Abstract
Background: We have previously shown that Diethyldithiophosphate (DEDTP), a metabolite of Organophosphorous (OP) compounds biotransformation with longer half life than its parental compound, can modulate T CD4 lymphocyte functions. To explore if DEDTP can also alter T CD8 homeostasis and proliferation we evaluated cellular viability and proliferation by propidium iodide (PI) incorporation and carboxyfluorescein succinimidyl ester (CFSE) assay by flow cytometry, respectively, in peripheral blood mononuclear cells (PBMCs) and T CD8 cells from healthy male donors. Results: In vitro exposure to 1-50 µM DEDTP decreased T CD4 vs. T CD8 proportion on resting T CD3 lymphocytes. DEDTP decreased T CD8 viability in a dose-dependent manner after 24 h without affecting the rest of T CD3 lymphocytes. DEDTP also decreases CFSE dilution in T CD8 cells stimulated with anti-CD3/CD28 by arresting cells at the first round of division (M1). Decrease in cell proliferation was not only due to cellular arrest, but also to a consequence of cell death. Although cell death and cell cycle arrest were observed in the majority of the T CD8 cells, some particular T CD8 subset clones presented a high proliferative rate in the presence of DEDTP. Conclusion: DEDTP showed higher toxicity and cytostaticity in T CD8 cells than in T CD4 lymphocytes. This is relevant in exposed individuals as their ability to deal with viral infections and cancer cells could be limited by exposure to OP pesticides.
Highlights
Today, organophosphorous (OP) compounds are widely used as pesticides due to their low residual power into the environment and have replaced chlorinated compounds as the famous DDT
We have previously reported that exposure to some DAPs alters the proliferation induced by interleukin (IL)-2 in human peripheral blood mononuclear cells (PBMCs) [4] and especially, DEDTP modifies T CD4 lymphocyte IL-2 receptor-dependent proliferation by modifying the phosphorylation status of MAPKs and STAT5 proteins [5]
PBMCs we treated resting cells with different concentrations of DEDTP within the range of levels found on human plasma from intoxicated people [10]
Summary
Organophosphorous (OP) compounds are widely used as pesticides due to their low residual power into the environment and have replaced chlorinated compounds as the famous DDT. We have previously reported that exposure to some DAPs alters the proliferation induced by interleukin (IL)-2 in human peripheral blood mononuclear cells (PBMCs) [4] and especially, DEDTP modifies T CD4 lymphocyte IL-2 receptor-dependent proliferation by modifying the phosphorylation status of MAPKs and STAT5 proteins [5]. Besides T CD4 lymphocytes, T CD8 cells have an essential role in some cellular processes, such as the cytotoxic response known as CTL to kill virus and cancer cells. This subset of CD3 lymphocytes are very important as part of the immune response inducing clonal expansion of effectors and memory clones, which are determinant to control pathogens or cancer development [6]. To explore if DEDTP can alter T CD8 homeostasis and proliferation we evaluated cellular viability and proliferation by propidium iodide (PI) incorporation and carboxyfluorescein succinimidyl ester (CFSE) assay by flow cytometry, respectively, in peripheral blood mononuclear cells (PBMCs) and T CD8 cells from healthy male donors
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