Glyphosate commercial formulation causes cytotoxicity, oxidative effects, and apoptosis on human cells: Differences with its active ingredient
In the present study, the effects on oxidative balance and cellular end points of glyphosate, aminomethylphosphonic acid (AMPA), and a glyphosate formulation (G formulation) were examined in HepG2 cell line, at dilution levels far below agricultural recommendations. Our results show that G formulati...
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2014
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| 001 | PAPER-14366 | ||
| 003 | AR-BaUEN | ||
| 005 | 20240904172457.0 | ||
| 008 | 190411s2014 xx ||||fo|||| 00| 0 eng|d | ||
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| 100 | 1 | |a Chaufan, G. | |
| 245 | 1 | 0 | |a Glyphosate commercial formulation causes cytotoxicity, oxidative effects, and apoptosis on human cells: Differences with its active ingredient |
| 260 | |c 2014 | ||
| 270 | 1 | 0 | |m Chaufan, G.; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina; email: gchaufan@qb.fcen.uba.ar |
| 506 | |2 openaire |e Política editorial | ||
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| 520 | 3 | |a In the present study, the effects on oxidative balance and cellular end points of glyphosate, aminomethylphosphonic acid (AMPA), and a glyphosate formulation (G formulation) were examined in HepG2 cell line, at dilution levels far below agricultural recommendations. Our results show that G formulation had toxic effects while no effects were found with acid glyphosate and AMPA treatments. Glyphosate formulation exposure produced an increase in reactive oxygen species, nitrotyrosine formation, superoxide dismutase activity, and glutathione (GSH) levels, while no effects were observed for catalase and GSH-S-transferase activities. Also, G formulation triggered caspase 3/7 activation and hence induced apoptosis pathway in this cell line. Aminomethylphosphonic acid exposure produced an increase in GSH levels while no differences were observed in other antioxidant parameters. No effects were observed when the cells were exposed to acid glyphosate. These results confirm that G formulations have adjuvants working together with the active ingredient and causing toxic effects that are not seen with acid glyphosate. © The Author(s) 2014. |l eng | |
| 536 | |a Detalles de la financiación: Consejo Nacional de Investigaciones Científicas y Técnicas, PIP 11220090100492 | ||
| 536 | |a Detalles de la financiación: Universidad de Buenos Aires, UBACyT K140, UBACyT X187 | ||
| 536 | |a Detalles de la financiación: In order to provide evidence of glyphosate-induced cytotoxicity on hepatic cells, we compared the action of glyphosate, AMPA, the main breakdown product, and a G formulation. We found that G formulation induces dose-dependent cytotoxicity, while we did not find toxic effects with acid glyphosate and AMPA at assayed concentrations. These results are consistent with the concept that additives in commercial formulations play a role in toxicity attributed to herbicides. 10 Furthermore, the G formulation LC 50 value determined in HepG2 cells in this work was 100 times below the agriculture concentration (3.73 mg/L, Roundup UltraMax 28 ). Also, Benachour and Séralini 13 found that, for all Roundup formulations assayed, human umbilical cell, embryonic cell, and placental cell mortalities were not linearly linked to glyphosate concentration. In addition, these authors tested the effect of the supposed inert product polyethoxylated tallow amine present in the formulation of Roundup and they found that this compound produced cytotoxicity. Benachour and Séralini 13 found that AMPA and glyphosate concentrations 10 times higher than those used in this work promote cell death. Other recent works have also showed that G formulations toxicity is dependent on adjuvants present in commercial mixtures. 14 , 15 , 21 Then, we evaluated the involvement of oxidative stress in cytotoxicity. It has been reported that many pesticides (including herbicides) generate intracellular ROS. - 11 , 16 18 We demonstrated that the increased ROS trigger oxidative damage to proteins, nucleic acids, and lipids as well as the increase in activity of different antioxidant enzymes. 19 , 20 Free radical scavengers with antioxidant properties in animal cells compensate for damaging effects caused by reactive free radicals. Antioxidant enzymes such as SOD and CAT constitute the major defensive system against ROS formation. 20 Glutathione-S-transferase is also recognized as an important catalyst in xenobiotic biotransformation, including drugs, environmental pollutants, and by-products of oxidative stress. 38 A significant increase in SOD activity and GSH levels (for G formulation but not for acid glyphosate) was observed. No differences between control and treatment groups were observed for CAT and GST activities in HepG2 cells. Our results agree with previous findings - 39 42 that observed a decrease or no alteration in CAT activity when cells were treated with G formulation. These results could be explained at least in 2 ways, first, inactivation of CAT activity resulting in accumulation of intracellular ROS or second, CAT is a less sensitive biomarker for oxidative stress than SOD when HepG2 cells were exposed to G formulation. In the present work, cells exposed to the G formulation showed no variation in GST activity, which might indicate that the metabolism of the compounds present in G formulation occurs by other biotransformation pathways. Thus, although CAT and GST activities showed no alteration, the hypothesis that exposure to G formulation generates ROS cannot be discarded, since other parameters of the antioxidant response have been affected in this work. It was demonstrated that increases in SOD activity and GSH levels induced by oxidative stress may be linked to adaptive responses. - 43 45 These adaptive responses could depend on the studied system, the glyphosate concentrations, and formulations. Glutathione increase found in the cell line could be related to an induction of γ-glutamylcysteine synthetase, the enzyme that controls the biosynthesis of GSH, or to an increase in the levels of reduced GSH as a result of an increase in activity of GSH reductase. We evaluated for the first time whether exposure to G formulation increases ROS formation. We found an important increase in ROS production (140% of control) in cells treated with G formulation. Neither acid glyphosate nor AMPA treatment caused differences in ROS formation. There is a single recent work in the literature, which measures ROS formation as a result of pure glyphosate exposure using the H2DCFDA dye method. 