Toxic Effects of Glyphosate on the Nervous System: A Systematic Review
Abstract
:1. Introduction
2. Methodology
Exclusion and Inclusion Criteria
3. Results
3.1. Effects of Glyphosate in Humans
3.1.1. Descriptive and Analytical Studies
3.1.2. In Vitro Studies with Human Line Cells
3.2. Effects of Glyphosate in Rodents
3.2.1. Development of Nervous System
3.2.2. Effects on Neurotransmission
3.2.3. Effects on Behavior
3.2.4. Induction of Oxidative Stress and Inflammation
3.2.5. Induction of Apoptosis and Autophagy
3.3. Effects of Glyphosate in Fish
3.3.1. Development of Nervous System
3.3.2. Effects on Behavior
3.3.3. Effects on Neurotransmission
3.3.4. Induction of Oxidative Stress and Inflammation
3.3.5. Effects on Energy Metabolism
3.4. Effects of Glyphosate on Invertebrates
4. Discussion
4.1. Overview of the Main Mechanisms of Action of Glyphosate on the Nervous System
4.2. Relationship between Glyphosate Doses and Neurotoxic Effects in Rodents and Humans
4.3. Exposure Levels and Neurotoxic Effects in Fish
5. Limitations
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Type of Study | Toxic Agent | Exposure Mode/Objetives | Results | Reference |
---|---|---|---|---|
Transversal study | GBH | Occupational exposure |
| [45] |
Prospective cohort study | GBH | Not specified |
| [46] |
Population-based case-control study | GBH | Occupational exposure |
| [47] |
Cohort study | GBH | Occupational exposure |
| [48] |
Cohort study | GBH | Occupational exposure |
| [49] |
In vitro SH-SY5Y cell line | GLY alone or mixed with other formulants: 5.33 to 3.200 μg/mL for 24 h | Investigate whether GBH toxicity is related to formulants |
| [50] |
In vitro IMR90-c4 iPSCs line | GLY, AMPA: 0.1 to 1000 μM for 24 or 48 h | Investigate the effect of GLY on the BBB in vitro and compare it with that of AMPA and glycine |
| [51] |
In vitro SH-SY5Y cell line | GLY, AMPA: 0.1 to 20 mM for 48 h | Investigate the effects of GLY and AMPA on oxidative stress, neurodevelopment, and cell death. |
| [52] |
Species | Dose and Exposition | Time Exposition | Objectives | Results | Reference |
---|---|---|---|---|---|
Swiss mice | Roundup®: 250 or 500 mg/kg/day orally | Subchronic exposition: 6 weeks Chronic exposition: 12 weeks | Assess the effects of acute or repeated GBH exposure on the developing brain of young and adult mice | Chronic/subchronic exposure:
| [62] |
Swiss mice | Roundup®: 250 or 500 mg/kg/day orally | Subchronic exposition: 6 weeks Chronic exposition: 12 weeks | Evaluate the effects of GBH on learning and memory functions, AChE activity, and oxidation/antioxidation homeostasis | Chronic/subchronic exposure:
| [63] |
Swiss mice | Roundup®: 250 or 500 mg/kg/day orally | From GD0 to PND21 | Evaluate the behavioral (PND5-PND25) and biochemical (PND60) effects of gestational and lactational exposure to GBH on offspring |
| [64] |
CF-1 mice | Glifloglex®: 50 mg/kg/day intranasally | Three days a week for four weeks | Assess the neurobehavioral effects of repeated intranasal administration of a GBH |
| [65] |
Wistar rats | Roundup®: 70 mg/kg/day orally | Chronic exposition: from GD5 to PND15. Acute exposition: 30 min in vitro | Determine the neurotoxic effects of GBH on the hippocampal function of immature rats after chronic exposure (pregnancy and lactation) and after acute in vitro exposition. | Acute in vitro exposition:
| [37] |
Wistar rats | Roundup®: 1% in drinking water (0.38% GLY) | Subchronic exposition: from GD5 to PND21. Chronic exposition: from GD5 to PND60. | Investigate the effects of subchronic exposure to GBH on neurochemical and behavioral parameters in immature and adult offspring |
| [3] |
Wistar rats | Roundup®: 70 mg/kg/day orally | Subchronic exposition: from GD5 to PND15. | Investigate possible biochemical and cell-persistent effects in the brain of adult rats following perinatal exposure to GBH |
| [66] |
Wistar rats | GLY: 24 or 35 mg/kg intraperitoneally | Dams received injections every 48 h from GD8 to GD20, totaling seven injections over two weeks | Evaluate the neurobehavioral effects of GLY in neonate rats after gestational exposure |
| [67] |
Sprague-Dawley rats | GLY, Roundup®: 5 mg/kg/day orally | From GD10 to PND22 | Compare the potential effects of a low dose of GLY and GBH on maternal behavior and maternal neuroplasticity, focusing on the hippocampus and cingulate gyrus |
