Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production

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-kappaB 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

Functioning of a karst aquifer from S Spain under highly variable climate conditions, deduced from hydrochemical records

Over a period of three hydrological years during which precipitation was highly variable, measurements of discharge, electrical conductivity, temperature and chemical components of the water at the Cañamero spring (southern Spain) were taken in order to characterise the hydrogeological functioning of the karst aquifer that it drains. The results obtained from analysis of the frequency distribution of electrical conductivity data revealed histograms with a plurimodal morphology (up to 5 modes) and a range of variation that increased with greater pluviometry during the study period. The discharge from this spring increased sharply a few days after major rainfall episodes and, when the discharge reached a value of approximately 3.73 m3/s, an overflow spring started to function. During high-water periods, there were sudden and large falls in EC, temperature and all the chemical components dissolved in the water. This high variability reflects the predominance of groundwater flow through karst drains, a typical feature of conduit flow systems. The considerable hydrochemical heterogeneity observed is caused by the mobilisation of important volumes of recharge waters from shallow areas of the aquifer (soil, epikarst) towards the discharge point, with greater participation of the unsaturated zone during high-water conditions, and a more active role played by the saturated zone during low-water conditions. In karst systems such as the one drained by the Cañamero spring, it is important to monitor several responses (hydrodynamic, hydrothermal, hydrochemical, etc.), with an appropriate sampling frequency and under different hydrometeorological conditions, in order to achieve an adequate hydrological characterisation. This is fundamental for planning, management and protection of groundwater in karst aquifers