46 These authors observed that glyphosate provokes ROS production in a dose dependent manner. It should be taken into account that the concentrations of glyphosate used in this study were at least 2 times higher than those used in that study. In addition to the increase in ROS, it was observed high levels of nitrotyrosine when cells were treated with G formulation as measured by immunofluorescence. The formation of 3-nitrotyrosine represents a specific peroxynitrite-mediated protein modification. Peroxynitrite is a strong oxidant formed by reaction of nitric oxide with superoxide. As known, high levels of nitrotyrosine can lead to loss or alteration in protein function and are associated with a large numbers of diseases. Reactive oxygen species play a critical role in apoptosis signalling. Glutathione acts as a major antioxidant against free radicals and it was shown that GSH is involved in apoptosis induction modulation. 47 , 48 Also, increase in GSH at earlier stages can be considered as a cell response (protective) mechanism. Increases in GSH levels in AMPA treatment could be an adaptive single response since no other parameter was affected. In this work, the increase in GSH, induced by G formulation, triggers caspase 3/7 activation and hence induced apoptosis pathway. However other works showed that this activation was switched on by depletion of GSH. 45 , 49 In this report, we demonstrate that cell death induced by G formulation is predominantly apoptotic, as determined by DAPI staining and caspase-3/7 activation. We found a 23.5% increase in morphological changes (condensed and fragmented nuclei) consistent with apoptotic cell death using G formulation at LC 20 . These results agree to those found by Gui et al 50 who demonstrated that glyphosate induced both apoptotic and autophagic cell death in PC12 cells as a neuronal model. Aminomethylphosphonic acid only caused an adaptative response that was not observed in glyphosate treatment at the same doses. However, Benachour and Séralini 13 found that AMPA is more toxic than glyphosate in human umbilical, embryonic, and placental cells, targeting their cell membranes. Furthermore, it was demonstrated that AMPA has a potential genotoxicity. 51 The comparative study of the breakdown products and their parent compounds is important because some metabolites present higher toxic effects than their parent compounds, and these are often detected in the environment. 3 Although it is known that in vtro studies do not take into consideration the toxicokinetics of chemicals (absorption, distribution, metabolism, and excretion), these studies are useful to evaluate the mechanism of action of G formulation. In conclusion, our results clearly demonstrated that G formulation induced cytotoxicity, ROS production, antioxidant defense induction, and apoptosis at subagriculture concentrations. This indicates that G formulations have adjuvants that, together with the active ingredient, cause toxic effects not observed with glyphosate itself. Considering that G formulation LC 50 , obtained in this work, was 100 times lower than the concentration used in agricultural praying, agricultural workers and rural populations are the group at greatest risk. Taking into account the great deal of controversy about the risk of glyphosate-containing herbicide exposure, - 5 , 6 , 51 53 more investigation on this area should be necessary to understand the effect of chronic exposure on human health. The effects observed by G formulation on HepG2 cells may provide evidence of cytotoxicity related to oxidative stress and cellular end points. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by grants from CONICET-Argentina (Consejo Nacional de Investigaciones Científicas y Técnicas, PIP 11220090100492) and from Universidad de Buenos Aires-Argentina (UBACyT X187 and UBACyT K140). | ||
| 593 | |a Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina | ||
| 690 | 1 | 0 | |a APOPTOSIS |
| 690 | 1 | 0 | |a CYTOTOXICITY |
| 690 | 1 | 0 | |a GLYPHOSATE |
| 690 | 1 | 0 | |a IN VTRO |
| 690 | 1 | 0 | |a OXIDATIVE STRESS |
| 690 | 1 | 0 | |a APOPTOSIS |
| 690 | 1 | 0 | |a CYTOTOXICITY |
| 690 | 1 | 0 | |a GLYPHOSATE |
| 690 | 1 | 0 | |a IN VTRO |
| 690 | 1 | 0 | |a OXIDATIVE STRESS |
| 690 | 1 | 0 | |a ADJUVANTS, PHARMACEUTIC |
| 690 | 1 | 0 | |a APOPTOSIS |
| 690 | 1 | 0 | |a CHEMISTRY, PHARMACEUTICAL |
| 690 | 1 | 0 | |a DRUG SYNERGISM |
| 690 | 1 | 0 | |a GLUTATHIONE |
| 690 | 1 | 0 | |a GLYCINE |
| 690 | 1 | 0 | |a HEP G2 CELLS |
| 690 | 1 | 0 | |a HEPATOCYTES |
| 690 | 1 | 0 | |a HERBICIDES |
| 690 | 1 | 0 | |a HUMANS |
| 690 | 1 | 0 | |a LETHAL DOSE 50 |
| 690 | 1 | 0 | |a ORGANOPHOSPHONATES |
| 690 | 1 | 0 | |a OSMOLAR CONCENTRATION |
| 690 | 1 | 0 | |a OXIDATION-REDUCTION |
| 690 | 1 | 0 | |a OXIDATIVE STRESS |
| 690 | 1 | 0 | |a REACTIVE OXYGEN SPECIES |
| 690 | 1 | 0 | |a SUPEROXIDE DISMUTASE |
| 690 | 1 | 0 | |a TYROSINE |
| 690 | 1 | 0 | |a UP-REGULATION |
| 700 | 1 | |a Coalova, I. | |
| 700 | 1 | |a Ríos de Molina, María del Carmen | |
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