Skip to main content

Advertisement

SpringerLink
Log in

Subchronic exposure to a glyphosate-based herbicide causes dysplasia in the digestive tract of Wistar rats

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Glyphosate-based herbicides (GBH) are the most widely used herbicide for treatment of crops in the world. The digestive tract is one of the first systems exposed to pesticides, and damage to this system can affect the general health of individuals. The aim of this study was to evaluate the effects of subchronic inhalation and oral exposure to GBH on the digestive tract in rats. Six groups of Wistar rats (male and female) were exposed to nebulization with three concentrations of GBH [3.71 × 10−3 grams of active ingredient per hectare (g.a.i./ha), 6.19 × 10−3 g.a.i./ha and 9.28 × 10−3 g.a.i./ha] administered orally or by inhalation for 75 days. Bone marrow cells, smears of the tongue and fragments of the tongue, oesophagus, stomach and intestine were collected for histopathological analysis. Congestion, inflammation, an increase in the number of mast cells and nucleoli-organizing regions were detected in the tongue in the groups exposed to GBH. Females had a higher number of mast cells in the tongue than males. Animals in the groups exposed to higher concentrations of GBH showed dysplasia in the oesophagus and small and large intestine regardless of sex. Gastric changes were not observed. Animals exposed to GBH showed increased micronucleus formation. Our data indicate that GBH causes oral allergies and dysplastic lesions in the oesophagus and small and large intestine and has genotoxic potential.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig 1
Fig 2
Fig 3
Fig 4
Fig 5
Fig 6
Fig 7
Fig 8
Fig 9
Fig 10
Fig 11
Fig 12

Similar content being viewed by others

Data Availability

All data generated or analysed during this study are included in this published article.

References

  • Authority EFS (2015) Conclusion on the peer review of the pesticide risk assessment of the active substance glyphosate. EFSA J 13(11):4302

    Google Scholar 

  • Battaglin WA, Meyer MT, Kuivila KM, Dietze JE (2014) Glyphosate and its degradation product AMPA occur frequently and widely in U.S. soils, surface water, groundwater, and precipitation. JAWRA 50(2):275–290. https://doi.org/10.1111/jawr.12159

    Article  CAS  Google Scholar 

  • Benbrook C (2016) Trends in the use of glyphosate herbicide in the U.S. and globally. Environ Sci Eur 28(1):3. https://doi.org/10.1186/s12302-016-0070-0

    Article  CAS  Google Scholar 

  • Chen HH, Lin JL, Huang WH, Weng CH, Lee SY, Hsu CW, Chen KH, Wang IK, Liang CC, Chang CT, Yen TH (2013) Spectrum of corrosive esophageal injury after intentional paraquat or glyphosate-surfactant herbicide ingestion. Int J Gen Med 6:677–683. https://doi.org/10.2147/IJGM.S48273

    Article  CAS  Google Scholar 

  • Chłopecka M, Mendel M, Dziekan N, Karlik W (2014) Glyphosate affects the spontaneous motoric activity of intestine at very low doses - in vitro study. Pestic Biochem Physiol 113:25–30. https://doi.org/10.1016/j.pestbp.2014.06.005

    Article  CAS  Google Scholar 

  • Cho I, Blaser MJ (2012) The human microbiome: at the interface of health and disease. Nat Rev Genet 13:260–270. https://doi.org/10.1038/nrg3182

    Article  CAS  Google Scholar 

  • Conrad A, Schroter-Kermani C, Hoppe HW, Ruther M, Pieper S, Kolossa-Gehring M (2017) Glyphosate in German adults - time trend (2001 to 2015) of human exposure to a widely used herbicide. Int J Hyg Environ Health 220(1):8–16. https://doi.org/10.1016/j.ijheh.2016.09.016

    Article  CAS  Google Scholar 

  • Cushman JR, Street JC (1982) Allergic hypersensitivity to the herbicide 2,4-D in BALB/c mice. J Toxicol Environ Health 10(4-5):729–741

    Article  CAS  Google Scholar 

  • Defarge N, Takács E, Lozano VL, Mesnage R, Spiroux de Vendômois J, Séralini GE, Székács A (2016) Co-formulants in glyphosate-based herbicides disrupt aromatase activity in human cells below toxic levels. Int J Environ Res Public Health 13(3):264. https://doi.org/10.3390/ijerph13030264

    Article  CAS  Google Scholar 

  • Deo SP, Shetty P (2012) Accidental chemical burns of oral mucosa by herbicide. JNMA J Nepal Med Assoc 52(185):40–42

    CAS  Google Scholar 

  • R Development Core Team (2019) R Software: a language and environment for statistical computing. Vienna. http://www.r-project.org. Accessed 19 March 2020.

