Structures of Endocrine-Disrupting Chemicals Determine Binding to and Activation of the Estrogen Receptor alpha and Androgen Receptor

Tan, Haoyue1; Wang, Xiaoxiang2; Hong, Huixiao3; Benfenati, Emilio4; Giesy, John P.5,6,7; Gini, Giuseppina C.8; Kusko, Rebeca9; Zhang, Xiaowei1; Yu, Hongxia1; Shi, Wei1

2020-09-15

10.1021/acs.est.0c02639

ENVIRONMENTAL SCIENCE & TECHNOLOGY   影响因子和分区

0013-936X

1520-5851

Endocrine-disrupting chemicals (EDCs) can interact with nuclear receptors, including estrogen receptor alpha (ER alpha) and androgen receptor (AR), to affect the normal endocrine system function, causing severe symptoms. Limited studies queried the EDC mechanisms, focusing on limited chemicals or a set of structurally similar compounds. It remained uncertain how hundreds of diverse EDCs could bind to ER alpha and AR and cause distinct functional consequences. Here, we employed a series of computational methodologies to investigate the structural features of EDCs that bind to and activate ER alpha and AR based on more than 4000 compounds. We used molecular docking and molecular dynamics simulations to elucidate the functional consequences and validated structure-function correlations experimentally using a time-resolved fluorescence resonance energy-transfer assay. We found that EDCs share three levels of key fragments. Primary (20 for ER alpha and 18 for AR) and secondary fragments (38 for ER alpha and 29 for AR) are responsible for the binding to receptors, and tertiary fragments determine the activity type (agonist, antagonist, or mixed). In summary, our study provides a general mechanism for the EDC function. Discovering the three levels of key fragments may drive fast screening and evaluation of potential EDCs from large sets of commercially used synthetic compounds.

SCI ; EI

英语

NI期刊 ; NI论文

其他

National Key R&D Program of China[2018YFC1801604] ; National Natural Science Foundation of China[21922603] ; Science Fund for Excellent Young Scholars of Jiangsu Province[BK20170077] ; Fundamental Research Funds for the Central Universities[021114380139] ; National Water Pollution Control and Treatment Science and Technology Major Project[2017ZX07202-001][2017ZX07602-002]

Engineering ; Environmental Sciences & Ecology

Engineering, Environmental ; Environmental Sciences

WOS:000572834700045

AMER CHEMICAL SOC

20204509455553

Endocrine disrupters ; Energy transfer ; Chemicals ; Binding energy ; Fluorescence

Health Care:461.7 ; Light/Optics:741.1 ; Physical Chemistry:801.4 ; Chemical Agents and Basic Industrial Chemicals:803 ; Chemical Products Generally:804

ENVIRONMENT/ECOLOGY

Web of Science

1.Nanjing Univ, Sch Environm, State Key Lab Pollut Control & Resources Reuse, Nanjing 210023, Jiangsu, Peoples R China
2.Southern Univ Sci & Technol, State Environm Protect Key Lab Integrated Surface, Sch Environm Sci & Engn, Shenzhen 518055, Guangdong, Peoples R China
3.US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA
4.Ist Ric Farmacol Mario Negri IRCCS, Lab Environm Chem & Toxicol, Dept Environm Hlth Sci, I-20156 Milan, Italy
5.Univ Saskatchewan, Toxicol Ctr, Saskatoon, SK S7N 5B3, Canada
6.Univ Saskatchewan, Dept Vet Biomed Sci, Saskatoon, SK S7N 5B3, Canada
7.Baylor Univ, Dept Environm Sci, Waco, TX 76706 USA
8.Politecn Milan, Dept Elect & Informat, I-20133 Milan, Italy
9.Immuneering Corp, Cambridge, MA 02142 USA

Tan, Haoyue,Wang, Xiaoxiang,Hong, Huixiao,et al. Structures of Endocrine-Disrupting Chemicals Determine Binding to and Activation of the Estrogen Receptor alpha and Androgen Receptor[J]. ENVIRONMENTAL SCIENCE & TECHNOLOGY,2020,54(18):11424-11433.

Tan, Haoyue.,Wang, Xiaoxiang.,Hong, Huixiao.,Benfenati, Emilio.,Giesy, John P..,...&Shi, Wei.(2020).Structures of Endocrine-Disrupting Chemicals Determine Binding to and Activation of the Estrogen Receptor alpha and Androgen Receptor.ENVIRONMENTAL SCIENCE & TECHNOLOGY,54(18),11424-11433.

Tan, Haoyue,et al."Structures of Endocrine-Disrupting Chemicals Determine Binding to and Activation of the Estrogen Receptor alpha and Androgen Receptor".ENVIRONMENTAL SCIENCE & TECHNOLOGY 54.18(2020):11424-11433.