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Pesticide dichorvos induces early solid Ehrlich tumoral development associated with a non-protective pro-inflammatory response

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Prolonged exposure to dichlorvos (DDVP), a common pesticide used for food crops, has been related to the development of infections and malignancies. Macrophages are used as bioindicators of immunotoxicity; thus, evaluation of their activity in solid Ehrlich tumor-bearing mice (TBM) may be useful to evaluate the influence of pesticides on human health. To investigate the effects of low DDVP doses, Swiss mice were divided into the following groups: the DDVP group, composed of mice fed diets containing 10 mg/kg of DDVP; the TBM group, consisting of mice subcutaneously inoculated with 107 tumor cells/100 μl and fed a basal diet; the DDVP-TBM group, consisting of mice previously fed DDVP-containing diets for 28 days and then subcutaneously inoculated with tumor cells; and the control (CTRL) group, composed of mice fed a basal diet. After 7 and 21 days of tumor inoculation, the mice were euthanized; and after necroscopic examination, the neoplastic mass, organs, and intraperitoneal fluid were collected. Adherent peritoneal cells were cultivated to determine the production of H2O2 and TNF. Altogether, our results indicate that even at low doses, the intake of DDVP caused weight loss and increased tumor mass, which were associated with H2O2 production and high levels of TNF, a pro-inflammatory cytokine. These data are important as the exposure to pesticides, even at low doses, could potentially hinder the immune response against tumors and, consequently, create favorable conditions for their development.

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  1. Abe E, Duverneuil C, de la Grandmaison G, Alvarez JC (2008) A fatal dichlorvos poisoning: concentrations in biological specimens. J Forensic Sci 53(4):997–1000. https://doi.org/10.1111/j.1556-4029.2008.00774.x

  2. Abdollahi M, Rainba A, Shadnia S, Nikfar S, Rezaie A (2004) Pesticide and oxidative stress: a review. Med Sci Monit 10:RA141–RA147

  3. Almeida VES, Friedrich K, Tygel AF, Melgarejo L, Carneiro FF (2017) Use of genetically modified crops and pesticides in Brazil: growing hazards. Cien Saude Colet 22(10):3333–3339. https://doi.org/10.1590/1413-812320172210.17112017

  4. ANVISA (2008) (Agência Nacional de Vigilância Sanitária). Programa de Análise de Resíduos em Alimentos (PARA). Nota técnica sobre o risco de consumo de frutas e hortaliças cultivadas com agrotóxicos, Disponível em:www.anvisa.gov.br (acesso:30/09/2009)

  5. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3(9):745–756. https://doi.org/10.1038/nri1184

  6. Akhgari M, Abdollahi M, Kebryaeezadeh A, Hosseini R, Sabzevari O (2003) Biochemical evidence for free radical induced lipid peroxidation as a mechanism for subchronic toxicity of malathion in blood and liver of rats. Hum Exp Toxicol 22(4):205–208. https://doi.org/10.1191/0960327103ht346oa

  7. Argiles JM, Martinez CG, Llovera M et al (1998) The role of tumor necrosis factor- α in muscle wasting disorders. Basic Appl Myol 8:371–380

  8. Barnett JB, Brundage KM (2010) Evaluating macrophages in immunotoxicity testing. Methods Mol Biol 598:75–94. https://doi.org/10.1007/978-1-60761-401-2_6

  9. Baud V, Karin M (2001) Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11(9):372–377. https://doi.org/10.1016/S0962-8924(01)02064-5

  10. Camargo MR, Venturini J, Vilani-Moreno FR, Arruda MSP (2009) Modulation of macrophage cytokine profiles during solid tumor progression: susceptibility to Candida albicans infection. BMC Infect Dis 9(1):98. https://doi.org/10.1186/1471-2334-9-98

  11. Camargo MR et al (2013) Macrophage activity and histopathology of the lymphohematopoietic organs in male Wistar rats orally exposed to single or mixed pesticides. J Environ Sci Health B 48(7):607–613. https://doi.org/10.1080/03601234.2013.775020

  12. Chambers JE, Carr RL, Boone S, Chambers HW (2001) The metabolism of organophosphorus insecticides. In: Handbook of pesticide toxicology. Academic Press, USA, pp 919–927. https://doi.org/10.1016/B978-012426260-7.50048-3

