):117-65.
Aspelin A, Grube AH. Pesticide industry sales and usage: 1996 and 1997 market estimates, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D.C.; 1999. http://1.usa.gov/20qXcOb. Acceso: 24/03/2016
Benbrook C. Trends in the use of glyphosate herbicide in the U.S. and globally. Environmental Sciences Europe. 2015; 28(3). http://dx.doi.org/10.1186/s12302-016-0070-0. Acceso: 24/03/2016.
UK Department for Environment, Food & Rural Affairs. PRiF: Monitoring program. http://www.food.gov.uk/business-industry/farmingfood/pesticides. Acceso: 24/04/2016.
Test Biotech. High levels of residues from spraying with glyphosate found in soybeans in Argentina. 2013. http://www.testbiotech.org/node/926. Acceso: 24/03/2016.
Aris A, Leblanc S. Maternal and fetal exposure to pesticides associated to genetically modified foods in Eastern Townships of Quebec, Canada. Reprod. Toxicol. 2011, 31:528-33.
Krüger M, Schrödl W, Neuhaus J, Shehata AA. Field investigations of glyphosate in urine of danish dairy cows. J. Environ Anal Toxicol. (2013) 3: 186. doi:10.4172/2161-0525.1000186.
Myers JP, Antoniou MN, Blumberg B, Carroll L, Colborn T, Everett LG, Hansen M, Landrigan PJ, Lanphear BP, Mesnage R, Vandenberg LN, Vom Saal FS, Welshons WV, Benbrook CM. Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement. Environ Health. 2016; 15:19.
Guyton KZ, Loomis D, Grosse Y, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Scoccianti C, Mattock H, Straif K, International Agency for Research on Cancer Monograph Working Group ILF. Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Lancet Oncol. 2015; 16:490-491.
Astiz M, Alaniz MT, Marra CA. Effect of pesticides on cell survival in liver and brain rat tissues. Ecotoxicology and Environmental Safety 2009; 72: 2025-2032.
Peixoto F. Comparative effects of the Roundup and glyphosate on mitochondrial oxidative phosphorylation. Chemosphere 2005; 61: 1115-1122.
Montgomery MP, Kamel F, Saldana TM, Alavanja MCR, Sandler DP. Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural Health Study, 1993-2003. Am. J. Epidemiol. 2008; 167:1235-1246.
Mink PJ, Mandel JS, Lundin J, Sceurman BK. Epidemiologic studies of glyphosate and non-cancer health outcomes: a review. Regulatory Toxicology and Pharmacology 2011; 61:172-184.
El-Shenawy NS. Oxidative stress responses of rats exposed to Roundup and its active ingredient glyphosate. Environmental Toxicology and Pharmacology 2009; 28: 379-385.
Astiz M, Hurtado de Catalfo GE, García MN, Galletti SM, Errecalde AL, de Alaniz MJT, Marra CA. Pesticide-induced decrease in rat testicular steroidogenesis is differentially prevented by lipoate and tocopherol. Ecotoxicology and Environmental Safety 2013; 91:129-138.
Ackermann W, Coenen M, Schrödl W, Shehata AA, Krüger M. The influence of glyphosate on the microbiota and production of botulinum neurotoxin during ruminal fermentation. Curr. Microbiol. 2015; 70:374-82.
Shehata AA, Schrödl W, Aldin AA, Hafez HM, Krüger M. The effect of glyphosate on potential pathogens and beneficial members of poultry microbiota in vitro. Curr. Microbiol. 2013; 66:350-8.
Martini CN, Gabrielli M, Brandani JN, Vila M del C. Glyphosate inhibits PPAR gamma induction and differentiation of preadipocytes and is able to induce oxidative stress. J. Biochem. Mol. Toxicol. 2016; Apr 4. doi: 10.1002/jbt.21804. [Epub previo a la impresión]
Nufarm. http://www.nufarm.com/assets/17054/1/CREDIT480SL.pdf. Acceso: 24/03/2016.
Kim YH, Hong JR, Gil HW, Song HY, Hong SY. Mixtures of glyphosate and surfactant TN20 accelerate cell death via mitochondrial damage-induced apoptosis and necrosis. Toxicol. In Vitro 2013; 27: 191-197.
Defarge N, Mesnage R, Gress S, Seralini GE. Letter to the editor: developmental and reproductive outcomes of roundup and glyphosate in humans and animals. Journal of Toxicology and Environmental Health, Part B: Critical Reviews 2012; 15: 433-440.
Chaufan G, Coalova I, Ríos de Molina M del C. Glyphosate commercial formulation causes cytotoxicity, oxidative effects, and apoptosis on human cells: differences with its active ingredient. Int. J. Toxicol. 2014; 33: 29-38.
Defarge N, Takács E, Lozano VL, Mesnage R, Spiroux-Vendômois J, Séralini GE, Székács A. Co-formulants in glyphosate-based herbicides disrupt aromatase activity in cells below toxic levels. Int. J. Environ Res. Public Health 2016; 13, 264; doi:10.3390/ijerph13030264.
Mañas F, Peralta L, Raviolo J, García Ovando H, Weyers A, Ugnia L, González Cid M, Larripa I, Gorla N. Genotoxicity of AMPA, the environmental metabolite of glyphosate, assessed by the Comet assay and cytogenetic tests. Ecotoxicology and Environmental Safety 2009; 72: 834-7.
Caglar S, Kolankaya D. The effect of sub-acute and sub-chronic exposure of rats to the glyphosate-based herbicide Roundup. Environmental Toxicology and Pharmacology 2008; 25: 57-62.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Dirección Nacional de Derecho de Autor, Exp. N° 5.333.129. Instituto Nacional de la Propiedad Industrial, Marca «Revista de la Sociedad Argentina de Diabetes - Asociación Civil» N° de concesión 2.605.405 y N° de disposición 1.404/13.
La Revista de la SAD está licenciada bajo Licencia Creative Commons Atribución – No Comercial – Sin Obra Derivada 4.0 Internacional.
Por otra parte, la Revista SAD permite que los autores mantengan los derechos de autor sin restricciones.