Screening (ant)agonistic activities of xenobiotics on the retinoic acid receptor alpha (RARα) using in vitro and in silico analysis

• Published in: The Science of the total environment Vol. 947; p. 174717
• Main Authors: Su, Jiahui, Yang, Xiaoxi, Xu, Hanqing, Pei, Yao, Liu, Qian S., Zhou, Qunfang, Jiang, Guibin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.10.2024
• Subjects: (ant)agonistic activities; Computer Simulation; Emerging chemicals; Endocrine Disruptors; Humans; In silico analysis; Molecular Docking Simulation; Receptors, Retinoic Acid - metabolism; Recombinant two-hybrid yeast; Retinoic Acid Receptor alpha - genetics; Retinoic Acid Receptor alpha - metabolism; Retinoid acid receptor alpha (RARα); Transcriptional level; Xenobiotics; Transcriptional level; Recombinant two-hybrid yeast; Retinoid acid receptor alpha (RARα); Emerging chemicals; In silico analysis; (ant)agonistic activities
• ISSN: 0048-9697; 1879-1026; 1879-1026
• DOI: 10.1016/j.scitotenv.2024.174717

Retinoic acid receptors (RARs) are known as crucial endocrine receptors that could mediate a broad diversity of biological processes. However, the data on endocrine disrupting effects of emerging chemicals by targeting RAR (ant)agonism are far from sufficient. Herein, we investigated the RARα agonistic or antagonistic activities for 75 emerging chemicals of concern, and explored their interactions with this receptor. A recombinant two-hybrid yeast assay was used to examine the RARα activities of the test chemicals, wherein 7 showed effects of RARα agonism and 54 exerted potentials of RARα antagonism. The representative chemicals with RARα agonistic activities, i.e. 4-hydroxylphenol (4-HP) and bisphenol AF (BPAF), significantly increased the mRNA levels of CRABP2 and CYP26A1, while 4 select chemicals with RARα antagonistic potentials, including bisphenol A (BPA), tetrabromobisphenol A (TBBPA), 4-tert-octylphenol (4-t-OP), and 4-n-nonylphenol (4-n-NP), conversely decreased the transcriptional levels of the test genes. The in silico molecular docking analysis using 3 different approaches further confirmed the substantial binding between the chemicals with RARα activities and this nuclear receptor protein. This work highlights the promising strategy for screening endocrine-disrupting effects of emerging chemicals of concern by targeting RARα (ant)agonism. [Display omitted] •Seven chemicals exhibited RARα agonistic activities, and 54 ones displayed antagonistic activity.•Chemicals with RARα activities could disrupt the transcriptional levels of relevant genes.•Molecular docking analysis verified the interaction between chemicals and RARα.