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Tributyltin and triphenyltin induce 11β-hydroxysteroid dehydrogenase 2 expression and activity through activation of retinoid X receptor α.
- Source :
-
Toxicology Letters . Apr2020, Vol. 322, p39-49. 11p. - Publication Year :
- 2020
-
Abstract
- • TBT and TPT induce the transcription of 11β-HSD2 in JEG-3 cells. • Upregulation of 11β-HSD2 results in reduced cortisol-dependent activation of the GR. • RXRα is involved in the TBT and TPT induced effect on 11β-HSD2. • Fludioxonil and chlorotriphenylsilane activate RXRα and induce 11β-HSD2 expression. Exposure to the environmental pollutants organotins is of toxicological concern for the marine ecosystem and sensitive human populations, including pregnant women and their unborn children. Using a placenta cell model, we investigated whether organotins at nanomolar concentrations affect the expression and activity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 11β-HSD2 represents a placental barrier controlling access of maternal glucocorticoids to the fetus. The organotins tributyltin (TBT) and triphenyltin (TPT) induced 11β-HSD2 expression and activity in JEG-3 placenta cells, an effect confirmed at the mRNA level in primary human trophoblast cells. Inhibition/knock-down of retinoid X receptor alpha (RXRα) in JEG-3 cells reduced the effect of organotins on 11β-HSD2 activity, mRNA and protein levels, revealing involvement of RXRα. Experiments using RNA and protein synthesis inhibitors indicated that the effect of organotins on 11β-HSD2 expression was direct and caused by increased transcription. Induction of placental 11β-HSD2 activity by TBT, TPT and other endocrine disrupting chemicals acting as RXRα agonists may affect placental barrier function by altering the expression of glucocorticoid-dependent genes and resulting in decreased availability of active glucocorticoids for the fetus, disturbing development and increasing the risk for metabolic and cardiovascular complications in later life. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03784274
- Volume :
- 322
- Database :
- Academic Search Index
- Journal :
- Toxicology Letters
- Publication Type :
- Academic Journal
- Accession number :
- 141633145
- Full Text :
- https://doi.org/10.1016/j.toxlet.2020.01.001