Characterization of diphenyl phthalate as an agonist for estrogen receptor: an in vitro and in silico study

Abstract

Phthalate esters (PAEs) are important pollutants in the environment, which can interfere with the endocrine system by mimicking estrogen. However, limited information is available on modulating the estrogen receptor (ER) of five PAEs including di (2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), benzyl butyl phthalate (BBP), diphenyl phthalate (DPhP) and dicyclohexyl phthalate (DCHP). This study evaluated the agonistic effects of PAEs on human ER. The cytotoxicity assay showed that there were a significant inhibition of the cell proliferation with treatment of five PAEs. Moreover, DPhP does-dependently enhanced ER-mediated transcriptional activity in the reporter gene assay. The increased expression of estrogen-responsive genes (TFF1, CTSD, and GREB1) was also observed in MCF-7 cells treated with DPhP. The result of molecular docking showed that DPhP tended to bind to the agonist conformation of ER compared with the antagonist conformation of ER, demonstrating its agonist characteristic that has been confirmed in the reporter gene assay. Thus, we found that DPhP may be evaluated as an ER agonist in vitro and it can interfere with the normal function of human ER.

Keywords:

• Phthalate esters
• estrogen receptor
• endocrine disruption
• estrogen activity

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (31701349 and U19A2035), the Science and Technology Development Project Foundation of Jilin Province (20210203182SF), the Agricultural Science and Technology Innovation Program of Jilin Province (CXGC2021TD006), and Administration of Traditional Chinese Medicine of Jilin Province (2021100).