Stronger estrogenic and antiandrogenic effects on zebrafish larvae displayed by 6:2 polyfluoroalkyl phosphate diester than the 8:2 congener at environmentally relevant concentrations

By Pengyu Chen, Ruihan Wang, Jing Yang, Wenjue Zhong, Menglin Liu, Shujun Yi, and Lingyan Zhu
Sci. of Total Env.
August 19, 2019
DOI: 10.1016/j.scitotenv.2019.133907


Polyfluoroalkyl phosphate esters (PAPs) are one kind of emerging polyfluoroalkyl substances in the environment. However, their in vivo toxicities are largely unknown, especially at environmental relevant concentrations. To fill this gap, zebrafish embryos were exposed to 6:2 or 8:2 diPAP at environmentally relevant concentrations (0.5, 5, 50 ng/L) for 7 d. 6:2 and 8:2 diPAPs upregulated the mRNA and protein levels of aromatase in the exposed larvae, and elevated estradiol (E2) and vitellogenin (VTG) levels, but reduced testosterone (T) and 11-ketotestosterone (11-KT) levels, demonstrating estrogenic and antiandrogenic effects. Among the three ER subtypes, ERβ2 displayed the highest in vivo mRNA expression and the lowest in silico binding energies, suggesting that it was the main target ER subtype responsible for the estrogenic effect. Molecular simulation results indicated that diPAPs and E2 could bind to one common residue, arginine (Arg) 87, in the binding pocket of ERβ2, inducing similar estrogenic disruption mechanisms as E2. Both compounds could form hydrophobic interaction with glutamic acid (Glu) 12 and tryptophan (Trp) 80 and two hydrogen bonds with Arg81 of androgen receptor (AR) ligand-binding domains (LBDs) in antagonistic mode, resulting in a reduced level of AR upon exposure. The in silico binding energies of 6:2 diPAP with both ER and AR were lower than 8:2 diPAP, explaining the observed greater in vivo estrogenic and antiandrogenic activities of 6:2 diPAP. This study provided the first line of evidences that diPAPs could display adverse effects on the endocrine functions of fish species.



• Antiandrogenic and estrogenic effects of diPAPs were revealed in zebrafish larvae.

• Molecular simulations were used to explore recognition mechanisms.

• 6:2 diPAP showed higher antiandrogenic and estrogenic activities than 8:2 diPAP.

• Estrogen receptor (ER) β2 was the predominant target ER subtype.

View on PubMed