Chemically engineered agricultural products such as pesticides, insecticides, and herbicides, although used considerably for both industrialized and personal agricultural use, have recently been associated with a number of serious human health disorders. This rapid literature review aims to accumulate and analyze research from the last ten years, focusing specifically on the effects of exposure to glyphosate-based herbicide products such as Roundup as associated with the formation of various neurological disorders. Specifically, this review focuses on laboratory research using animal models or human cell cultures as well as human population-based epidemiological studies. It associates exposure to glyphosate or glyphosate-based products with the formation or exacerbation of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, seizures, and autism spectrum disorder. In addition, it examines the correlation between the gut-brain axis, exposure to glyphosate, and neurodegeneration.
Pathak, V.M., Verma, V.K., Rawat, B.S., Kaur, B., Babu, N., Sharma, A., et al . (2022) Current Status of Pesticide Effects on Environment, Human Health and It’s Eco-Friendly Management as Bioremediation: A Comprehensive Review. Frontiers in Microbiology , 13, Article 962619. https://doi.org/10.3389/fmicb.2022.962619
Hartzler, B. (2001) Glyphosate—A Review. Iowa Soybean Digest. Iowa State University Extension and Outreach. https://crops.extension.iastate.edu/encyclopedia/glyphosate-review
Henderson, A.M., Gervais, J.A., Luukinen, B., Buhl, K., Stone, D., Cross, A. and Jenkins, J. (2010) Glyphosate General Fact Sheet. National Pesticide Information Center, Oregon State University Extension Services. http://npic.orst.edu/factsheets/glyphogen.html
Connolly, A., Jones, K., Basinas, I., Galea, K.S., Kenny, L., McGowan, P., et al . (2019) Exploring the Half-Life of Glyphosate in Human Urine Samples. Intern a tional Journal of Hygiene and Environmental Health , 222, 205-210. https://doi.org/10.1016/j.ijheh.2018.09.004
Soares, D., Silva, L., Duarte, S., Pena, A. and Pereira, A. (2021) Glyphosate Use, Toxicity and Occurrence in Food. Foods , 10, Article 2785. https://doi.org/10.3390/foods10112785
Eskenazi, B., Gunier, R.B., Rauch, S., Kogut, K., Perito, E.R., Mendez, X., et al . (2023) Association of Lifetime Exposure to Glyphosate and Aminomethylphosphonic Acid (AMPA) with Liver Inflammation and Metabolic Syndrome at Young Adulthood: Findings from the CHAMACOS Study. Environmental Health Perspe c tives , 131, Article ID: 37001. https://doi.org/10.1289/ehp11721
Jarrell, Z.R., Ahammad, M.U. and Benson, A.P. (2020) Glyphosate-Based Herbicide Formulations and Reproductive Toxicity in Animals. Veterinary and Animal Science , 10, Article ID: 100126. https://doi.org/10.1016/j.vas.2020.100126
Zhang, L., Rana, I., Shaffer, R.M., Taioli, E. and Sheppard, L. (2019) Exposure to Glyphosate-Based Herbicides and Risk for Non-Hodgkin Lymphoma: A Meta-Analysis and Supporting Evidence. Mutation Research / Reviews in Mutation R e search , 781, 186-206. https://doi.org/10.1016/j.mrrev.2019.02.001
Cattani, D., Cesconetto, P.A., Tavares, M.K., Parisotto, E.B., De Oliveira, P.A., Rieg, C.E.H., et al . (2017) Developmental Exposure to Glyphosate-Based Herbicide and Depressive-Like Behavior in Adult Offspring: Implication of Glutamate Excitotoxicity and Oxidative Stress. Toxicology , 387, 67-80. https://doi.org/10.1016/j.tox.2017.06.001
Chang, E.T., Odo, N.U. and Acquavella, J.F. (2022) Systematic Literature Review of the Epidemiology of Glyphosate and Neurological Outcomes. International Ar c hives of Occupational and Environmental Health , 96, 1-26. https://doi.org/10.1007/s00420-022-01878-0
