Disruption of endocrine signalling by environmental pollutants is a recognised global crisis. Endocrine disrupting chemicals (EDCs), ubiquitous in the environment globally, disrupt nuclear hormone receptor signalling causing developmental, reproductive, metabolic, neurological disorders and disease in humans and wildlife. A primary target of EDCs is the transcriptional regulator estrogen receptor (ER) which plays a critical role in reproductive function and development in all vertebrates. The function of ER is endogenously regulated by estrogens such as estradiol (E2). The binding of E2 to the ERα ligand binding domain (LBD) facilitates translocation into the nucleus where the DNA-binding domain (DBD) binds to specific DNA elements and recruits coregulators to control target gene expression. EDCs are known to disrupt human ER function through binding to the ER LBD, but the effects of EDCs on ER of native Australian species is unknown.
The aim of this work was to characterise the ER LBDs of the native species platypus, echidna and the Murray River rainbow fish and compare the effects of E2 and prevalent EDCs (bisphenol derivatives and alkylphenols) on ER LBD structure and function. We determined the first crystal structures of the platypus, echidna and Murray River rainbow fish ER LBDs in complex with E2 and coactivator peptide revealing a high degree of structural conservation. Fluorescence polarisation and transactivation assays confirmed that each ER LBD responds to E2, indicating the ligand-dependent activation mechanism is conserved. Most importantly, EDCs were found to modulate the activity of ER LBDs in all species investigated, indicating that endocrine disruption is likely to occur in these native animals. In conclusion, this study provides the first insight into the activity of EDCs prevalent in Australian environments in native species, highlighting the threat posed by these chemicals to native populations.