  • EPA (1993) Re-registration Eligibility Decision (RED) glyphosate: EPA-738-R-93-014. US Environmental Protection Agency, Office of Pesticide Programs and Toxic Substances, Washington

  • Espírito-Santo H, Daniel F (2015) Calculating and reporting effect sizes on scientific papers (1): p < 0.05 limitations in the analysis of mean differences of two groups. Port J Behav Soc Res 1(1):3–16

    Google Scholar 

  • Fenech M, Holland N, Chang WP, Zeiger E, Bonassi S (1999) The HUman MicroNucleus Project - an international collaborative study on the use of the micronucleus technique for measuring DNA damage in humans. Mutat Res 428:271–283

    Article  CAS  Google Scholar 

  • Fukuyama T, Tajima Y, Ueda H, Hayashi K, Shutoh Y, Harada T, Kosaka T (2009) Allergic reaction induced by dermal and/or respiratory exposure to low-dose phenoxyacetic acid, organophosphorus, and carbamate pesticides. Toxicol 261:152–161

    Article  CAS  Google Scholar 

  • Gill JPK, Sethi N, Mohan, A, Datta S, Girdhar M (2018) Glyphosate toxicity for animals. Environ Chem Lett 16:401–426. https://doi.org/10.1007/s10311-017-0689-0

  • Gochfeld M (2017) Sex differences in human and animal toxicology. Toxicol Pathol 45(1):172–189. https://doi.org/10.1177/0192623316677327

    Article  Google Scholar 

  • Greim H, Saltmiras D, Mostert V, Strupp C (2015) Evaluation of carcinogenic potential of the herbicide glyphosate, drawing on tumor incidence data from fourteen chronic/carcinogenicity rodent studies. Crit Rev Toxicol 45:185–208. https://doi.org/10.3109/10408444.2014.1003423

    Article  CAS  Google Scholar 

  • Grube A, Donaldson D, Kiely T, Wu L (2011) Pesticide industry sales and usage: 2006 and 2007 market stimates. US EPA, Washington, DC

  • Guilherme S, Gaivão I, Santos MA, Pacheco M (2012) DNA damage in fish (Anguilla anguilla) exposed to a glyphosate-based herbicide - elucidation of organ-specificity and the role of oxidative stress. Mutat Res 743(1-2):1–9. https://doi.org/10.1016/j.mrgentox.2011.10.017

    Article  CAS  Google Scholar 

  • Hanlon SM, Lynch KJ, Parris MJ (2013) Mouthparts of southern leopard frog, Lithobates sphenocephalus, tadpoles not affected by exposure to a formulation of glyphosate. Bull Environ Contam Toxicol 91(6):611–615. https://doi.org/10.1007/s00128-013-1117-1

    Article  CAS  Google Scholar 

  • Heydens WF, Healy CE, Hotz KJ, Kier LD, Martens MA, Wilson AG, Farmer DR (2008) Genotoxic potential of glyphosate formulations: mode-of-action investigations. J Agric Food Chem 56(4):1517–1523. https://doi.org/10.1021/jf072581i

    Article  CAS  Google Scholar 

  • IARC Working Group (2015) Glyphosate. In: Some organophosphate insecticides and herbicides: diazinon, glyphosate, malathion, parathion, and tetrachlorvinphos. Vol 112 IARC Monogr Prog, pp 1–92

  • Jayasumana C, Gunatilake S, Siribaddana S (2015) Simultaneous exposure to multiple heavy metals and glyphosate may contribute to Sri Lankan agricultural nephropathy. BMC Nephrol 16:103. https://doi.org/10.1186/s12882-015-0109-2

    Article  CAS  Google Scholar 

  • Kier LD, Kirkland DJ (2013) Review of genotoxicity studies of glyphosate and glyphosate-based formulations. Crit Rev Toxicol 43(4):283–315. https://doi.org/10.3109/10408444.2013.770820

    Article  CAS  Google Scholar 

  • Krüger M, Schledorn P, Schrödl W, Hoppe HW, Lutz W, Shehata AA (2014) Detection of glyphosate residues in animals and humans. J Environ Anal Toxicol 4:210. https://doi.org/10.4172/2161-0525.1000210

    Article  Google Scholar 

  • Laffont S, Guéry JC (2019) Deconstructing the sex bias in allergy and autoimmunity: from sex hormones and beyond. Adv Immunol 142:35–64. https://doi.org/10.1016/bs.ai.2019.04.001

