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it is clear that the assumption of a simple one-receptor pathway underlying current in vitro screening assays is out of date.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.

Keywords:

• TT21C
• endocrine disruption
• human health safety assessment
• alternative models
• in vitro models
• estrogen receptor

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Acknowledgements

The authors would like to thank Dr. Rebecca Alyea for her assistance in selecting publications with appropriate content for this review. The authors are grateful for the extensive and knowledgeable feedback provided by tehe anonymous peer reviewers selected by they Editor of the journal.

Declaration of interest

The current employment affiliation of the authors is as shown on the cover page. Prior to 1 January 2016, all the authors were employed by the Hamner Institutes for Health Sciences as part of the Institute for Chemical Safety Sciences (ICSS). The Hamner Institutes was a non-profit toxicology research institution that ceased operations on 31 December 2015. SciMetrika, a privately owned population health consulting commercial entity, acquired the assets of the ICSS division, including former members of ICSS leadership and staff, through its wholly owned subsidiary, ScitoVation. ScitoVation is a privately owned research company dedicated to advancing human health through the development of research tools, processes and technologies using human cell-based and computational methods. The authors have sole responsibility for the writing and content of the paper. This work was supported by the Long-Range Research Initiative (LRI) of the American Chemistry Council and was also performed as part of the Hamner Institutes’ “TT21C Consortium” with funding from Agilent Technologies, CropLife America, Dow Chemical Company, Dow Corning, and ExxonMobil Biomedical Sciences Foundation. The funding organizations were able to view early drafts of the paper. The funding organizations did not have direct influence on this review and did not contribute to any part of the writing or editorial process. The final work product, including conclusions drawn and recommendations offered, is the exclusive professional work product of the authors and may not necessarily represent the views of the sponsoring organizations or ScitoVation. None of the authors has appeared during the past five years in any legal or regulatory proceedings related to the material covered in this review.

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