Induction of Hepatic Peroxisome Proliferation by 8–2 Telomer Alcohol Feeding In Mice: Formation of Perfluorooctanoic Acid in the Liver

Abstract

The effects of dietary administration of 1H, 1H, 2H, 2H-perfluorodecanol (8-2 telomer alcohol), on peroxisome proliferation in the liver of mice were studied. Male ddY mice were fed on a diet containing 8-2 telomer alcohol at concentrations of 0, 0.025, 0.05, 0.1, and 0.2% (w/w) for 7, 14, 21, and 28 days. These treatments with 8-2 telomer alcohol caused liver enlargement in a dose- and duration-dependent manner. Peroxisome proliferation in the liver of mice was confirmed by electron microscopic examination. Peroxisomal acyl-CoA oxidase was induced by these treatments with 8-2 telomer alcohol in a dose- and time-dependent manner. The concentration of perfluorooctanoic acid (PFOA) and related compounds were determined in the liver and plasma, since PFOA had been shown to be a possible metabolite of 8-2 telomer alcohol and to cause significant peroxisome proliferation in rodents. Five metabolites, namely, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), 2H, 2H-perfluorodecanoic acid (8-2 telomer acid), and two unidentified metabolites, were present in the liver and serum. PFOA was confirmed to be accumulated in the liver of mice following the administration of 8-2 telomer alcohol in a dose- and duration-dependent manner. A linear relationship was observed between the concentration of PFOA and the activity of peroxisomal acyl-CoA oxidase in the liver of mice. These results strongly suggest that PFOA, but not 8-2 telomer alcohol itself, caused peroxisome proliferation in the liver. The present study provided evidence that 8-2 telomer alcohol is converted into PFOA in vivo and that the PFOA formed produces biological effects in the liver of mice.

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

“…In fact, the activities of acyl-CoA oxidase, a peroxisomal enzyme, was far greater than those expected by PFOA concentrations remained in the liver of 8-2 fluorotelomer alcohol-administered rats. 43) The present study showed that the administration of 8-2 fluorotelomer alcohol to rats decreased the proportion of 18 : 2 (n-6) and increased the proportion and the content of 20 : 3 (n-6) and 20 : 4 (n-6) in the liver. The biosynthesis of 20 : 4 (n-6) from 18 : 2 (n-6) involves sequential reactions catalyzed by D 6 desaturase, elongase for 18 : 3 (n-6) and D 5 desaturase.…”

“…Several studies have shown that PFOA is formed from 8-2 fluorotelomer alcohol as a metabolic product in mammals. 43,44) It is possible that PFOA formed induces SCD and PCE since administration of rats with PFOA induces both enzymes 45) and increases mRNA levels of SCD1 and rELO2 (Kudo et al, unpublished data). However, it cannot be excluded that 8-2 fluorotelomer alcohol itself and/or its metabolites induce these enzymes.…”

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

“…In experimental animals such as rats, 8:2 FTOH was metabolically converted to PFOA associated with the induction of hepatic peroxisome proliferation and ACOX activity. 6) These compounds were observed at concentrations ranging from 7 to 196 pg/m 3 and from 11 to 165 pg/m 3 in the troposphere. 4,5) There is no information about the contamination levels of FTOHs in the human body; therefore, further studies are necessary to investigate the contamination level, potential biological effects and the risks of these compounds.…”

“…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).…”

“…5,6,6,7,7,8,8,9,9,10,10,10-nonadecafluoro-1-decanol, Wako Pure Chemical Industries, Ltd., Tokyo, Japan), PFOS (Avocado Research Chemicals Ltd., Lancashire, U.K.), PFOA (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan) and E2 (estradiol-17b, Sigma, St. Louis, MO, U.S.A.), as a positive control substance, were used in this study. These reagents were dissolved in DMSO (dimethyl sulfoxide, Wako Pure Chemical Industries, Ltd.) to prepare test solutions.…”