Dibutyltin activates MAP kinases in human natural killer cells, in vitro

Abstract

Previous studies have shown that dibutyltin (DBT) interferes with the function of human natural killer (NK) cells, diminishing their capacity to destroy tumor cells, in vitro. DBT is a widespread environmental contaminant and has been found in human blood. As NK cells are our primary immune defense against tumor cells, it is important to understand the mechanism by which DBT interferes with their function. The current study examines the effects of DBT exposures on key enzymes in the signaling pathway that regulates NK responsiveness to tumor cells. These include several protein tyrosine kinases (PTKs), mitogen activated protein kinases (MAPKs) and mitogen activated protein kinase kinases (MAP2Ks). The results showed that in vitro exposures of NK cells to DBT had no effect on PTKs. However, exposures to DBT for as little as 10 min were able to increase the phosphorylation (activation) of the MAPKs. The DBT-induced activations of these MAPKs, appears to be due to DBT-induced activations of the immediate upstream activators of the MAPKs, MAP2Ks. The results suggest that DBT-interference with the MAPK signaling pathway is a consequence of DBT exposures, which could account for DBT-induced decreases in NK function.

Brominated flame retardants, tetrabromobisphenol A and hexabromocyclododecane, activate mitogen-activated protein kinases (MAPKs) in human natural killer cells

“…The effects of the compounds on MAPK phosphorylation were no longer consistently measurable after 1h. This too is consistent previous studies (Trotta et al, 1998; Aluoch and Whalen, 2005; Aluoch et al, 2006; Odman-Ghazi et al, 2010; Taylor and Whalen, 2011). Longer term consequences of this early activation would result in a number of cellular changes, which could include the types of effects on lytic function and protein expression that were described in previous studies (Hinkson and Whalen, 2009; Hinkson and Whalen, 2010; Kibakaya et al, 2009; Hurd and Whalen, 2011).…”

“…Longer incubations of 1 h and 6 h were also carried out to examine the length of any consistent activation of p44/42. The choice of exposure conditions was based on past studies including those where we examined the effect of other compounds known to inhibit NK lytic function on MAPK activation (Trotta et al, 1998; Aluoch and Whalen, 2005; Aluoch et al, 2006; Odman-Ghazi et al, 2010; Taylor and Whalen, 2011.) Those studies showed that the environmental contaminants tributyltin (TBT), dibutyltin (DBT), and ziram inhibit NK lytic function and cell surface-protein expression while altering the activation state of MAPK pathway components (Aluoch and Whalen, 2005; Aluoch et al, 2006; Odman-Ghazi et al, 2010; Taylor and Whalen, 2011).…”

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.…”

O desregulador endócrino, dibutilestanho, é um antagonista de PPAR-alfa em ensaios de gene repórter

“…Another study suggest that in vitro DBT exposure to natural killer cells activated the MAPK, while it did not showed any effect to protein tyrosine kinase [69]. In addition,…”

“…Subunit of ion channel is the target of ATPase inhibition by means of organotin compounds [68]. Another report suggest that DBT treatment with natural killer cells increased the activation of MAPK, could decrease the function of natural killer cells, while it did not showed any effect to protein tyrosine kinase [69]. TBT treatment to immature male mice has reduced the serum testosterone concentration , downregulated the expression of various enzymes for cholesterol side chain cleavage enzyme P450, 17α-hydoxylase, 3βhydroxysteroid dehydrogenase and 17β hydroxysteroid dehydrogenase.…”