TY - JOUR
T1 - Differential in vitro biological action, coregulator interactions, and molecular dynamic analysis of bisphenol A (BPA), BPAF, and BPS ligand–ERα complexes
AU - Li, Yin
AU - Perera, Lalith
AU - Coons, Laurel A.
AU - Burns, Katherine A.
AU - Tyler Ramsey, J.
AU - Pelch, Katherine E.
AU - Houtman, René
AU - Van Beuningen, Rinie
AU - Teng, Christina T.
AU - Korach, Kenneth S.
N1 - Funding Information:
We thank B. Goodwin of the National Center for Advancing Translational Sciences (NCATS)/National Institutes of Health (NIH) for providing the U2OS cell lyses. We thank S. Fenton and L. Pedersen for critical review of this manuscript. Research support was provided by the Division Intramural Research of the NIEHS/NIH to K.S.K. through Z01 ES70065 and to L.P. through Z01 ES043010.
Publisher Copyright:
© 2018, Public Health Services, US Dept of Health and Human Services. All rights reserved.
PY - 2018/1
Y1 - 2018/1
N2 - BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that might be harmful to human health. Recently, there has been widespread usage of bisphenol chemicals (BPs), such as bisphenol AF (BPAF) and bisphenol S (BPS), as replacements for BPA. However, the potential biological actions, toxicity, and the molecular mechanism of these compounds are still poorly understood. OBJECTIVES: Our objective was to examine the estrogenic effects of BPA, BPAF, and BPS and the molecular mechanisms of action in the estrogen receptor alpha (ERα) complex. METHODS: In vitro cell models were used to compare the estrogenic effects of BPA, BPAF, and BPS to estrogen. Microarray Assay for Real-Time Coregulator-Nuclear receptor Interaction (MARCoNI) analysis was used to identify coregulators of BPA, BPAF, and BPS, and molecular dynamic (MD) simulations were used to determine the compounds binding in the ERα complex. RESULTS: We demonstrated that BPA and BPAF have agonistic activity for both ERα and ERβ, but BPS has ERα-selective specificity. We concluded that coregulators were differentially recruited in the presence of BPA, BPAF, or BPS. Interestingly, BPS recruited more corepressors when compared to BPA and BPAF. From a series of MD analysis, we concluded that BPA, BPAF, and BPS can bind to the ER–ligand-binding domain with differing energetics and conformations. In addition, the binding surface of coregulator interactions on ERα was characterized for the BPA, BPAF, and BPS complexes. CONCLUSION: These findings further our understanding of the molecular mechanisms of EDCs, such as BPs, in ER-mediated transcriptional activation, biological activity, and their effects on physiological functions in human health.
AB - BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that might be harmful to human health. Recently, there has been widespread usage of bisphenol chemicals (BPs), such as bisphenol AF (BPAF) and bisphenol S (BPS), as replacements for BPA. However, the potential biological actions, toxicity, and the molecular mechanism of these compounds are still poorly understood. OBJECTIVES: Our objective was to examine the estrogenic effects of BPA, BPAF, and BPS and the molecular mechanisms of action in the estrogen receptor alpha (ERα) complex. METHODS: In vitro cell models were used to compare the estrogenic effects of BPA, BPAF, and BPS to estrogen. Microarray Assay for Real-Time Coregulator-Nuclear receptor Interaction (MARCoNI) analysis was used to identify coregulators of BPA, BPAF, and BPS, and molecular dynamic (MD) simulations were used to determine the compounds binding in the ERα complex. RESULTS: We demonstrated that BPA and BPAF have agonistic activity for both ERα and ERβ, but BPS has ERα-selective specificity. We concluded that coregulators were differentially recruited in the presence of BPA, BPAF, or BPS. Interestingly, BPS recruited more corepressors when compared to BPA and BPAF. From a series of MD analysis, we concluded that BPA, BPAF, and BPS can bind to the ER–ligand-binding domain with differing energetics and conformations. In addition, the binding surface of coregulator interactions on ERα was characterized for the BPA, BPAF, and BPS complexes. CONCLUSION: These findings further our understanding of the molecular mechanisms of EDCs, such as BPs, in ER-mediated transcriptional activation, biological activity, and their effects on physiological functions in human health.
UR - http://www.scopus.com/inward/record.url?scp=85041426407&partnerID=8YFLogxK
U2 - 10.1289/EHP2505
DO - 10.1289/EHP2505
M3 - Article
C2 - 29389661
AN - SCOPUS:85041426407
SN - 0091-6765
VL - 126
JO - Environmental Health Perspectives
JF - Environmental Health Perspectives
IS - 1
M1 - 017012
ER -