| [68] |
CF-1 mice | Glifloglex®: 50 mg/kg/day intranasally | Four weeks (three injections per week) | Elucidate the mechanisms by which the intranasal administration of a GBH exerts its neuropathological effects |
| [69] |
Sprague-Dawley rats | GLY: 50, 100, or 150 mg/kg intraperitoneally | Two weeks (three injections per week) | Assess the integrity of the nigrostriatal and mesolimbic dopaminergic systems and their relationship with spontaneous locomotor activity after repeated or acute exposure to GLY |
| [70] |
ICR mice | Roundup®: 50 mg/kg/day orally | From GD14 to PND7 | Assess the miRNA expression patterns in the PFC of mouse offspring after exposure to GBH during pregnancy and lactation |
| [71] |
Balb/c mice | Roundup®: 25, 50 or 100 mg/kg orally | Acute exposure | Investigate the behavioral effects induced by acute exposure to a GBH in increasing doses |
| [72] |
Wistar rats | GBH: 2.5, 5, 10, 20 or 40 mM | Single dose | Assess the inhibitory potency of a GBH on AChE activity in rat tissues |
| [73] |
Wistar rats | GLY: 35 or 70 mg/kg subcutaneous injection | From PND7 to PND27 | Evaluate the effects of glyphosate on hippocampal synapses and cognitive functioning |
| [74] |
Wistar rats | GLY: 35, 75, 150 or 800 mg/kg/day orally | Six days | Determine the effects of GLY on the levels of DA, NE, and 5-HT and their metabolites, as well as the turnover in striatum, hippocampus, PFC, hypothalamus, and midbrain. |
| [13] |
Cellular Line | Dose and Time of Exposure | Objectives | Results | Reference |
---|---|---|---|---|
PC12 cells | GLY: 0, 5, 10, 20, or 40 mM for 12, 24, 48, or 72 h | Investigate the neurotoxicity of GLY in differentiated rat PC12 cells and explore the role of apoptosis and autophagy pathways in toxicity |
| [75] |
Hippocampal pyramidal cells | GLY: 0.5 or 1 mg/mL for five or ten days | Examine the effects of glyphosate on synapse formation and maturation in the hippocampus |
| [74] |
NSC | GLY: 0.1, 700, 7000, or 36,000 μg/L for 24 h | Understand the effects of two maximum permissible concentrations of GLY on the basic processes of neurogenesis in NSCs of the postnatal mouse subventricular zone. |
| [76] |
Astroglioma (C6) | GLY: concentrations from 0 to 160 mM for 24 h | Determine the activity of enzymes related to energy metabolism, as well as parameters of oxidative stress, mitochondrial mass, nuclear area, and autophagy in astrocytes treated with GBH |
| [77] |
Embryonic DRG and pure Schwann cells | GLY, Roundup®: 0.0005% and 0.005% for ten days (DRG) or 72 h (Schwann cells) | Investigate the effects of pure GLY and GBH in murine embryonic DRG cultures |
| [78] |
Embryonic DRG and pure Schwann cells | GLY, Roundup®: doses not specified for ten days (DRG) or 72 h (Schwann cells) | Study and compare the effects of pure GLY and GBH in murine embryonic DRG explant cultures |
| [79] |
Species | Dose and Time Exposure | Objectives | Results | Reference |
---|---|---|---|---|
Cnesterodon decemmaculatus (Ten-spotted livebearer) | GLY: 1 or 10 mg/L for 96 h | Assess the effect of seasonal variability on AChE activity in fish exposed to chlorpyrifos and GLY |
| [132] |
Colossoma macropomum (Blackfin pacu) | Roundup®: 10 or 15 mg/L for 96 h | Investigate the effects of GBH on gill morphology and function, hematological parameters, biotransformation enzymes, the antioxidant system in the gills and liver, as well as on both neurological and erythrocytic DNA damage |
| [133] |
Danio rerio (Zebrafish) | Roundup®, GLY: 0.01, 0.065, or 0.5 mg/L for 96 h | Evaluate the effects of GLY and GBH on morphological and behavioral parameters in larvae and adult zebrafish | GLY and GBH caused:
| [134] |
Danio rerio (Zebrafish) | GLY: 5, 10, or 50 μg/mL for 96 h | Identify a possible mechanism of toxicity for GLY related to changes in microtubule stability, which could alter the distribution and dynamics of cytoskeletal components |
| [135] |
Pintado da Amazônia | Roundup®: 0.37, 0.75, 2.25, 4.5, 7.5, 11.25, 15, 22.5, or 30 mg/L for 24, 48, 72, or 96 h | Evaluate the lethal concentration of the GLY and the oxidative stress parameters in tests with sublethal concentrations |
| [136] |
