Enhancing effect of the endocrine disruptor para-nonylphenol on the generation of reactive oxygen species in human blood neutrophils.

Abstract

Although para-nonylphenol (NP) is known as an endocrine disruptor, the immunologic effect of NP has been poorly analyzed. We found that NP from 5 to 50 microM caused a dose-dependent stimulatory effect on the generation of reactive oxygen species (ROS) in human blood neutrophils, which was measured by using a chemiluminescence reagent, luminol. Furthermore, ROS-scavenging enzymes such as catalase and superoxide dismutase and antioxidative agents alpha-tocopherol and beta-carotene showed strong preventive effects on NP-induced ROS generation. To analyze the biochemical mechanism of NP-induced ROS generation in human neutrophils, we investigated the effects of different types of metabolic inhibitor for the activation pathways of ROS generation in the cells. Reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase inhibitor, diphenyl iodonium chloride and the myeloperoxidase inhibitor sodium azide (NaN3) showed remarkable inhibitory effects on ROS generation induced by NP, but an inhibitor against mitochondrial respiratory function, potassium cyanide (KCN), did not exhibit significant effect. Furthermore, the phosphatidylinositol-3 (PI3) kinase inhibitor wortmannin and the tyrosine kinase inhibitor protein phosphorylation inhibitor 1 (PP1) caused strong suppression against NP-induced ROS generation. The selective protein kinase C inhibitor Ro-32-0432, p38 MAP kinase inhibitor SB 203580, and ERK MAP kinase inhibitor PD 98059 also showed significant suppressive effects on NP-induced ROS generation. These results suggest that NP causes an enhancing effect on ROS generation in human blood neutrophils through the activation of signal transduction pathways associated with the respiratory burst function in these cells. Additionally, to examine in vivo effects of NP, we also analyzed the effects of NP itself and the synergistic effects of NP and a typical inflammatory agent, opsonized zymosan, on human whole blood including neutrophils.

Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation

“…Using human and mouse primary cell cultures, it has been shown that all, BP, OP, and TBT, enhance reactive oxygen species generation, which might result in the depletion of intracellular GSH [34][35][36]. In the present study, we have demonstrated that intracellular GSH levels in TDS used as APC were clearly decreased by BP, OP, and TBT at the concentrations that induced Th2 polarization.…”

Protein Kinase C- and Reactive Oxygen Species-Dependent Stimulation of Intracellular cAMP in Human Eosinophils

“…A similar sequence of events was also suggested for the involvement of H 2 O 2 in cytokine gene expression and apoptosis [22,23] . Other studies in both animal models and human neutrophils [24,25] have, on the other hand, reported an ERK1/2-dependent activation of NADPH oxidase, in agreement with our present results. These conflicting observations may be explained by cellspecific differences in the signaling pathways commonly observed across cell types.…”

Energy-sensitive regulation of Na+/K+-ATPase by Janus kinase 2

“…Activation of JAK2 by DNP and NaN 3 in the present study indicates, however, that energy depletion can activate JAK2 also in a ROS-independent manner. Both DNP, a mitochondrial uncoupler, and NaN 3 , an inhibitor of the ROS-generating myeloperoxidase, are known to suppress ROS generation (62,63).…”