Costas-Ferreira, C., Durán, R. and Faro, L.R.F. (2022) Toxic Effects of Glyphosate on the Nervous System: A Systematic Review. International Journal of Molecular Sciences , 23, Article 4605. https://doi.org/10.3390/ijms23094605
Rubio-Tomás, T. and Tavernarakis, N. (2022) Lipid Metabolism and Ageing in Caenorhabditis Elegans: A Complex Interplay. Biogerontology , 23, 541-557. https://doi.org/10.1007/s10522-022-09989-4
NIH National Institute on Aging (2022) Parkinson’s Disease: Causes, Symptoms, and Treatments. National Institutes of Health. https://www.nia.nih.gov/health/parkinsons-disease/parkinsons-disease-causes-symptoms-and-treatments
Kouli, A., Torsney, K.M. and Kuan, W.L. (2018) Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis. Parkinson’s Disease: Pathogenesis and Clinical Aspects. Brisbane (AU): Codon Publications. https://doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch1
Goetz, C.G., Emre, M. and Dubois, B. (2009) Parkinson’s Disease Dementia: Definitions, Guidelines, and Research Perspectives in Diagnosis. Annals of Neurology , 64, S81-S92. https://doi.org/10.1002/ana.21455
Chinta, S.J. and Andersen, J.K. (2005) Dopaminergic Neurons. The International Journal of Biochemistry & Cell Biology , 37, 942-946. https://doi.org/10.1016/j.biocel.2004.09.009
Damier, P., Hirsch, E.C., Agid, Y. and Graybiel, A.M. (1999) The Substantia Nigra of the Human Brain. Brain , 122, 1437-1448. https://doi.org/10.1093/brain/122.8.1437
Stefanis, L. (2011) α -Synuclein in Parkinson’s Disease. Cold Spring Harbor Perspe c tives in Medicine , 2, a009399. https://doi.org/10.1101/cshperspect.a009399
Shults, C.W. (2006) Lewy Bodies. Proceedings of the National Academy of Sciences of the United States of America , 103, 1661-1668. https://doi.org/10.1073/pnas.0509567103
Spillantini, M.G., Schmidt, M.L., Lee, V.M.Y., Trojanowski, J.Q., Jakes, R. and Goedert, M. (1997) α -Synuclein in Lewy Bodies. Nature , 388, 839-840. https://doi.org/10.1038/42166
Gruden, M.A., Davydova, T.V., Narkevich, V.B., Fomina, V.G., Wang, C., Kudrin, V.S., et al . (2014) Intranasal Administration of α -Synuclein Aggregates: A Parkinson’s Disease Model with Behavioral and Neurochemical Correlates. Behavioural Brain Research , 263, 158-168. https://doi.org/10.1016/j.bbr.2014.01.017
Hernández-Plata, I., Giordano, M., Díaz-Muñoz, M. and Rodríguez, V.M. (2015) The Herbicide Glyphosate Causes Behavioral Changes and Alterations in Dopaminergic Markers in Male Sprague-Dawley Rat. NeuroToxicology , 46, 79-91. https://doi.org/10.1016/j.neuro.2014.12.001
Pu, Y., Chang, L., Qu, Y., Wang, S., Tan, Y., Wang, X., et al . (2020) Glyphosate Exposure Exacerbates the Dopaminergic Neurotoxicity in the Mouse Brain after Repeated Administration of MPTP. Neuroscience Letters , 730, Article ID: 135032. https://doi.org/10.1016/j.neulet.2020.135032
Costas-Ferreira, C., Durán, R. and Faro, L.F. (2023) Neurotoxic Effects of Exposure to Glyphosate in Rat Striatum: Effects and Mechanisms of Action on Dopaminergic Neurotransmission. Pesticide Biochemistry and Physiology , 193, Article ID: 105433. https://doi.org/10.1016/j.pestbp.2023.105433
Zhang, S., Song, Y., Wang, M., Xiao, G., Gao, F., Li, Z., et al . (2018) Real-Time Simultaneous Recording of Electrophysiological Activities and Dopamine Overflow in the Deep Brain Nuclei of a Non-Human Primate with Parkinson’s Disease Using Nano-Based Microelectrode Arrays. Microsystems & Nanoengineering , 4, Article No. 17070. https://doi.org/10.1038/micronano.2017.70
