Abstract
Abstract Background. Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function.Methodology. We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. Principal findings. We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-[alpha]-induced NF-[kappa]B activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-[alpha] production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. Conclusions. DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.
Highlights
Organotins are among the most toxic and widely distributed environmental chemicals
With the goal of elucidating the immunotoxic mechanism of DBT and other organotins, we investigated their potential interference with glucocorticoid action using cells expressing recombinant glucocorticoid receptor (GR), as well as macrophages expressing endogenous GR
Dibutyltin, but not other organotins tested, inhibits the transcriptional activity of GR To investigate whether organotins disrupt GR-dependent transcriptional regulation, we employed HEK-293 cells transiently expressing recombinant human GRα and a βgalactosidase reporter driven by a glucocorticoid-responsive MMTV-promoter
Summary
Organotins are among the most toxic and widely distributed environmental chemicals. The most abundant organotin in the environment is tributyltin (TBT), a molluscicide and fungicide widely used as an antifouling paint for boat and fish nets and that is dispersed into the marine environment [1,2]. TBT interferes with reproduction in marine animals, inducing imposex (superimposition of male sexual characters in females) in gastropod molluscs, an effect used to measure TBT pollution in sea-water [3,4]. TBT concentrations ranging from 4-323 nM were measured in blood samples from healthy human subjects [5]. At doses comparable with those found in human blood, TBT promotes Th2 cell polarization and exacerbates airway inflammation, providing a possible mechanism for enhanced susceptibility to allergic diseases [6]. TBT contamination represents a serious health problem and the great concern about the toxicity of TBT is underlined by recent negotiations of the United Nations’ International Maritime Organization for a global ban in the use of TBT
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