Persistent inhibition of human natural killer cell function by ziram and pentachlorophenol

Abstract

Ziram is a currently used agricultural fungicide. It is also used as an additive in the production of latex gloves. Because of these uses, there is a potential for human exposure to this compound. Pentachlorophenol (PCP) has been used as an insecticide, fungicide, disinfectant, and ingredient in antifouling paints. Currently, it is used as a wood preservative for power-line poles and fence posts. Measurable levels of PCP have been detected in human blood and urine. In previous studies we demonstrated that both these compounds could cause very significant inhibition of the tumor-killing function of human natural killer (NK) cells. NK lymphocytes play a central role in immune defense against viral infection and the formation of primary tumors. So interference with their function could increase the risk of tumor development. In the present study we examined the effects of exposure to ziram or PCP of brief duration (1 h) on the ability of NK cells to destroy tumor cells. NK cells were exposed to either ziram (5-0.5 microM) or PCP (10-5 microM) for 1 h followed by 0 h, 24 h, 48 h, or 6 days in compound-free media and then were tested for the ability to lyse as well as to bind tumor cells. A 1-h exposure to as little as 2.5 microM ziram decreased the ability of NK cells to lyse target tumor cells, which persisted up to 6 days following exposure. The loss of lytic function for from 24 h to 6 days following exposure was accompanied by a comparable loss of NK capacity to bind tumor cells. Exposure to 10 microM PCP for 1 h caused a progressive loss (greater than 80%) of lytic function within 6 days of exposure. In contrast to ziram, PCP exposure caused no accompanying loss of binding function.

Mechanism of ziram-induced apoptosis in human T lymphocytes

“…Several studies have found ziram to show immunotoxicity including inhibition of natural killer (NK) activity (Whalen et al 2003;Wilson et al 2004;Taylor et al 2005;Taylor and Whalen 2009) and inhibition of TNF-alpha production in a human promyelocytic cell line, THP-1 (Corsini et al 2006). We also found that ziram significantly inhibits NK, lymphokineactivated killer (LAK), and cytotoxic T lymphocyte (CTL) activity (Li et al 2011a); however, the precise mechanism underlying its inhibition of CTL activity is still unclear.…”

Dithiocarbamate fungicides increase intracellular Zn2+ levels by increasing influx of Zn2+ in rat thymic lymphocytes

“…6). This concentration of Ziram to increase the cells at early stage of apoptosis in the external presence of Zn 2+ is lower than those to affect cellular functions of immune cells [43,45]. Therefore, this in vitro study has a toxicological implication.…”

“…However, Zn 2+ -related toxicity was not reported in previous animal experiments. In addition, there is also no information on Ziram-induced immunotoxicity in humans [10] although immunotoxic actions were suggested only by in vitro studies [43,45]. It may be necessary to specifically study Zn 2+ -dependent immune functions in Ziram-treated mammals.…”

Mechanism and Ziram-Induced Apoptosis in Human Natural Killer Cells

“…The NK-92MI cells at lx l Ovml were treated with ziram at 0 (0.1% DMSO), 0.0625, 0.125, 0.25, 0.5, 1,2, or 4 11M for 2,4,8,16,24,48 or 64 h at 37°C in a 5% CO 2 incubator. The treated cells were stained with FITCAnnexin-V/PI, and 10,000 cells were acquired and stored for analysis with a FACScan flow cytometer (Becton Dickinson, San Jose, CA, USA) as described previously (9,12,13,15,16).…”