Estrogen-Like Properties of Fluorotelomer Alcohols as Revealed by MCF-7 Breast Cancer Cell Proliferation

Abstract

We investigated estrogen-like properties of five perfluorinated compounds using a combination of three in vitro assays. By means of an E-screen assay, we detected the proliferation-promoting capacity of the fluorotelomer alcohols 1H,1H,2H,2H-perfluorooctan-1-ol (6:2 FTOH) and 1H,1H,2H,2H-perfluoro-decan-1-ol (8:2 FTOH). The more widely environmentally distributed compounds perfluoro-1-octane sulfonate, perfluorooctanoic acid, and perfluorononanoic acid did not seem to possess this hormone-dependent proliferation capacity. We investigated cell cycle dynamics using flow cytometric analyses of the DNA content of the nuclei of MCF-7 breast cancer cells. Exposure to both fluorotelomer alcohols stimulated resting MCF-7 cells to reenter the synthesis phase (S-phase) of the cell cycle. After only 24 hr of treatment, we observed significant increases in the percentage of cells in the S-phase. In order to further investigate the resemblance of the newly detected xenoestrogens to the reference compound 17β-estradiol (E2), gene expression of a number of estrogen-responsive genes was analyzed by real-time polymerase chain reaction. With E2, as well as 4-nonylphenol and the fluorotelomer alcohols, we observed up-regulation of trefoil factor 1, progesterone receptor, and PDZK1 and down-regulation of ERBB2 gene expression. We observed small but relevant up-regulation of the estrogen receptor as a consequence of exposures to 6:2 FTOH or 8:2 FTOH. The latter finding suggests an alternative mode of action of the fluorotelomer alcohols compared with that of E2. This study clearly underlines the need for future in vivo testing for specific endocrine-related end points.

Evaluation of estrogenic activities and mechanism of action of perfluorinated chemicals determined by vitellogenin induction in primary cultured tilapia hepatocytes

“…A significant inhibition of VTG induction was observed upon co-exposure of E2, 4-NP, PFOS, PFOA and 6:2 FTOH with tamoxifen, suggesting that the estrogenic effects of PFCs may be mediated through the ER. Maras et al (2006) demonstrated that 6:2 FTOH, 8:2 FTOH and PFOA caused a significant up-regulation of ER-␣ gene expression, while expression was down-regulated upon exposure to PFOS in MCF-7 breast cancer cells. An in vivo study also demonstrated that ER-␤ was significantly up-regulated in Chinese rare minnow exposed to PFOA (Wei et al, 2007).…”

“…Indeed, it seems likely that the binding pool is made up of serum albumins since PFOS is generally bound to serum albumins in common carp (Jones et al, 2003). A previous study by Maras et al (2006) showed that 6:2 FTOH was a stronger xenoestrogen than 8:2 FTOH and they suggested that it is very likely that the chain length of the alkyl group is the responsible factor. As stated above, 8:2 FTOH can be metabolized to PFOA in rats as well as in cultured rat hepatocytes.…”

Endocrine disruption and reproductive impairment in zebrafish by exposure to 8:2 fluorotelomer alcohol

“…Various studies have investigated endocrine disruption, such as those of Maras et al (2006) and Vanparys et al (2006) who reported the estrogen-like properties of 6:2 FTOH and 8:2 FTOH in human breast cancer cells (MCF-7). The estrogenic activities were further demonstrated in primary cultured tilapia hepatocytes (Liu et al, 2007) and in Japanese medaka (Ishibashi et al, 2008).…”

Effects of 8-2 Fluorotelomer Alcohol on Oleic Acid Formation in the Liver of Rats

“…However, information about toxicological effects of this chemical is just becoming available. [21][22][23] A study on one-generation reproductive toxicity of fluoroalkylethanol mixture having fully fluorinated alkyl chain with six to twelve carbons showed no harmful effect on reproduction in rats. 21) Another study on subchronic toxicity of fluoroalkylethanol mixture demonstrated tooth alterations, hepatocellular hypertrophy, elevation of liver weight and thyroid follicular hypertrophy in rats.…”

“…22) The subsequent study characterized fluorotelomer alcohols as xenoestrogens in vitro. 23) Thus, information concerning toxicological effects of 8-2 fluorotelomer alcohol is very limited. Therefore, further investigations with regard to biological effects of 8-2 fluorotelomer alcohol are required to provide information for the safe use of this compound.…”