TY - JOUR
T1 - Tributyltin and triphenyltin induce 11β-hydroxysteroid dehydrogenase 2 expression and activity through activation of retinoid X receptor α
AU - Inderbinen, Silvia G.
AU - Engeli, Roger T.
AU - Rohrer, Simona R.
AU - Di Renzo, Erminio
AU - Aengenheister, Leonie
AU - Buerki-Thurnherr, Tina
AU - Odermatt, Alex
N1 - Funding Information:
This work was supported by the Swiss Centre for Applied Human Toxicology to SGI, RTE, SRR and AO, and the Swiss Federal Laboratories for Materials Science and Technology to EDR, LA and TB. We thank Prof. Dr. Bruce Blumberg and Prof. Dr. Henriette E. Meyer zu Schwabedissen for expert input to the project as well as Prof. Dr. Albert Jordan for providing of 11β-HSD2 reporter constructs.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - 11beta-hydroxysteroid dehydrogenase
KW - Glucocorticoid
KW - Organotin
KW - Placenta
KW - Retinoid X receptor alpha
UR - http://www.scopus.com/inward/record.url?scp=85078139108&partnerID=8YFLogxK
U2 - 10.1016/j.toxlet.2020.01.001
DO - 10.1016/j.toxlet.2020.01.001
M3 - Article
C2 - 31927052
AN - SCOPUS:85078139108
SN - 0378-4274
VL - 322
SP - 39
EP - 49
JO - Toxicology Letters
JF - Toxicology Letters
ER -