  13. Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296(5573):1634–1635. https://doi.org/10.1126/science.1071924

  14. Colovic M, Krstic D, Petrovic S, Leskovac A et al (2010) Toxic effects of diazinon and its photodegradation products. Toxicol Lett 193(1):9–18. https://doi.org/10.1016/j.toxlet.2009.11.022

  15. Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM (2013) Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 11(3):315–335. https://doi.org/10.2174/1570159X11311030006

  16. Dagli MLZ, Guerra JL, Saldiva PHN (1992) An experimental study on the lymphatic dissemination of the solid Ehrlich tumor in mice. Braz J Vet Res Anim Sci 29(1):97–103. https://doi.org/10.11606/issn.1678-4456.bjvras.1992.51958

  17. Descotes J (2006) Methods of evaluating immunotoxicity. Expert Drug Opin Drug Metab Toxicol 2:249–259

  18. FAO - Food and Agriculture Organization of the United Nations (2003) International Code of Conduct on the Distribution and Use of Pesticides. FAO, Rome

  19. Galloway T (2003) Immunotoxicity of organophosphorous pesticides. Ecotoxicology 12(1/4):345–363. https://doi.org/10.1023/A:1022579416322

  20. Hubbard AK (1999) Effects of xenobiotics on macrophage function: evaluation in vitro. Methods 19(1):8–16. https://doi.org/10.1006/meth.1999.0822

  21. Huh H, Pearce SF, Yesner LM, Schindler JL, Silverstein RL (1996) Regulated expression of CD36 during monocyte-to-macrophage differentiation: potential role of CD36 in foam cell formation. Blood 87(5):2020–2028

  22. Idriss HT, Naismith JH (2000) TNF-alpha and the TNF receptor superfamily: structure—junction relationship(s). Microsc Res Tech 50(3):184–195. https://doi.org/10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H

  23. Ivanovic-Matic S et al (2008) The organophosphate-induced acute-phase response is characterized by synthesis of 1-acid glycoprotein that exhibits an immunomodulatory effect. J Appl Toxicol 28(1):63–71. https://doi.org/10.1002/jat.1254

  24. Kuang DM, Wu Y, Chen N, Cheng J, Zhuang SM, Zheng L (2007) Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood 110(2):587–595. https://doi.org/10.1182/blood-2007-01-068031

  25. Li Y et al (2005) Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor- and interleukin-6. J Biol Chem 23(10):21763–21772

  26. Li Q, Kobayashi M, Kawada T (2007) Organophosphorus pesticides induce apoptosis in human NK cells. Toxicology 239(1-2):89–95. https://doi.org/10.1016/j.tox.2007.06.100

  27. Monti P, Leone BE, Zerbi A, Balzano G, Cainarca S, Sordi V, Pontillo M, Mercalli A, di Carlo V, Allavena P, Piemonti L (2004) Tumor-derived MUC1 mucins interact with differentiating monocytes and induce IL-10 high IL-12 low regulatory dendritic cell. J Immunol 172(12):7341–7349. https://doi.org/10.4049/jimmunol.172.12.7341

  28. Muller PY, Dieterle F (2009) Tissue-specific, non-invasive toxicity biomarkers: translation from preclinical safety assessment to clinical safety monitoring. Expert Opin Drug Metab Toxicol 5(9):1023–1038. https://doi.org/10.1517/17425250903114174

  29. OECD (1995) Guide line for the testing of chemicals. Repeated dose 28-day Oral Toxicity Study in rodents. v. 407

  30. OECD DDVP (1998) Risk assessment issues for the FIFRA science advisory panel

  31. Oga S (2008) Fundamentos de Toxicologia, 3th edn. Atheneu Editora, São Paulo

  32. Oliva R, Gemal AL, Nobrega AW, Araujo AC (2003) Pesticide monitoring programme of the Ministry of Health of Brazil. Food Addit Contam 20(8):758–763. https://doi.org/10.1080/0265203031000138295

  33. Patel HJ, Patel BM (2017) TNF-α and cancer cachexia: molecular insights and clinical implications. Life Sci 170:56–63. https://doi.org/10.1016/j.lfs.2016.11.033

  34. Podstawka U (1994) Toxic effects of dichlorvos on neutrophils of human peripheral blood in vitro. Rocz Panstw Zakl Hig 45(1-2):119–123

