Assessment of Estrogenic Activity of Perfluoroalkyl Acids Based on Ligand-induced Conformation State of Human Estrogen Receptor

Abstract

Perfluoroalkyl acids (PFAAs) have been reported to interfere with the endocrine system in vivo by mimicking endogenous hormone activities and causing adverse effects. Some exoestrogens bind to estrogen receptor (ER) and subsequently induce an ERmediated response. The transcriptional activity of ER is regulated by its distinct conformational states that are the results of ligand binding. In this work, a biosensor based on surface plasmon resonance (SPR) technique was developed which can discriminate between agonist and antagonist of human ERα (hERα) by monitoring the conformation state of the protein induced by ligand binding. The biosensor utilized the specific interaction between hERα and conformation-selective peptides. Six PFAAs with different chain lengths and acid groups were tested by the biosensor, and perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were found to be ER agonists. Kinetic analyses of direct interaction between PFAAs and hERα by SPR revealed that PFOS and PFOA were both weak binders of ER with K D values of 2.19 and 107 μM respectively, whereas the other four PFAAs did not bind with ER. To understand the differences in ER binding affinity and estrogenic activity among the six PFAAs, molecular docking based on the crystal structure of hERα ligand binding domain was performed. PFOS and PFOA were efficiently docked with hERα and formed hydrogen bonds with Arg394 in a manner similar to estradiol. Overall, the two 8-carbon PFAAs were assessed as weak agonists of hERα and are of potential concern.

Estrogen receptor preparation effects on the receptor–DNA interaction by surface plasmon resonance

“…The first one is the molecular mechanism by which ER bind with E2 [10,12], form a dimer [11,14] and then interact alone or with cofactor on ERE [4,11,[15][16][17]. This knowledge was used for the determination of interaction properties (i.e interaction constant) and recently for environmental purpose (i.e detection or quantification) [11,18,19]. But a discrepancy in the experimental conditions reported in the literature can be noticed [20] and few publications have detailed the biochemical parameters used and the influence of the parameters choice.…”

Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

“…Direct binding and activation to PPARs have been demonstrated (Wolf et al 2012;Takacs and Abbott 2007). Recently, some other nuclear receptors, such as estrogen receptor (ER), constitutive androstane receptor, pregnane X receptor, androgen receptor, and aryl hydrocarbon receptor have also been identified as possible targets of PFCs (Benninghoff et al 2011;Bjork et al 2011;Gao et al 2013).…”

Comparative in vivo and in vitro analysis of possible estrogenic effects of perfluorooctanoic acid

“…Therefore, the transient transfection assays used for the studies by Du and Benninghoff potentially overestimated estrogenic activity of PFOA. A recent study also reported that PFOA can bind to human ERa with a similar binding pattern to E 2 (Gao et al, 2013). However, the binding affinity was much weaker compared to E 2 , and only relatively high concentrations of PFOA (10-250 mM) were capable of causing a shift in ER structure from the resting state to the agonist-activated state (Gao et al, 2013).…”