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Estrogen-Like Activity of Perfluoroalkyl Acids In Vivo and Interaction with Human and Rainbow Trout Estrogen Receptors In Vitro

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The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species comparison approaches. Perfluorooctanoic (PFOA), perfluorononanoic (PFNA), perfluorodecanoic (PFDA), and perfluoroundecanoic (PFUnDA) acids were all potent inducers of the estrogen-responsive biomarker protein vitellogenin (Vtg) in vivo, although at fairly high dietary exposures. A structure-activity relationship for PFAAs was observed, where eight to ten fluorinated carbons and a carboxylic acid end group were optimal for maximal Vtg induction. These in vivo findings were corroborated by in vitro mechanistic assays for trout and human ER. All PFAAs tested weakly bound to trout liver ER with half maximal inhibitory concentration (IC(50)) values of 15.2-289 μM. Additionally, PFOA, PFNA, PFDA, PFUnDA, and perlfuorooctane sulfonate (PFOS) significantly enhanced human ERα-dependent transcriptional activation at concentrations ranging from 10-1000 nM. Finally, we employed an in silico computational model based upon the crystal structure for the human ERα ligand-binding domain complexed with E2 to structurally investigate binding of these putative ligands to human, mouse, and trout ERα. PFOA, PFNA, PFDA, and PFOS all efficiently docked with ERα from different species and formed a hydrogen bond at residue Arg394/398/407 (human/mouse/trout) in a manner similar to the environmental estrogens bisphenol A and nonylphenol. Overall, these data support the contention that several PFAAs are weak environmental xenoestrogens of potential concern.
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... PFAS may promote modifications of endogenous hormone regulation in humans and in wildlife [19,[53][54][55]. PFAS showed weak estrogenic effects in animal experiments, which manifested in increased estrogen and progesterone concentrations or mimicked the effect of endogenous estrogen [56][57][58]. PFAS can modulate the endocrine system by up-or downregulation of the expression of proteins responsible for cholesterol transport and ovarian steroidogenesis [53,59,60]. PFOAtreated ovary-intact mice had significantly increased serum progesterone (P) levels [56]. ...
... Cytological findings suggest that PFOS inhibits the conversion of P to testosterone by inhibiting CYP17 [61]. PFOA, PFNA, PFDA, and PFOS are all efficiently combined with estrogen receptors alpha (ERα) in different species [57]. Meanwhile, PFOS induced E2 production and reduced testosterone (T) production in a concentration-dependent manner in the H295R cells [61]. ...
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... There is evidence for PFAS affecting ER signaling in humans and animals although it is not consistent [190]. Study reports suggest an ability of PFAS to modulate and/or further activate ER-mediated effects [36,99,104,109,195,196] with some effects only observed in aquatic organisms [106,119,197]. Microarray analyses of human primary hepatocytes confirmed that PFOA activated the ER pathway [131]. ...
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... PFASs could interfere with the estrogen receptor of the human body (Kjeldsen and Bonefeld-Jørgensen 2013). PFASs could also affect the expression of the estrogen response gene and cause the change of estrogen synthesis (Benninghoff, Bisson et al. 2011). Exposure to PFASs might affect the estrogen homeostasis and fetal growth during pregnancy (Wang, Du et al. 2019), resulting in LBW. ...
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