Abstract
Glyphosate (G) is the active ingredient of the most used herbicides worldwide. Its use is currently very debated, as several studies indicating its hazard and toxicity are emerging. Among them, there is evidence of adverse effects on the immune system. The aim of this work was to investigate if G could directly affect immune cells. Peripheral blood mononuclear cells (PBMC) obtained from healthy donors were used as experimental model. PBMC were expose to G and stimulated with PMA/ionomycin, T helper (Th) cell differentiation and cytokine production were assessed by flow cytometry and enzyme-linked immunosorbent assay, respectively. A reduction of Th1/Th2 ratio, mainly due to a decrease in Th1 cells, was observed following G exposure. Results show an enhancement of IL-4 and IL-17A production, and a reduction of IFN-γ. Based on literature evidence that suggest G being an endocrine disruptor, we investigated the role of nuclear estrogen receptors (ER). ERα/ERβ inhibition by ICI 182,780 abolished the effects of G on IFN-γ and IL-4 release, suggesting a role of ER in the observed effects. To further characterize the mechanism of action of G, miRNAs, both in exosome and intracellular, were investigated. A statistically significant increase in miR-500a-5p was observed following G treatment. The blockage of miR-500a-5p, using a specific antagomir, prevented G-induced reduction of IFN-γ production. Finally a relationship between miR-500a-5p up-regulation and ER was observed. Overall, these results suggest that G can directly act on T cells, altering T cell differentiation and cytokines production.
Highlights
Glyphosate (N-(phosphonomethyl) glycine; G) is the active ingredient of the most used broadspectrum herbicide worldwide [1, 2]
Peripheral blood mononuclear cells (PBMC) were treated with G alone at increasing concentrations for 1 hour and stimulated with PMA and ionomycin for subsequent 5 hours
Data indicate that G can directly affect T helper (Th) cell differentiation, resulting in an imbalance of Th1/Th2 subpopulations, supporting an increase in Th2 responses
Summary
Glyphosate (N-(phosphonomethyl) glycine; G) is the active ingredient of the most used broadspectrum herbicide worldwide [1, 2]. It was commercialized starting from 1974 under the name of Roundup®, together with adjuvants, like polyoxyethylene tallowamine, that, considered inert compounds, can increase G toxicity [3]. The herbicidal activity is based on the competitive inhibition of the shikimate pathway, which leads to the blockage of the synthesis of aromatic amino acids in plants [5]. Since animals do not have this pathway, G has always been considered safe for humans by regulatory agencies [6, 7]. The majority of studies addressing G toxicity used high doses, there are studies using environmental relevant doses showing noxious effects in both animals and humans [12–16]
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