INHIBITION OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION BY PERFLUORINATED FATTY-ACIDS IS DEPENDENT ON THE CHAIN-LENGTH OF THE FLUORINATED TAIL

Perfluorinated fatty acids (PFFAs), such as perfluorooctanoic acid (PF OA) and perfluorodecanoic acid (PFDA), are known peroxisome proliferat ors and hepatocarcinogens. A causal link between an increase in the ox idative stress by peroxisomes and tumor promotion has been proposed to explain the hepatocarcinogenicity of PFOA and PFDA, However, the down -regulation of gap junctional intercellular communication (CJIC) has a lso been linked to the tumor-promoting properties of many carcinogens. Therefore, the effect of PFFAs on GJIC in WE-rat liver epithelial cel ls was determined. The chain length of the PFFAs tested for an effect on GJIC ranged from 2 to 10, 16 and 18 carbons. Carbon lengths of 7 to 10 inhibited GJIC in a dose-response fashion, whereas carbon lengths of 2 to 5, 16 and 18 did not appreciably inhibit CJIC. Inhibition occu rred within 15 min and was reversible, with total recovery from inhibi tion occurring within 30 min after the removal of the compound from th e growth medium, This short time of inhibition suggests that GJIC was modified at the post-translational level. Also, this short time period was not long enough for peroxisome proliferation. The post-translatio nal modification of the gap junction proteins was not a consequence of altered phosphorylation as determined by Western blot analysis, Perfl uorooctanesulfonic acid also inhibited GJIC in a dose-response fashion similar to PFDA, indicating that the determining factor of inhibition was probably the fluorinated tail, which required 7-10 carbons, Our r esults suggest that PFFAs could potentially act as hepatocarcinogens a t the level of gap junctions in addition to or instead of through pero xisome proliferation. (C) 1998 Wiley-Liss, Inc.