Butyltins (BTs) have been in widespread use. Tributyltin (TBT) has been used as a biocide in a variety of applications and is found in human blood samples. Dibutyltin (DBT) has been used as a stabilizer in polyvinyl chloride plastics and as a de-worming agent in poultry. DBT, like TBT, is found in human blood. Human natural killer (NK) cells are the earliest defense against tumors and viral infections and secrete the cytokine tumor necrosis factor (TNF) alpha (α). TNFα is an important regulator of adaptive and innate immune responses. TNFα promotes inflammation and an association between malignant transformation and inflammation has been established. Previously, we have shown that TBT and DBT were able to interfere with the ability of NK cells to lyse tumor target cells. Here we show that BTs alter cytokine secretion by NK cells as well as a mixture of T and NK lymphocytes (T/NK cells). We examined 24 h, 48 h, and 6 day exposures to TBT (200- 2.5 nM) and DBT (5- 0.05 µM) on TNFα secretion by highly enriched human NK cells and T/NK cells. The results indicate that TBT (200 - 2.5 nM) decreased TNFα secretion from NK cells. In the T/NK cells 200 nM TBT decreased secretion while 100-5 nM TBT increased secretion of TNFα. NK cells or T/NK cells exposed to higher concentrations of DBT showed decreased TNFα secretion while lower concentrations showed increased secretion. The effects of BTs on TNFα secretion are seen at concentrations present in human blood.

1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) and triclosan (TCS) are organochlorine (OC) compounds that contaminate the environment, are found in human blood, and have been shown to decrease 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 DDT and TCS that decrease lytic function for alteration of NK binding to tumor targets. Levels of either compound that caused loss of binding function were then examined for effects on expression of cell-surface proteins needed for binding. NK cells exposed to 2.5 μM DDT for 24 h (which caused a greater than 55% loss of lytic function) showed a decrease in NK binding function of about 22%, and a decrease in CD16 cell-surface protein of 20%. NK cells exposed to 5 μM TCS for 24 h showed a decrease in ability to bind tumor cells of 37% and a decrease in expression of CD56 of about 34%. This same treatment caused a decrease in lytic function of greater than 87%. These results indicated that only a portion of the loss of NK lytic function seen with exposures to these compounds could be accounted for by loss of binding function. They also showed that loss of binding function is accompanied by a loss cell-surface proteins important in binding function.

4, 4′-Dichlorodiphenyltrichloroethane (DDT) and Triclosan (TCS) are organochlorine compounds that contaminate the environment, are found in human blood, and have been shown to decrease the tumor-cell killing (lytic) function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. This study examined concentrations of DDT and PCP that decrease lytic function for alteration of NK binding to tumor targets. Levels of either compound that caused loss of binding function were then examined for effects on expression of cell-surface proteins needed for binding. CD16 is an Fc receptor and CD56 is a cognate of neural cell adhesion molecules, both of which are present on NK cells and involved in recognition and lysis of NK target. NK cells exposed to 2.5 µM DDT for 24 h (which caused a greater than 55% loss of lytic function) showed a decrease in NK binding function of about 23%, and a decrease in CD16 of 20%. NK cells exposed to 5 µM TCS for 24 h showed a decrease in ability to bind tumor cells of 44% and a decrease in expression of CD56 of about 34%. This same treatment caused a decrease in lytic function of greater than 87%These results indicated that only a portion of the loss of NK lytic function seen with exposures to these compounds could be accounted for by loss of binding function and also accompanied by loss of cell-surface protein expression. Supported by NIH grant 1U54CA163066-01 and S06 GM008092-35 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 521. doi:1538-7445.AM2012-521

Cytokines are important regulators of immune responsiveness. Alterations of cytokine secretion from immune cells would have the potential to disrupt both immune destruction of cancer cells and to alter the proliferation and invasiveness of tumor cells due to their capacity to act as growth factors, angiogenic factors, and inducers of epithelial-mesenchymal transition. Tributyltin (TBT) is a widespread environmental contaminant having been used in a variety of industrial applications and is found in human blood at levels ranging as high as 261 nM. Studies in human immune cells have shown that secretion of tumor necrosis factor alpha (TNFα) is altered by exposures to TBT. There have been no in vivo studies of the effects of exposure to TBT on the cytokine communication network. As it is not possible to examine alterations of this network in exposed humans, we examined the effects of TBT exposure in a mouse model using Milliplex mouse cytokine/chemokine magnetic bead premixed 32 plex kit. Serum and spleens of TBT-exposed mice were analyzed for changes in cytokine secretion/levels. TBT increased the levels of IL13 in the serum of non-tumor-bearing mice and increased IL1β, IL6, KC, and M-CSF in tumor-bearing mice. The spleens of both non-tumor-bearing and tumor-bearing mice showed increases in Eotaxin when exposed to TBT. Of significant interest is the fact that the presence of tumor causes increases in Eotaxin, IL12p40, M-CSF, and TNFα and exposure to TBT alone can cause increases in these same cytokines. Tumors are known to increase levels of cytokines that enhance their ability to survive. The results showing that TBT can amplify the levels of several cytokines that are increased by tumor suggest that TBT may have tumor-promoting abilities by modulating tumor growth and/or invasiveness. Experiments are under way to dissect cytokine signaling pathways that are affected by TBT. The findings will allow identification of molecular targets that are necessary to intercept the tumor promoting signaling following TBT exposure. Supported by: NIH grant 5U54CA163066-03 Citation Format: Shanieek Lawrence, Samuel Troy Pellom, Tasia Hurd-Brown, Anil Shanker, Margaret Whalen. Elevation of tumor-promoting cytokines in mice exposed to the environmental contaminant tributyltin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3191. doi:10.1158/1538-7445.AM2014-3191