    Article  CAS  Google Scholar 

  • Landrigan PJ, Belpoggi F (2018) The need for independent research on the health effects of glyphosate-based herbicides. Environ Health 17:51. https://doi.org/10.1186/s12940-018-0392-z

    Article  Google Scholar 

  • Lopez Gonzalez EC, Latorre MA, Larriera A, Siroski PA, Poletta GL (2013) Induction of micronuclei in broad snouted caiman (Caiman latirostris) hatchlings exposed in vivo to Roundup_ (glyphosate) concentrations used in agriculture. Pestic Biochem Physiol 105:131–134. https://doi.org/10.1016/j.pestbp.2012.12.009

    Article  CAS  Google Scholar 

  • Lozano VL, Defarge N, Rocque LM, Mesnage R, Hennequin D, Cassier R, de Vendômois JS, Panoff JM, Séralini GE, Amiel C (2017) Sex-dependent impact of Roundup on the rat gut microbiome. Toxicol Rep 5:96–107. https://doi.org/10.1016/j.toxrep.2017.12.005

    Article  CAS  Google Scholar 

  • MacGregor JT (1987) Guidelines for the conduct of micronucleus assays in mammalian bone marrow erythrocytes. Mutat Res 189(2):103–112

    Article  CAS  Google Scholar 

  • Martelli BKL, Melo DM, Nai GA, Parizi JLS (2014) Influence of water pH in oral changes caused by cadmium poisoning: an experimental study in rats. Rev Odontol UNESP 43(3):1–5

    Article  Google Scholar 

  • Mello FA, Quinallia G, Marion AL, Jorge FC, Marinelli LM, Salge AKM, Fagiani MAB, Mareco EA, Favareto APA, Rossi e Silva RC (2018) Evaluation of the nasal cavity mice submitted to the inhalation exposure to the herbicide 2,4-dichlorophenoxyacetic acid. Medicina (Ribeirão Preto, Online) 51(4):247–253. https://doi.org/10.11606/issn.2176-7262.v51i4p00-00

    Article  Google Scholar 

  • Mertens M, Höss S, Neumann G, Afzal J, Reichenbecher W (2018) Glyphosate, a chelating agent-relevant for ecological risk assessment? Environ Sci Pollut Res Int 25(6):5298–5317. https://doi.org/10.1007/s11356-017-1080-1

    Article  CAS  Google Scholar 

  • Mesnage R, Bernay B, Séralini GE (2013) Ethoxylated adjuvants of glyphosate-based herbicides are active principles of human cell toxicity. Toxicology 313(2-3):122–128 https://doi.org/10.1016/j.tox.2012.09.006

    Article  CAS  Google Scholar 

  • Moreno NC, Sofia SH, Martinez CB (2014) Genotoxic effects of the herbicide Roundup Transorb and its active ingredient glyphosate on the fish Prochilodus lineatus. Environ Toxicol Pharmacol 37(1):448–454. https://doi.org/10.1016/j.etap.2013.12.012

    Article  CAS  Google Scholar 

  • Mui PC (1993) Endoscopic evaluation of paraquat-induced upper gastrointestinal injury. Gastrointest Endosc 39(1):105–106. https://doi.org/10.1016/s0016-5107(93)70032-2

    Article  CAS  Google Scholar 

  • 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 (2016) Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement. Environ Health 15:19. https://doi.org/10.1186/s12940-016-0117-0

    Article  CAS  Google Scholar 

  • Nagy K, Tessema RA, Budnik LT, Ádám B (2019) Comparative cyto- and genotoxicity assessment of glyphosate and glyphosate-based herbicides in human peripheral white blood cells. Environ Res 179(Pt B):108851. https://doi.org/10.1016/j.envres.2019.108851

    Article  CAS  Google Scholar 

  • Nai GA, Filho MAG, Estrella MPS, Teixeira LDS (2015) Study of the influence of the ph of water in the initiation of digestive tract injury in cadmium poisoning in rats. Toxicol Rep 2:1033–1038. https://doi.org/10.1016/j.toxrep.2015.07.012

    Article  CAS  Google Scholar 

  • National Research Council (2011) Guide for the care and use of laboratory animals, eighth edition, vol 10. The National Academies Press, Washington, DC, p 17226/12910

  • Parizi ACG, Barbosa RL, Parizi JLS, Nai GA (2010) A comparison between the concentration of mast cells in squamous cell carcinomas of the skin and oral cavity. An Bras Dermatol 85(6):811–818

