Abstract
BackgroundOrganotins 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.MethodologyWe 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 FindingsWe 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-α-induced NF-κB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-α production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages.ConclusionsDBT 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
Principal Findings: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to glucocorticoid receptor (GR) and its transcriptional activity
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 GR, as well as macrophages expressing endogenous GR
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 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]. 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 the major metabolite formed from tributyltin (TBT) in vivo. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function
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