Organotin Compounds Act as Inhibitor of Transcriptional Activation with Human Estrogen Receptor

Abstract

In aquatic invertebrates, particularly marine gastropods, organotin compounds induce irreversible sexual abnormality in females, which is termed imposex, at very low concentrations. Organotin compounds are agonists for nuclear receptors such as RXRs and PPARγ. However, the imposex phenomenon has not been reported to act as an antagonist on estrogen receptors in other species, including vertebrates and invertebrates. In order to gain insights into the antagonistic activity of organotin compounds on estrogen receptors (ERs), we examined the inhibitive effect of these compounds on estradiol-dependent β-galactosidase activity using the yeast two-hybrid detection system consisting of a combination of the human estrogen receptor (hERβ) ligand-binding domain and the co-activator steroid receptor co-activator-1 (SRC1). Tributyltin-hydroxide (TBT-OH) and triphenyltin-chlorine (TPT-Cl) exhibited an inhibitive effect on E 2-dependent transcriptional activity, similar to antagonistic chemicals such as 4-hydroxytamoxifen (OHT) or ICI 182,780, at a very low concentration of 10-14 M TBT or 10-10 M TPT, respectively. The yeast growth and transcriptional activity with transcriptional factor GAL4 did not exhibit any effect at the tested concentration of TBT or TPT. Moreover, the yeast two-hybrid system using the interaction between p53 and the T antigen of SV40 large did not describe any effect at the tested concentration of OHT or ICI 182,780. However, the interaction between p53 and T antigen was inhibited at a TBT or TPT concentration of 10-9 M, respectively. These results indicate that TBT and TPT act as inhibitors of ER-dependent reporter gene transcriptional activation and of the interaction between hERβ LBD and the co-activator SRC1 in the yeast two-hybrid system. Consequently, our data could partly explain the occurrence of organotin compoundinduced imposex on the endocrine system of mammals, including humans.

In vitro screening for estrogenic endocrine disrupting compounds using Mozambique tilapia and sea bass scales

“…TPT bioaccumulates in fish and other aquatic organisms, inducing high toxicity, malformations and disrupting reproduction (Yi et al, 2012). TPT acts as an antagonist of E2 and blocks human ERβ transcriptional activity (Cho et al, 2012), although so far no interactions with GPERs or fish estrogen receptors have been described.…”

Estrogens counteract tributyltin-induced toxicity in the rat islets of Langerhans

“…The results of different studies indicated that TBT interacts with ERs more than the other metals. Hence, TBT can disrupt transcriptional activation of ER pathways and the related endocrine functions [3,4,5,6,7].…”

Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights

“…Previous reports on the in silico studies of organotins with sex steroid nuclear receptors are not available to the best of our knowledge. However, organotins, TBT and TPT, were shown to have competitive binding antagonistic activity against human ER in vitro [ 42 ]. The inhibitory effect on ER similar to other ER antagonists, such as 4-hydroxytamoxifen, was shown on ER-dependent reporter gene transcriptional activation by TBT and TPT at very low concentrations by interactions between human ERβ LBD and the co-activator SRC1 in a yeast two-hybrid detection system.…”