    Article  Google Scholar 

  • Parizi JLS, Tolardo AJ, Lisboa ACG, Barravieira B, Mello FA, Rossi RC, Nai GA (2020) Evaluation of buccal damage associated with acute inhalation exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) in mice. BMC Vet Res 16:244. https://doi.org/10.1186/s12917-020-02461-w

    Article  CAS  Google Scholar 

  • Pegoraro CMR, Nai GA, Garcia LA, Serra FM, Alves JA, Chagas PHN, Oliveira DG, Zocoler MA (2018) Protective effects of Bidens pilosa on hepatoxicity and nephrotoxicity induced by carbontetrachloride in rats. Drug Chem Toxicol 5:1–11. https://doi.org/10.1080/01480545.2018.1526182

    Article  CAS  Google Scholar 

  • Ploton D, Menager M, Jeannensson P, Himberg G, Adnet JJ PF (1986) Improvement in the staining and in the visualization of the argyrophilic proteins of the nucleolar organizer region of the optical level. Histochem J 18:5–14

    Article  CAS  Google Scholar 

  • Portier CJ, Armstrong BK, Baguley BC, Baur X, Belyaev I, Bellé R, Belpoggi F, Biggeri A, Bosland MC, Bruzzi P, Budnik LT, Bugge MD, Burns K, Calaf GM, Carpenter DO, Carpenter HM, López-Carrillo L, Clapp R, Cocco P, Consonni D, Comba P, Craft E, Dalvie MA, Davis D, Demers PA, De Roos AJ, DeWitt J, Forastiere F, Freedman JH, Fritschi L, Gaus C, Gohlke JM, Goldberg M, Greiser E, Hansen J, Hardell L, Hauptmann M, Huang W, Huff J, James MO, Jameson CW, Kortenkamp A, Kopp-Schneider A, Kromhout H, Larramendy ML, Landrigan PJ, Lash LH, Leszczynski D, Lynch CF, Magnani C, Mandrioli D, Martin FL, Merler E, Michelozzi P, Miligi L, Miller AB, Mirabelli D, Mirer FE, Naidoo S, Perry MJ, Petronio MG, Pirastu R, Portier RJ, Ramos KS, Robertson LW, Rodriguez T, Röösli M, Ross MK, Roy D, Rusyn I, Saldiva P, Sass J, Savolainen K, Scheepers PT, Sergi C, Silbergeld EK, Smith MT, Stewart BW, Sutton P, Tateo F, Terracini B, Thielmann HW, Thomas DB, Vainio H, Vena JE, Vineis P, Weiderpass E, Weisenburger DD, Woodruff TJ, Yorifuji T, Yu IJ, Zambon P, Zeeb H, Zhou SF (2016) Differences in the carcinogenic evaluation of glyphosate between the International Agency for Research on Cancer (IARC) and the European Food Safety Authority (EFSA). J Epidemiol Community Health 70(8):741–745. https://doi.org/10.1136/jech-2015-207005

    Article  Google Scholar 

  • Prasad S, Srivastava S, Singh M, Shukla Y (2009) Clastogenic effects of glyphosate in bone marrow cells of Swiss albino mice. J Toxicol 2009:1–6. https://doi.org/10.1155/2009/308985

    Article  CAS  Google Scholar 

  • Punchard NA, Whelan CJ, Adcock I (2004) The Journal of Inflammation. Editorial J Inflamm 1:1. https://doi.org/10.1186/1476-9255-1-1

    Article  Google Scholar 

  • Qiu S, Fu H, Zhou R, Yang Z, Bai G, Shi B (2020) Toxic effects of glyphosate on intestinal morphology, antioxidant capacity and barrier function in weaned piglets. Ecotoxicol Environ Saf 187:109846. https://doi.org/10.1016/j.ecoenv.2019.109846

    Article  CAS  Google Scholar 

  • Sanchis J, Kantiani L, Llorca M, Rubio F, Ginebreda A, Fraile J, GarridoT FM (2012) Determination of glyphosate in groundwater samples using an ultrasensitive immunoassay and confirmation by online solid-phase extraction followed by liquid chromatography coupled to tandem mass spectrometry. Anal Bioanal Chem 402(7):2335–2345

    Article  CAS  Google Scholar 

  • Sribanditmongkol P, Jutavijittum P, Pongraveevongsa P, Wunnapuk K, Durongkadech P (2012) Pathological and toxicological findings in glyphosate-surfactant herbicide fatality: a case report. Am J Forensic Med Pathol 33(3):234–237