Costas-Ferreira, C., Silva, A.C.d.J., Hage-Melim, L.I.d.S. and Faro, L.R.F. (2023) Role of Voltage-Dependent Calcium Channels on the Striatal in v ivo Dopamine Release Induced by the Organophosphorus Pesticide Glyphosate. Environmental To x icology and Pharmacology , 104, Article ID: 104285. https://doi.org/10.1016/j.etap.2023.104285
Caballero, M., Amiri, S., Denney, J.T., Monsivais, P., Hystad, P. and Amram, O. (2018) Estimated Residential Exposure to Agricultural Chemicals and Premature Mortality by Parkinson’s Disease in Washington State. International Journal of E n vironmental Research and Public Health , 15, Article 2885. https://doi.org/10.3390/ijerph15122885
American Psychiatric Association (2022) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. https://doi.org/10.1176/appi.books.9780890425596
Bayer, T.A., Cappai, R., Masters, C.L., Beyreuther, K. and Multhaup, G. (1999) It All Sticks Together—The App-Related Family of Proteins and Alzheimer’s Disease. Molecular Psychiatry , 4, 524-528. https://doi.org/10.1038/sj.mp.4000552
Liu, C., Kanekiyo, T., Xu, H. and Bu, G. (2013) Apolipoprotein E and Alzheimer Disease: Risk, Mechanisms and Therapy. Nature Reviews Neurology , 9, 106-118. https://doi.org/10.1038/nrneurol.2012.263
Plantone, D., Pardini, M., Righi, D., Manco, C., Colombo, B.M. and De Stefano, N. (2023) The Role of TNF- α in Alzheimer’s Disease: A Narrative Review. Cells , 13, Article 54. https://doi.org/10.3390/cells13010054
Murphy, M.P. and LeVine, H. (2010) Alzheimer’s Disease and the Amyloid- β Peptide. Journal of Alzheimer ’ s Disease , 19, 311-323. https://doi.org/10.3233/jad-2010-1221
Qing, H., Li, N., Liu, K., Qiu, Y., Zhang, H. and Nakanishi, H. (2019) Mutations of β -Amyloid Precursor Protein Alter the Consequence of Alzheimer’s Disease Pathogenesis. Neural Regeneration Research , 14, 658-665. https://doi.org/10.4103/1673-5374.247469
Masuda, A., Kobayashi, Y., Kogo, N., Saito, T., Saido, T.C. and Itohara, S. (2016) Cognitive Deficits in Single App Knock-In Mouse Models. Neurobiology of Lear n ing and Memory , 135, 73-82. https://doi.org/10.1016/j.nlm.2016.07.001
Sienski, G., Narayan, P., Bonner, J.M., Kory, N., Boland, S., Arczewska, A.A., et al . (2021) APOE4 Disrupts Intracellular Lipid Homeostasis in Human iPSC-Derived Glia. Science Translational Medicine , 13, eaaz4564. https://doi.org/10.1126/scitranslmed.aaz4564
Hartman, R.E., Wozniak, D.F., Nardi, A., Olney, J.W., Sartorius, L. and Holtzman, D.M. (2001) Behavioral Phenotyping of GFAP-apoE3 and-apoE4 Transgenic Mice: apoE4 Mice Show Profound Working Memory Impairments in the Absence of Alzheimer’s-Like Neuropathology. Experimental Neurology , 170, 326-344. https://doi.org/10.1006/exnr.2001.7715
Schmitt, J., Paradis, A., Boucher, M., Andrieu, L., Barnéoud, P. and Rondi-Reig, L. (2021) Flexibility as a Marker of Early Cognitive Decline in Humanized Apolipoprotein E ε 4 (ApoE4) Mice. Neurobiology of Aging , 102, 129-138. https://doi.org/10.1016/j.neurobiolaging.2021.01.013
McAlpine, F.E., Lee, J., Harms, A.S., Ruhn, K.A., Blurton-Jones, M., Hong, J., et al . (2009) Inhibition of Soluble TNF Signaling in a Mouse Model of Alzheimer’s Disease Prevents Pre-Plaque Amyloid-Associated Neuropathology. Neurobiology of Disease , 34, 163-177. https://doi.org/10.1016/j.nbd.2009.01.006
Winstone, J.K., Pathak, K.V., Winslow, W., Piras, I.S., White, J., Sharma, R., et al . (2022) Glyphosate Infiltrates the Brain and Increases Pro-Inflammatory Cytokine TNF α : Implications for Neurodegenerative Disorders. Journal of Neuroinflamm a tion , 19, Article No. 193. https://doi.org/10.1186/s12974-022-02544-5
Martínez, M., Rodríguez, J., Lopez-Torres, B., Martínez, M., Martínez-Larrañaga, M., Maximiliano, J., et al . (2020) Use of Human Neuroblastoma SH-SY5Y Cells to Evaluate Glyphosate-Induced Effects on Oxidative Stress, Neuronal Development and Cell Death Signaling Pathways. Environment International , 135, Article ID: 105414. https://doi.org/10.1016/j.envint.2019.105414