Danio rerio (Zebrafish) | GLY: 0.3 or 3 μg/L for 2 weeks | Analyze the neurotoxicity of GLY in adult zebrafish after exposure through water to environmentally relevant concentrations |
| [130] |
Danio rerio (Zebrafish) | GLY: 0.05 to 10.000 μg/L for a period of 1.5 to 120 h after fertilization | Explore the effects of the use of different concentrations of GLY on anatomy and behavior of fish | High concentrations of GLY (≥1000 μg/L) caused:
| [137] |
Hypomesus transpacificus (Delta smelt) | Roundup®: 0.064, 0.64, 6.4, 64, or 640 mg/L for 6 h | Compare the sublethal toxicity of four herbicides (penoxsulam, imazamox, fluridone, and GBH). |
| [138] |
Cyprinus carpio (European carp) | GLY: 0.02, 0.05, 0.07, or 0.1 mg/L for 24, 48, 72, or 96 h | Analyze the effect of GLY and atrazine on the hematological and biochemical parameters of blood and on behavioral aspects |
| [139] |
Danio rerio (Zebrafish) | Roundup®: 2, 5, or 8.5 μg/mL for 72 h | Investigate the lethal and sublethal developmental effects, neurotoxic potential, and oxidative stress responses after GBH exposure | High concentrations of GBH caused:
| [140] |
Danio rerio (Zebrafish) | Roundup®: 1, 2, or 5 μg/mL for 72 h | Assess GBH effects at environmentally relevant concentrations through a set of behavioral patterns |
| [141] |
Carassius auratus (Goldenfish) | Nongteshi®: 0.22, 0.44, or 0.88 mmol/L for 96 h | Investigate the toxic effects of GBH exposure using a metabolomic approach supplemented with histological inspection and hematological evaluation |
| [142] |
Carassius auratus | Nongteshi®: 0.2 mmol/L for 90 days | Assess GBH toxicity after prolonged exposure | Results in the brain:
| [143] |
Danio rerio (Zebrafish) | GLY: 5 or 10 mg/L for 24 and 96 h | Evaluate oxidative stress parameters, as well as the activity and expression of AChE |
| [144] |
Cnesterodon decemmaculatus | GLY: 1, 17.5, or 35 mg/L for 96 h | Assess the toxic effect of acute exposure to sublethal GLY concentrations on AChE activity in different parts of the body |
| [145] |
Odontesthes bonariensis (Argentinian silverside) | GBH: 1 or 10 mg/L for 15 days | Determine the basal levels of adenylates, phosphagens, and the AEC index in the brain, muscle, and liver, as well as the impact of exposure to sublethal GBH on the subcellular energy balance |
| [146] |
Danio rerio (Zebrafish) | GBH, GLY: 0.065, 1, 10, 160, 1.6 × 103, 4 × 103, or 8 × 103 mg/L for 3 h (in vitro) or for 7 days (in vivo) | Investigate the neurotoxic effects of GBH by focusing on acute toxicity, activity, and transcription levels of mitochondrial respiratory chain complexes, mitochondrial membrane potential, reactive species formation, and behavioral repertoire | In vivo exposure to GBH (7 days) caused:
| [147] |
Danio rerio (Zebrafish) | Roundup®, GLY: 50 μg/mL for 24 h | Investigate the neurotoxic effects of GBH and GLY exposure on the developing brain | Both GBH and GLY caused:
| [148] |
Jenynsia multidentate (Onesided livebearer) | Roundup® (Original, Transorb or WG): 0.5 mg/L for 96 h | Evaluate and compare the effects of three GBH formulations on behavior patterns | Roundup WG® was the most harmful formulation and negatively affected:
| [149] |
Rhamdia quelen (Silver catfish) | GLY: 6.5 mg/L for 12, 24, 48, or 72 h | Investigate the effects of GLY on the antioxidant system, as well as the neurotoxic effects on eggs and larvae |
| [150] |
Danio rerio (Zebrafish) | GLY: 0.01, 0.1, 0.5, 1, 5, 10, 100, 200, 400, or 600 mg/L from 3 hpf until 96 hpf | Assess the developmental, morphological, and genetic effects of GLY in zebrafish embryos |
| [151] |
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Costas-Ferreira, C.; Durán, R.; Faro, L.R.F. Toxic Effects of Glyphosate on the Nervous System: A Systematic Review. Int. J. Mol. Sci. 2022, 23, 4605. https://doi.org/10.3390/ijms23094605
Costas-Ferreira C, Durán R, Faro LRF. Toxic Effects of Glyphosate on the Nervous System: A Systematic Review. International Journal of Molecular Sciences. 2022; 23(9):4605. https://doi.org/10.3390/ijms23094605
Chicago/Turabian StyleCostas-Ferreira, Carmen, Rafael Durán, and Lilian R. F. Faro. 2022. "Toxic Effects of Glyphosate on the Nervous System: A Systematic Review" International Journal of Molecular Sciences 23, no. 9: 4605. https://doi.org/10.3390/ijms23094605