Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action

Abstract

Many endocrine disrupting chemicals (EDCs) adversely impact estrogen signaling by interacting with two estrogen receptors (ERs): ERα and ERβ. Though the receptors have similar ligand binding and DNA binding domains, ERα and ERβ have some unique properties in terms of ligand selectivity and target gene regulation. EDCs that target ER signaling can modify genomic and nongenomic ER activity through direct interactions with ERs, indirectly through transcription factors such as the aryl hydrocarbon receptor (AhR), or through modulation of metabolic enzymes that are critical for normal estrogen synthesis and metabolism. Many EDCs act through multiple mechanisms as exemplified by chemicals that bind both AhR and ER, such as 3-methylcholanthrene. Other EDCs that target ER signaling include phytoestrogens, bisphenolics, and organochlorine pesticides, and many alter normal ER signaling through multiple mechanisms. EDCs can also display tissue-selective ER agonist and antagonist activities similar to selective estrogen receptor modulators (SERMs) designed for pharmaceutical use. Thus, biological effects of EDCs need to be carefully interpreted because EDCs can act through complex tissue-selective modulation of ERs and other signaling pathways in vivo. Current requirements by the U.S. Environmental Protection Agency require some in vitro and cell-based assays to identify EDCs that target ER signaling through direct and metabolic mechanisms. Additional assays may be useful screens for identifying EDCs that act through alternative mechanisms prior to further in vivo study.

Figure 1

Crystal structures of ERα and ERβ LBD bound to E2 (shown in red) modified from PDB 1ERE and PDB 2J7X. A) Comparison of ERα and ERβ hydrogen bond network with E2 (H bonds shown in green); B) ERα and ERβ differ in only two amino acids in the ligand binding pocket (shown in yellow).

Figure 2

Chemical structures of estrogenic ligands and EDCs that target ER signaling.

Scheme 1

Ligand dependent ER signaling pathways. Genomic signaling occurs when ligands enter the cell and bind ER to induce dimerization. ER dimers bind DNA directly at ERE sequences or indirectly by tethering to DNA through other transcriptions factors like Sp1 or AP-1. Non-genomic signaling occurs when ligands bind membrane bound receptors, which leads to activation of kinase signaling cascades.