Hsiao, C.C., Yang, A., Wang, C. and Lin, C. (2023) Association between Glyphosate Exposure and Cognitive Function, Depression, and Neurological Diseases in a Representative Sample of US Adults: NHANES 2013-2014 Analysis. Environmental R e search , 237, Article ID: 116860. https://doi.org/10.1016/j.envres.2023.116860
Mayo Clinic (2023) Seizures. https://www.mayoclinic.org/diseases-conditions/seizure/symptoms-causes/syc-20365711
Jewett, B.E. and Sharma, S. (2023) GABA. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK513311/
Macdonald, R.L., Kang, J. and Gallagher, M.J. (2010) Mutations in GABA A Receptor Subunits Associated with Genetic Epilepsies. The Journal of Physiology , 588, 1861-1869. https://doi.org/10.1113/jphysiol.2010.186999
Petroff, O.A.C., Rothman, D.L., Behar, K.L. and Mattson, R.H. (1996) Low Brain GABA Level Is Associated with Poor Seizure Control. Annals of Neurology , 40, 908-911. https://doi.org/10.1002/ana.410400613
Naraine, A.S., Aker, R., Sweeney, I., Kalvey, M., Surtel, A., Shanbhag, V., et al . (2022) Roundup and Glyphosate’s Impact on GABA to Elicit Extended Proconvulsant Behavior in Caenorhabditis Elegans. Scientific Reports , 12, Article No. 13655. https://doi.org/10.1038/s41598-022-17537-w
Park, S., Kim, D., Park, S., Gil, H. and Hong, S. (2017) Seizures in Patients with Acute Pesticide Intoxication, with a Focus on Glufosinate Ammonium. Human & Experimental Toxicology , 37, 331-337. https://doi.org/10.1177/0960327117705427
Requena, M., Parrón, T., Navarro, A., García, J., Ventura, M.I., Hernández, A.F., et al . (2018) Association between Environmental Exposure to Pesticides and Epilepsy. NeuroToxicology , 68, 13-18. https://doi.org/10.1016/j.neuro.2018.07.002
Komiya, Y. and Habas, R. (2008) Wnt Signal Transduction Pathways. Organogen e sis , 4, 68-75. https://doi.org/10.4161/org.4.2.5851
Sowers, L.P., Loo, L., Wu, Y., Campbell, E., Ulrich, J.D., Wu, S., et al . (2013) Erratum: Disruption of the Non-Canonical WNT Gene PRICKLE2 Leads to Autism-Like Behaviors with Evidence for Hippocampal Synaptic Dysfunction. Molec u lar Psychiatry , 19, 742-742. https://doi.org/10.1038/mp.2013.143
Das, J. and Geetha, R. (2023) Corpus Callosum Agenesis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK540986/
Lau, Y.C., Hinkley, L.B.N., Bukshpun, P., Strominger, Z.A., Wakahiro, M.L.J., Baron-Cohen, S., et al . (2012) Autism Traits in Individuals with Agenesis of the Corpus Callosum. Journal of Autism and Developmental Disorders , 43, 1106-1118. https://doi.org/10.1007/s10803-012-1653-2
Zhang, J. and An, J. (2007) Cytokines, Inflammation, and Pain. International Ane s thesiology Clinics , 45, 27-37. https://doi.org/10.1097/aia.0b013e318034194e
Nadeem, A., Ahmad, S.F., Al-Harbi, N.O., AL-Ayadhi, L.Y., Sarawi, W., Attia, S.M., et al . (2022) Imbalance in Pro-Inflammatory and Anti-Inflammatory Cytokines Milieu in B Cells of Children with Autism. Molecular Immunology , 141, 297-304. https://doi.org/10.1016/j.molimm.2021.12.009
Beversdorf, D.Q., Stevens, H.E., Margolis, K.G. and Van de Water, J. (2020) Prenatal Stress and Maternal Immune Dysregulation in Autism Spectrum Disorders: Potential Points for Intervention. Current Pharmaceutical Design , 25, 4331-4343. https://doi.org/10.2174/1381612825666191119093335
Pu, Y., Yang, J., Chang, L., Qu, Y., Wang, S., Zhang, K., et al . (2020) Maternal Glyphosate Exposure Causes Autism-Like Behaviors in Offspring through Increased Expression of Soluble Epoxide Hydrolase. Proceedings of the National Academy of Sciences of the United States of America , 117, 11753-11759. https://doi.org/10.1073/pnas.1922287117
