Direct Effects of Glyphosate on In Vitro T Helper Cell Differentiation and Cytokine Production

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.

In Vitro Effects of Cypermethrin and Glyphosate on LPS-Induced Immune Cell Activation

“…A reduction of Th1/Th2 ratio, mainly due to a decrease in Th1 cells, was observed following Glyp exposure, together with an enhancement of IL-4 and IL-17A production, as well as a reduction of IFN-γ. Based on literature evidence that suggested Glyp being an endocrine disruptor, we also demonstrated a role of ER in the observed effects [29].…”

Effect of zinc supplementation on immunotoxicity induced by subchronic oral exposure to glyphosate-based herbicide (GOBARA®) in Wistar rats

“…The production of other cytokines (IL 6, IL-4, and IL-17A) was also induced by glyphosate exposure in intestinal mucosal cells and peripheral blood mononuclear cells. 41,42 Interferon gamma production was reduced in blood mononuclear cells exposed to glyphosate. 42 IL-1b expression was reported to be unchanged in the intestines and decreased in the gills of sea bass fish, 43 suggesting that the effects of glyphosate on cytokine production could be bidirectional.…”

“…41,42 Interferon gamma production was reduced in blood mononuclear cells exposed to glyphosate. 42 IL-1b expression was reported to be unchanged in the intestines and decreased in the gills of sea bass fish, 43 suggesting that the effects of glyphosate on cytokine production could be bidirectional. The reason why GBH had no effect on serum IL-1b levels could not be identified, but it might be related to pathways of T cell differentiation and cytokine production.…”

“…The reason why GBH had no effect on serum IL-1b levels could not be identified, but it might be related to pathways of T cell differentiation and cytokine production. 42 The increasing levels of pro-inflammatory cytokines, especially cytotoxic TNF-a, might induce apoptosis in lymphocytes in the lymphoid organs. 44 Exposure to GBH decreased serum IgG and IgM concentrations in the rats, indicating decreased production of these immunoglobulins.…”

Occupational exposure to pesticides dysregulates systemic Th1/Th2/Th17 cytokines and correlates with poor clinical outcomes in breast cancer patients

“…In vitro data have evidenced that pesticide exposure favors malign breast cancer cells’ capabilities as migration, angiogenesis ( 15 ) and proliferation ( 16 ), which are biological features linked to highly aggressive breast tumors in humans. Also, in vitro data has pointed out the immunogenotoxicity of pesticides ( 16 – 19 ). However, little is known regarding the relationship between pesticide exposure, breast cancer behavior and immune response.…”