Multiple receptors shape the estrogen response pathway and are critical considerations for the future of in vitro-based risk assessment efforts

Abstract

Current in life toxicity testing paradigms are being challenged as the future of risk assessment moves towards more comprehensive mode of action/adverse outcome pathway based approaches. In particular, endocrine disruption screening is now a global activity and key initiatives in the United States focus on the use of high throughput in vitro assays to prioritize compounds for further testing of estrogen, androgen or thyroid disruption. Of these pathways, much of the emphasis to date has been on high-throughput methods for estrogenic activity primarily using ligand binding and trans-activation assays. However, as the knowledge regarding estrogen receptor signaling pathways continues to evolve, it is clear that the assumption of a simple one-receptor pathway underlying current in vitro screening assays is out of date. To develop more accurate models for estrogen-initiated pathways useful for quantitative safety assessments, we must design assays that account for the key signaling processes driving cellular dose response based on up-to-date understanding of the biological network. In this review, we summarize the state of the science for the estrogen receptor signaling network, particularly with regard to proliferative effects, and highlight gaps in current high throughput approaches. From the sum of this literature, we propose a model for the estrogen-signaling pathway that should serve as a starting point for development of new in vitro methods fit for the purpose of predicting dose response for estrogenic chemicals in the human.

Weighted Gene Correlation Network Analysis (WGCNA) Reveals Novel Transcription Factors Associated With Bisphenol A Dose-Response

“…Estrogen signaling is unique amongst nuclear receptors in that substantial number of the genes altered by estrogen do not have canonical estrogen response elements ( Miller et al, 2017 ) – estrogen signaling takes place within a transcriptomic and epigenomic context that markedly influences receptor activation. Our examination of the estrogen dose response curve network both confirmed several of the transcription factors identified previously, such as E2F1, ZNF217 and TFAP2C, as well as suggested other transcriptional factors such as PADI4 and RACK7/ZYMND8 that may impact estrogen signaling.…”

Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma

“…These conflicting results may be explained by differences in the tissue distribution of the ER subtypes and their splicing variants. Moreover, ER signaling is embedded in a complex signaling network controlling tumor cell growth and proliferation to the effect that context specific signaling interactions lead to different effects in different tissue types [ 52 ]. In the present study, the phosphorylation status of ERβ was not examined.…”

The tissue-specific effects of different 17β-estradiol doses reveal the key sensitizing role of AF1 domain in ERα activity

“…E2 effects are mediated by hormone binding to ERα, ERβ or GPR30 (Miller et al, 2017). ERα also exists as two isoforms, designated ERα66 and ERα46, based on their respective molecular weight, and both isoforms were reported to regulate E2-mediated proliferation in the mouse uterus (Abot et al, 2013).…”

“…In particular, varied affinities for distinct receptors having different intrinsic activity levels would essentially lead to a "mixture" effect, where the summation of their individual doseresponse curves would lead to composite behaviour that could be non-monotonic (Miller et al, 2017). In particular, we previously proposed that ERα46 counteracts ERα66 on E2induced cell proliferation (Abot et al, 2013;Penot et al, 2005).…”