  35. Proskocil BJ, Bruun DA, Jacoby DB, van Rooijen N, Lein PJ, Fryer AD (2013) Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs. Am J Physiol Lung Cell Mol Physiol 304:519–529

  36. Plu ddemann A, Neyen C, Gordon S (2007) Macrophage scavenger receptors and host-derived ligands. Methods 43:207–217

  37. Ranjbar A, Solhi H, Mashayekhi FJ, Susanabdi A, Rezaie A, Abdollahi M (2005) Oxidative stress in acute human poisoning with organophosphorus insecticides; a case control study. Environ Toxicol Pharmacol 20(1):88–91. https://doi.org/10.1016/j.etap.2004.10.007

  38. Righi DA, Palermo-Neto J (2005) Effects of type II pyrethroid cyhalothrin on peritoneal macrophage activity in rats. Toxicology 212(2-3):98–106. https://doi.org/10.1016/j.tox.2005.04.004

  39. Ross MK, Borazjani A, Mangum LC, Wang R, Crow JA (2014) Effects of toxicologically relevant xenobiotics and the lipid-derived electrophile 4-hydroxynonenal on macrophage cholesterol efflux: silencing carboxylesterase 1 has paradoxical effects on cholesterol uptake and efflux. Chem Res Toxicol 27(10):1743–1756. https://doi.org/10.1021/tx500221a

  40. Russo M, Teixeira HC, Marcondes MC, Barbuto JA (1989) Superoxide-independent hydrogen peroxide release by activated macrophages. Braz J Med Biol Res 22(10):1271–1273

  41. Salem BI, Boussabbeh M, Kantaoui H, Bacha H, Abid-Essefi S (2016) Crocin, the main active saffron constituent, mitigates dichlorvos-induced oxidative stress and apoptosis in HCT-116 cells. Biomed Pharmacother 82:65–71. https://doi.org/10.1016/j.biopha.2016.04.063

  42. Shen HM, Pervaiz S (2006) TNF receptor superfamily-induced cell death: redox dependent execution. FASEB J 20(10):1589–1598. https://doi.org/10.1096/fj.05-5603rev

  43. Silva RJ, Silva MG, Vilela LC, Fecchio D (2002) Cytokine profile of Ehrlich ascites tumor treated with Bothrops jararaca venom. Mediat Inflamm 11(4):197–201. https://doi.org/10.1080/0962935029000041

  44. Souza GS, da Costa LCA, Maciel AC, Reis FDV, Pamplona YAP (2017) Presence of pesticides in atmosphere and risk to human health: a discussion for the environmental surveillance. Cien Saude Colet 22(10):3269–3280. https://doi.org/10.1590/1413-812320172210.18342017

  45. Stout RD, Suttles J (2004) Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 76(3):509–513. https://doi.org/10.1189/jlb.0504272

  46. Tavares D, Ferreira P, Arala-Chaves M (2000) Increased resistance to systemic candidiasis in athymic or interleukin-10-depleted mice. J Infect Dis 182(1):266–273. https://doi.org/10.1086/315674

  47. Venturini J, Camargo MR, Vilani-Moreno FR, Arruda MSP (2009) Influence of tumor condition on the macrophage activity in Candida albicans infection. Scand J Immunol 70(1):10–17. https://doi.org/10.1111/j.1365-3083.2009.02260.x

  48. Vial T, Nicolas B, Descotes J (1996) Clinical immunotoxicity of pesticides. J Toxicol Environ Health 48(3):215–229. https://doi.org/10.1080/009841096161294

  49. Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10(1):45–65. https://doi.org/10.1038/sj.cdd.4401189

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We are thankful to Dr. Joao Lauro Viana de Camargo for supporting this study and to Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP 06/60506-1) for the grants that funded this research.

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Correspondence to Marcela Rodrigues de Camargo.

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Responsible editor: Philippe Garrigues

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de Camargo, M.R., Akamine, P.V.T., Venturini, J. et al. Pesticide dichorvos induces early solid Ehrlich tumoral development associated with a non-protective pro-inflammatory response. Environ Sci Pollut Res 25, 7681–7687 (2018). https://doi.org/10.1007/s11356-017-1104-x

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  • Dichorvos
  • Macrophage activity
  • Ehrlich tumor
  • Cytokines
  • Immunotoxicity
  • Organophosphorus