Pentachlorophenol decreases tumor-cell- binding capacity and cell-surface protein expression of human natural killer cellsTasia Hurd,aJasmine Walkerband Margaret M. Whalena*ABSTRACT: Pentachlorophenol (PCP) is an organochlorine pesticide that decreases the tumor-cell killing (lytic) function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. They bind to these targets, utilizing a variety of cell-surface proteins. This study examined concentrations of PCP that decrease lytic function for alter- ation of NK binding to tumor targets. Levels of PCP that caused loss of binding function were then examined for effects on expression of cell-surface proteins needed for binding. Exposure to 10mMPCP for 24h (which caused a greater than 70% loss of lytic function) decreased NK binding function (34.6%), and CD11a (21.7%) and CD56 (26.2%) cell-surface proteins. Both binding function and cell-surface proteins were decreased after longer exposures to lower concentrations of PCP. These data indicate that continuous exposures to PCP decreased binding function as well as cell-surface marker expression in NK cells and that these changes may in part explain the losses of lytic function seen with these exposures. PCP exposures have been shown to increase the incidence of blood and kidney cancers in humans. These data indicate that a possible explanation for this increased risk may be loss of NK lytic function, which is at least in part owing to the loss of the ability of the NK cell to bind to tumor cells. These data also indicate that lost binding function may be due to loss of important cell-surface proteins. Copyright 2011 John Wiley NK cells; binding function; CD16; CD56INTRODUCTIONNatural killer (NK) cells prevent the development as well as the metastases of tumors (Lotzova, 1993; Vivier et al., 2004). They also play a central role in defending against viral infections. Because of these functions, they are the primary immune defense against tumor cells and virally infected cells. Viral infection incidence has been shown to increase in individuals lacking NK cells (Fleisher et al., 1982; Biron et al., 1989). Importantly, it has been shown thata patient with a deficiency of NK cells suffered from both vulvar and cervical carcinomas (Ballas et al., 1990). Additionally, a correla- tion between the size of the tumor and a decrease in the number ofNKcellswasshowninbreastcancerpatients(Fultonetal.,1984). As these cells are the front line of immune response against tumorsandvirallyinfectedcells(owingtotheirabilitytolysetarget cellswithoutpriorsensitization),anythingthat interfereswith their function could lead to an increased incidence of tumors or viral infections. It has been shown that exposure to the environmental contaminant dichlorodiphenyltrichloroethane (DDT) decreases both the number and cytotoxic function of human NK cells (Svensson et al., 1994; Eskenazi et al., 2009). In keeping with its ef- fect on NK cell numbers and function, it has been found that DDT exposure at early ages (prior to age 14) causes a 5-fold increase in the risk of breast cancer (Cohn et al. 2007). The NK cell must physically bind to a target cell (be it a tumor cell or virally infected cell) in order to destroy (lyse) the target. CD11a and CD18 form the functional LFA-1 adhesion complex shown to be required for NK binding to tumor targets (Nitta et al., 1989). CD56, a cognate of the neural cell adhesion molecule, has also been shown to be important in NK binding to targets (Nitta et al., 1989; Lotzova, 1993). CD2, an NK cell adhesionmolecule, has been implicated in activation of the cytotoxic signaling response (Lotzova, 1993). CD16 has a role as activating receptor of the NK lytic process with antibody-coated (Lotzova, 1993) and tumor targets (Mandelboim et al., 1999). Pentachlorophenol (PCP) was at one time registered for use as an insecticide, fungicide, herbicide, molluscicide, algicide, disin- fectant and ingredient in antifouling paints (Cirelli 1978). Its use was restricted in 1984 (US Environmental Protection Agency, 2001). It is now mainly used as a wood preservative for power- line poles and fence posts. Approximately 80% of the PCP used in the USA is for the treatment of wooden utility poles (Agency for Toxic Substances and Disease Registry, 2001). As with other organochlorine compounds, PCP is quite stable. Owing to itsonce widespread use and chemical stability, it is a very signifi- cant environmental contaminant. Humans are exposed to PCP through inhalation, absorption through the skin and consump- tion of contaminated food and water (Agency for Toxic Substances and Disease Registry, 2001). Measurable levels of PCP have been detected in human blood and urine (Atuma and Okor, 1985; Centers for Disease Control and Prevention, 2005; Cline et al., 1989; Jones et al., 1986; Thornton et al., 2002; Uhl et al. 1986). Levels ranging from 0.26 to 5mMwere found in* Correspondence to: Whalen, Ma