    Article  Google Scholar 

  • Tarazona JV, Court-Marques D, Tiramani M, Reich H, Pfeil R, Istace F, Crivellente F (2017) Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC. Arch Toxicol 91(8):2723–2743. https://doi.org/10.1007/s00204-017-1962-5

    Article  CAS  Google Scholar 

  • Tolbert PE, Shy CM, Allen JW (1992) Micronuclei and other nuclear anomalies in buccal smears: methods development. Mutat Res 271:69–77

    Article  CAS  Google Scholar 

  • Vandenberg LN, Blumberg B, Antoniou MN, Benbrook CM, Carroll L, Colborn T, Everett LG, Hansen M, Landrigan PJ, Lanphear BP, Mesnage R, Vom Saal FS, Welshons WV, Myers JP (2017) Is it time to reassess current safety standards for glyphosate-based herbicides? J Epidemiol Community Health 71(6):613–618. https://doi.org/10.1136/jech-2016-208463

    Article  Google Scholar 

  • Williams GM, Berry C, Burns M, de Camargo JLV, Greim H (2016) Glyphosate rodent carcinogenicity bioassay expert panel review. Crit Rev Toxicol 46(sup1):44–55. https://doi.org/10.1080/10408444.2016.1214679

    Article  CAS  Google Scholar 

  • Yasunaga S, Nishi K, Nishimoto S, Sugahara T (2015) Methoxychlor enhances degranulation of murine mast cells by regulating Fc#RI-mediated signal transduction. J Immunotoxicol 12:283–289. https://doi.org/10.3109/1547691X.2014.962122

    Article  CAS  Google Scholar 

  • Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, Woodruff TJ, Vom Saal FS (2012) Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology 153(9):4097–4110. https://doi.org/10.1210/en.2012-1422

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the technicians of the Laboratory of Surgical Pathology and Cytopathology at UNOESTE, Carlos Alexandre Santana de Oliveira, Mariana Fonseca Motta Borges and Talita Rizo Pereira, for the histological processing of the specimens.

Funding

This study was financed with research funds from the Universidade do Oeste Paulista (UNOESTE). P. H. N. Chagas received a scholarship from the Scientific Initiation Scholarship Program of the National Council for Scientific and Technological Development (PIBIC/CNPq).

Author information

Authors and Affiliations

  1. Graduate Program in Animal Science, Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP, Brazil

    Fernanda de Maria Serra, Fabíola de Azevedo Mello & Gisele Alborghetti Nai

  2. Department of Pathology, Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP, Brazil

    José Luiz Santos Parizi & Gisele Alborghetti Nai

  3. Faculty of Medicine of Presidente Prudente (FAMEPP), Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP, Brazil

    José Luiz Santos Parizi, Pedro Henrique Nahas Chagas & Gisele Alborghetti Nai

  4. Faculty of Dentistry of Presidente Prudente (FOPP), Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP, Brazil

    Gisele Aparecida Sales de Mello Odorizzi, Grace Mitiko Rosati Hori Sato, Isabela Bocardi Patrão & Gisele Alborghetti Nai

  5. Laboratório de Anatomia Patológica e Citopatologia, Universidade do Oeste Paulista (UNOESTE), Rua José Bongiovani, 700, Presidente Prudente, SP, 19050-680, Brazil

    Gisele Alborghetti Nai

Authors
  1. Fernanda de Maria Serra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. José Luiz Santos Parizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gisele Aparecida Sales de Mello Odorizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Grace Mitiko Rosati Hori Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabela Bocardi Patrão
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pedro Henrique Nahas Chagas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fabíola de Azevedo Mello
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gisele Alborghetti Nai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FMS: performed the experiments, performed the analysis and interpretation of data and drafted the manuscript; JLSP: made substantial contributions to research design and performed the experiments; GASM, GMRHS, IBP and PHNC: performed the experiments; FMA: made substantial contributions to research design and performed the experiments; GAN: made substantial contributions to research design, performed histological analysis, prepared the histological images for publication and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Gisele Alborghetti Nai.

Ethics declarations

Ethical approval

This study was approved by the Ethics Committee on Animal Use of the Universidade do Oeste Paulista (UNOESTE) (protocol no. 3792).

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Responsible Editor: Mohamed M. Abdel-Daim

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Maria Serra, F., Parizi, J.L.S., Odorizzi, G.A.S. et al. Subchronic exposure to a glyphosate-based herbicide causes dysplasia in the digestive tract of Wistar rats. Environ Sci Pollut Res 28, 61477–61496 (2021). https://doi.org/10.1007/s11356-021-15051-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-021-15051-6

Keywords

Search

Navigation