Effect of tributyltin (TBT) on ATP levels in human natural killer (NK) cells: Relationship to TBT‐induced decreases in NK function

Abstract

The purpose of this study was to investigate the role that tributyltin (TBT)-induced decreases in ATP levels may play in TBT-induced decreases in the tumor lysing (lytic) function of natural killer (NK) cells. NK cells are a subset of lymphocytes that act as an initial immune defense against tumor cells and virally infected cells. TBT is an environmental contaminant that has been detected in human blood, which has been shown to interfere with ATP synthesis. Previous studies have shown that TBT is able to decrease very significantly the lytic function of NK cells. In this study NK cells were exposed to various concentrations of TBT and to two other compounds that interfere with ATP synthesis (rotenone a complex I inhibitor and oligomycin an ATP synthase inhibitor) for various lengths of time before determining the levels of ATP and lytic function. Exposures of NK cells to 10, 25, 50 and 100 nm TBT did not significantly reduce ATP levels after 24 h. However, these same exposures caused significant decreases in cytotoxic function. Studies of brief 1 h exposures to a range of TBT, rotenone and oligomycin concentrations followed by 24 h, 48 h and 6 day periods in compound-free media prior to assaying for ATP levels or cytotoxic function showed that each of the compounds caused persistent decreases in ATP levels and lytic function of NK cells. Exposures to 0.05-5 microm rotenone or oligomycin for 1 h reduced ATP levels by 20-25% but did not have any measurable effect on the ability of NK cells to lyse tumor cells. ATP levels were also decreased by about 20-25% after 24 h or 48 h exposures to rotenone or oligomycin (0.5 microm ), and the lytic function was decreased by about 50%. The results suggest that TBT-induced decreases in ATP levels were not responsible for the loss of cytotoxic function seen at 1 h and 24 h. However, TBT-induced decreases of NK-ATP levels may be at least in part responsible for losses of NK-cytotoxic function seen after 48 h and 6 day exposures.

Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-γ) from human immune cells

“…This inhibition of NK lytic function may be due to their ability to induce activation/phosphorylation of MAPKs and MAP2Ks (Cato et al, 2014). Other environmental contaminants such as tributyltin (TBT) and dibutyltin (DBT) (Kimbrough, 1976) that decrease NK lytic function (Dudimah et al, 2007a,b), while activating the MAPK pathway (Aluoch et al, 2006; Odman- Ghazi et al, 2010), have been shown to alter IFNγ secretion from human immune cells (Lawrence et al, 2015). Thus, it is crucial to determine whether HBCD and TBBPA are also able to alter the secretion of IFNγ from human immune cells.…”

Tetrabromobisphenol A has immunosuppressive effects on human natural killer cells

“…The light emission was then measured using a Fluoroskan Ascent FL luminescence plate reader (Thermo Electron Corp., Vantaa, Finland). ATP levels were then determined by extrapolation from a standard curve (Dudimah et al, 2007b). …”

Tributyltin exposure alters cytokine levels in mouse serum

“…It affects the function of human natural killer (NK) lymphocytes (Smialowicz et al 1989; van Loveren 1990; Ghoneum 1990) including interference with the ability of human NK cells to bind and lyse target cells (Whalen et al 1999; Dudimah et al 2007; Whalen et al 2002; Thomas et al 2004). Additionally, it has been shown to alter the secretion of the pro-inflammatory cytokines interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β from human immune cells ex vivo (Hurt et al 2013; Lawrence et al 2015; Brown and Whalen 2015).…”