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Effect of a series of triorganotins on the immune function of human natural killer cells
Fabiola D Gomez1, Paula Apodaca, Laurin N Holloway
1Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968, United States.
Abstract:
Natural killer (NK) cells are our initial immune defense against viral infections and cancer development. They are able to destroy tumor and virally infected cells. Thus, agents that are able to interfere with their function increase the risk of cancer and/or infection. Organotins (OTs) have been shown to interfere with the tumor-destroying function of human NK cells. The purpose of the current study was to explore the relationship of a series of triorganotins, that differ in structure by only a single organic group, for their capacity to block NK tumor-cell destroying (lytic) function. Here we examine the series: trimethyltin (TMT), dimethylphenyltin (DMPT), methyldiphenyltin (MDPT), and triphenyltin (TPT). NK cells were exposed to TMT, DMPT, MDPT or TPT for 1, 24, 48h, or 6d. A 1h exposure to TMT, at concentrations as high as 20μM, had no effect on lytic function. However, concentrations as low as 2.5μM were able to decrease NK tumor-destroying function after 6d. A 1h exposure to DMPT had no effect on lytic function, however, after 6d there was an 80-90% decrease in lytic function at 1μM. Exposure to MDPT (as low as 2.5μM) decreased NK function at 1h, after 6d there was as much as a 90% decrease at concentrations as low as 100nM MDPT. TPT decreased lytic function in a manner similar to MDPT, however, it was more effective at 1h than MDPT. The effect of the triorganotins on the ability of NK cells to bind to targets was studied, to determine if this contributed to the loss of lytic function. The relative immunotoxic potential of this series of compounds is TPT≈MDPT>DMPT>TMT.
Insights
Organotins impair natural killer (NK) cell function, increasing cancer and infection risks. Triphenyltin and methyldiphenyltin show the highest toxicity, significantly reducing NK cell tumor-destroying capabilities over time.
Area of Science:
- Immunology
- Toxicology
- Environmental Health
Background:
- Natural killer (NK) cells are crucial for innate immunity, defending against viral infections and cancer by eliminating compromised cells.
- Organotins (OTs) are environmental contaminants known to possess immunotoxic properties, potentially disrupting immune surveillance.
- Previous research indicates OTs can interfere with NK cell cytotoxic functions, necessitating further investigation into specific compound classes.
Purpose of the Study:
- To investigate the immunotoxic effects of a series of triorganotins (TMT, DMPT, MDPT, TPT) on human NK cell tumor-lytic function.
- To establish a structure-activity relationship for triorganotins concerning their capacity to inhibit NK cell cytotoxicity.
- To explore the impact of varying exposure durations and concentrations on NK cell function.
Main Methods:
- Human NK cells were exposed to varying concentrations of trimethyltin (TMT), dimethylphenyltin (DMPT), methyldiphenyltin (MDPT), and triphenyltin (TPT).
- Exposure durations ranged from 1 hour to 6 days to assess time-dependent effects on NK cell lytic function.
- NK cell target-binding capacity was evaluated to elucidate mechanisms of functional impairment.
Main Results:
- Trimethyltin (TMT) showed minimal impact on NK cell lytic function even at high concentrations after short exposure, but caused significant inhibition after 6 days.
- Dimethylphenyltin (DMPT) exhibited moderate toxicity, causing substantial NK cell function loss after 6 days at low micromolar concentrations.
- Methyldiphenyltin (MDPT) and triphenyltin (TPT) demonstrated potent immunotoxicity, significantly reducing NK cell function within 1 hour and at nanomolar concentrations after 6 days, with TPT being slightly more potent at 1h.
Conclusions:
- Triorganotins, particularly TPT and MDPT, significantly impair NK cell-mediated tumor cell killing, posing a risk to immune defense.
- The immunotoxic potential of the tested triorganotins follows the order: TPT ≈ MDPT > DMPT > TMT.
- These findings highlight the critical need to assess the immunotoxicity of organotin compounds and their potential health implications.
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