Immunotoxicity Induced by Acute Subtoxic Doses of Paraquat Herbicide: Implication of Shifting Cytokine Gene Expression toward T-Helper (T_H)-17 Phenotype

Abstract

Paraquat (PQ) is a free radical-inducing agent commonly used as an herbicide. This study assesses the acute immunotoxicity of PQ in BALB/c mice and examines its effect on cytokine gene expression profile. It was found that single subtoxic oral doses of 2, 4, and 20 mg/kg significantly inhibited the in vitro mitogen-induced proliferation in both T and B cells. Also, such acute doses have resulted in significant reduction of the IgM plaque-forming cells counts. The impact of PQ on the cytokine gene expression of in vitro PHA-activated splenocytes was assessed at 2.0 and 0.006 μg/mL. The concentrations used in vitro represent the lowest in vivo dose given in this study and FAO-WHO set PQ acceptable daily intake (ADI) dose, respectively. Interestingly, the RT²-PCR array for common cytokines' expression demonstrated that PQ had markedly elevated the mRNA expression of several proinflammatory cytokines at both concentrations. More importantly, at concentrations equivalent to ADI, PQ had caused a marked up-regulation of IL-17 cytokine family including IL-17B, C, E, and F. Also, PQ has up-regulated mRNA expression of the T(H)-17-promoting cytokines IL-9 and -21. Together, these results show that PQ at higher concentrations can deplete immune functions, but at lower concentrations, it has potential to alter immune responses toward the proinflammatory profiles as that of T(H)-17. Such a T cell helper profile has been implicated in the development and the pathophysiology of several autoimmune and allergic diseases. Thus, considering that maximum residue levels (MRLs) of PQ set by FAO and WHO for certain food and animal feed crops range between 0.005 and 10.0 mg/kg, our findings stress the importance of applying strict regulation on the use of PQ as an herbicide.

Paraquat Modulates Immunological Function in Bone Marrow-Derived Macrophages

“…Tissue injury is mainly due to reactive oxygen species (ROS) causing irreversible oxidative damage to molecular structures, cell functions and exacerbated immune response (Wu et al, 2018). Recent studies have shown that PQ directly impacts on immunity and immune cell activities (Hassuneh et al 2012;Riahi et al 2010) with effects such as decreased interferon (IFN)-γ production and phagocytic activity of monocytes in mice (Riahi et al 2011).…”

Environmental pollutants parathion, paraquat and bisphenol A show distinct effects towards nuclear receptors-mediated induction of xenobiotics-metabolizing cytochromes P450 in human hepatocytes

“…Thus, at this point it is difficult to distinguish if its proinflammatory activity is due to the GR antagonism or ROS formation. Nevertheless, it is clear that PRQ has ability to affect immune system, which was demonstrated in vivo in BALB/C mice, where single subtoxic oral doses (2, 4, and 20 mg/ kg) inhibited proliferation of T-and B-cells (Hassuneh et al, 2012). The results of this study also suggested that PRQ at higher concentrations can deplete immune functions, but it can alter immune responses towards the proinflammatory profiles at lower concentrations.…”

Retrospective analysis of the immunotoxic effects of plant protection products as reported in the Draft Assessment Reports for their peer review at EU level

“…One recent in vivo study with mice exposed acutely to paraquat (Hassuneh et al 2012), which included in vitro exposure of mouse splenocytes, found evidence of a negative dose response (more marked response at lower concentrations) in vivo and in vitro. It is unclear if this finding in a single study is reflective of a more general phenomenon.…”