Pu, Y., Ma, L., Shan, J., Wan, X., Hammock, B.D. and Hashimoto, K. (2021) Autism-Like Behaviors in Male Juvenile Offspring after Maternal Glyphosate Exposure. Clinical Psychopharmacology and Neuroscience , 19, 554-558. https://doi.org/10.9758/cpn.2021.19.3.554
von Ehrenstein, O.S., Ling, C., Cui, X., Cockburn, M., Park, A.S., Yu, F., et al . (2019) Prenatal and Infant Exposure to Ambient Pesticides and Autism Spectrum Disorder in Children: Population Based Case-Control Study. BMJ , 364, L962. https://doi.org/10.1136/bmj.l962
Coullery, R.P., Ferrari, M.E. and Rosso, S.B. (2016) Neuronal Development and Axon Growth Are Altered by Glyphosate through a WNT Non-Canonical Signaling Pathway. NeuroToxicology , 52, 150-161. https://doi.org/10.1016/j.neuro.2015.12.004
Coullery, R., Pacchioni, A.M. and Rosso, S.B. (2020) Exposure to Glyphosate during Pregnancy Induces Neurobehavioral Alterations and Downregulation of Wnt5a-CaMKII Pathway. Reproductive Toxicology , 96, 390-398. https://doi.org/10.1016/j.reprotox.2020.08.006
Alarcón, R., Rivera, O.E., Ingaramo, P.I., Tschopp, M.V., Dioguardi, G.H., Milesi, M.M., et al . (2020) Neonatal Exposure to a Glyphosate-Based Herbicide Alters the Uterine Differentiation of Prepubertal Ewe Lambs. Environmental Pollution , 265, Article ID: 114874. https://doi.org/10.1016/j.envpol.2020.114874
Appleton, J. (2018) The Gut-Brain Axis: Influence of Microbiota on Mood and Mental Health. Integrative Medicine , 17, 28-32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469458/pdf/imcj-17-28.pdf
Dechartres, J., Pawluski, J.L., Gueguen, M., Jablaoui, A., Maguin, E., Rhimi, M., et al . (2019) Glyphosate and Glyphosate-Based Herbicide Exposure during the Peripartum Period Affects Maternal Brain Plasticity, Maternal Behaviour and Microbiome. Journal of Neuroendocrinology , 31, e12731. https://doi.org/10.1111/jne.12731
Del Castilo, I., Neumann, A.S., Lemos, F.S., De Bastiani, M.A., Oliveira, F.L., Zimmer, E.R., et al . (2022) Lifelong Exposure to a Low-Dose of the Glyphosate-Based Herbicide Roundup® Causes Intestinal Damage, Gut Dysbiosis, and Behavioral Changes in Mice. International Journal of Molecular Sciences , 23, Article 5583. https://doi.org/10.3390/ijms23105583
Ruuskanen, S., Rainio, M.J., Gómez-Gallego, C., Selenius, O., Salminen, S., Collado, M.C., et al . (2020) Glyphosate-Based Herbicides Influence Antioxidants, Reproductive Hormones and Gut Microbiome But Not Reproduction: A Long-Term Experiment in an Avian Model. Environmental Pollution , 266, Article ID: 115108. https://doi.org/10.1016/j.envpol.2020.115108
Hu, J., Lesseur, C., Miao, Y., Manservisi, F., Panzacchi, S., Mandrioli, D., et al . (2021) Low-Dose Exposure of Glyphosate-Based Herbicides Disrupt the Urine Metabolome and Its Interaction with Gut Microbiota. Scientific Reports , 11, Article No. 3265. https://doi.org/10.1038/s41598-021-82552-2
Mesnage, R., Teixeira, M., Mandrioli, D., Falcioni, L., Ducarmon, Q.R., Zwittink, R.D., et al . (2021) Use of Shotgun Metagenomics and Metabolomics to Evaluate the Impact of Glyphosate or Roundup MON 52276 on the Gut Microbiota and Serum Metabolome of Sprague-Dawley Rats. Environmental Health Perspectives , 129, Article ID: 017005. https://doi.org/10.1289/ehp6990
Chávez-Reyes, J., Gutiérrez-Reyes, C.D., Hernández-Cuellar, E. and Marichal-Cancino, B.A. (2024) Neurotoxicity of Glyphosate: Focus on Molecular Mechanisms Probably Associated with Alterations in Cognition and Behavior. Env i ronmental Toxicology and Pharmacology , 106, Article ID: 104381. https://doi.org/10.1016/j.etap.2024.104381