Estrogenic Effects of Fluorotelomer Alcohols for Human Estrogen Receptor Isoforms .ALPHA. and .BETA. in Vitro

Abstract

The present study demonstrates the estrogenic effects of fluorotelomer alcohols (FTOHs). In a yeast two-hybrid assay, treatment with 1H,1H,2H,2H-perfluorooctan-1-ol (6:2 FTOH), 1H,1H,2H,2H-perfluoro-decan-1-ol (8:2 FTOH) and 2,2,3,3,4,-4,5,5,6,6,7,7,8,8,9,9,10,10,10-nonadecafluoro-1-decanol (NFDH) showed a dose-dependent interaction between the human estrogen receptor (hER) isoforms hERa a or hERb b ligand-binding domain and coactivator TIF2, whereas there were no estrogenic effects of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) for these hERs. The estrogenic effects of FTOHs on hERa a were higher than those on hERb b, indicating a differential responsiveness of hERs to FTOHs. The relative ranks of tested chemicals on the estrogenic effects for hERa a and hERb b descended in the order of estradiol-17b bϾ Ͼ Ͼ6:2 FTOHϾ NFDHϾ8:2 FTOH. These results suggest that certain FTOHs including 6:2 FTOH, 8:2 FTOH and NFDH interact with hER isoforms a a and b b in vitro. Further studies are necessary to investigate contamination levels, potential biological effects and the risks of these compounds on human health.Key words human estrogen receptor a; human estrogen receptor b; fluorotelomer alcohols; estrogenic effect Perfluorochemicals (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are widespread contaminants that have been detected in wildlife and humans. 1,2) Various studies have demonstrated the potential maternal and developmental toxicity of these compounds in experimental animals.3) Fluorotelomer alcohols (FTOHs) such as 6:2, 8:2 and 10:2 FTOH are classes of compounds recently identified as potential contaminant sources of PFCs, including PFOA, in the environment. Their presence is particularly noted in the atmospheric environment. 4,5) Limited information is currently available on the toxicological effects and the risks of FTOHs in experimental animals, although these compounds are metabolically converted to PFOA, associated with the induction of hepatic peroxisome proliferation and acyl-CoA oxidase (ACOX) activity. 6)Interestingly, a recent study showed the proliferation-promoting capacity of 6:2 FTOH and 8:2 FTOH with an E-screen assay of MCF-7 cell lines. 7) However, in that study there was no information on the interaction of FTOHs toward human estrogen receptor a (hERa) or b (hERb). To evaluate the potential risks of FTOHs in humans, it is important to investigate estrogenic effects at the molecular level, because PFCs including PFOA, which are degraded from FTOHs, are widespread contaminants that have been detected in human blood samples.2) Therefore, in this study, we investigated the estrogenic effects of FTOHs for the hERa or hERb using a yeast two-hybrid assay. MATERIALS AND METHODSTest Chemicals 6:2 FTOH (1H,1H,2H,2H-perfluorooctan-1-ol, Alfa Aesar, MA, U.S.A.), 8:2 FTOH (1H,1H,2H,-2H-perfluoro-decan-1-ol, Alfa Aesar), NFDH (2,2,3,3,4,4,-5,5,6,6,7,7,8,8,9,9,10,10,10-nonadecafluoro-1-decanol, Wako Pure Chemical Industries, Ltd., Tokyo, Japan), PFOS (Av...

Expression Analysis of Estrogen-responsive Genes Vitellogenin 1 and 2 in Liver of Male Medaka (Oryzias latipes) Exposed to Selective Ligands of Estrogen Receptor Subtypes

“…36) The assay has also been used to determine the estrogenic activity of test chemicals. 37) Novel E2 analogs, including orthoester 2k, were synthesized by Kato,34) and we investigated the affinity of each chemical for hERα and hERβ. Finally, we selected orthoester 2k as a novel ERα-specific agonistic ligand, as orthoester 2k was found to dosedependently induce chemiluminescence on hERα yeast two-hybrid assay [ Fig.…”

“…36) The exposure concentrations of orthoester 2k (concentration ranges tested: 0.36, 0.73, 1.5, 2.9, 5.8, 11.7 and 23.3 µM), and E2 (31-2000 pM) were selected based on the results of a previous study. 37) All experiments were performed in triplicate for each compound. Animals --Medaka (d-rR strain) have been kept in glass tanks for several years in our laboratory.…”

Maternal concentrations of perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) and duration of breastfeeding

“…These concentrations are still substantially higher than the concentrations found among the general population (average PFOA concentration in the US population is 4-5 ng/ml) (11). Moreover, PFOA or PFOS may have estrogenic effects, although the evidence from in vivo or in vitro studies is inconsistent (12)(13)(14)(15)(16)(17), and their potential effects on hormones, including prolactin, oxytocin, and estrogen may influence lactation. It is thus important to study if these compounds affect lactation at the concentrations found in humans.…”

Per- and polyfluorinated substances in the Nordic Countries

“…In vitro studies using human cells have reported following endocrine effects for fluorotelomer alchohols: 8:2 FTOH and 6:2 FTOH had potential estrogenic effects by inducing the proliferation of MCF-7 breast cancer cells in E-screen assay; by up-regulating of the estrogen receptor ; by interacting with the human estrogen receptor alpha and beta in vitro (Ishibashi H et al, 2007). Moreover, 8:2 FTOH showed the capacity to decrease testosterone levels in the human adrenal corticocarcinoma cell line (Liu et al, 2010b) but did not interfere with androgen receptor activation (Rosenmai et al, 2012).…”

“…Fluorotelomer alcohols have been shown to exert estrogenic activity in MCF-7 cells, in a yeast two-hybrid assay and in aquatic organisms where 6:2 FTOH has been characterised as a stronger xenoestrogen than 8:2 FTOH (Ishibashi et al, 2008;Maras et al, 2006;Vanparys et al, 2006;Wang et al, 2012). According to Ishibashi et al (2007) treatment with 6:2 FTOH, 8:2 FTOH and NFDH (nonadecafluoro-1-decanol) show a dose-dependent interaction with the human estrogen receptor (hER), and rank the estrogenic effects for hERα and hERβ in the descending order of 17β-estradiol>>> 6:2 FTOH > NFDH > 8:2 FTOH. Waterborne exposure of both 6:2 and 8:2 FTOH alter the plasma levels of testosterone and estradiol and 8:2 FTOH adversely impair reproductive success in the offspring of zebrafish (Liu et al, 2010a;Liu et al, 2009).…”