Inhibition of gap junctional intercellular communication by perfluorinated fatty acids is dependent on the chain length of the fluorinated tail

Abstract

Perfluorinated fatty acids (PFFAs), such as perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA), are known peroxisome proliferators and hepatocarcinogens. A causal link between an increase in the oxidative 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 (GJIC) has also been linked to the tumorpromoting properties of many carcinogens. Therefore, the effect of PFFAs on GJIC in WB-rat liver epithelial cells 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 GJIC. Inhibition occurred within 15 min and was reversible, with total recovery from inhibition occurring within 30 min after the removal of the compound from the 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-translational modification of the gap junction proteins was not a consequence of altered phosphorylation as determined by Western blot analysis. Perfluorooctanesulfonic 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 results suggest that PFFAs could potentially act as hepatocarcinogens at the level of gap junctions in addition to or instead of through peroxisome proliferation.

Acute and Chronic Effects of Perfluorobutane Sulfonate (PFBS) on the Mallard and Northern Bobwhite Quail

“…When compared on an average daily intake (ADI) basis, PFBS is at least 150-fold less toxic than PFOS. The difference in toxicity between PFBS and PFOS observed in the avian studies is not unexpected as the toxicity of PFAAs has been shown to be related to the number of perfluoroalkyl carbons (Goecke-Flora and Reo 1996;Upham et al 1998;Hu et al 2002;Martin et al 2003a). For instance, while gap junction communication (GJIC) was inhibited in liver epithelial cells (WB-F344) exposed to PFOS (eight perfluorinated carbons), it was not inhibited by PFAAs with carbon chain lengths of less than five or more than 16.…”

Fluorotelomer Acids are More Toxic than Perfluorinated Acids

“…Upham et al (33) found that only PFCAs with chain lengths of 7-10 C inhibited gap junction intercellular communication in rat liver epithelial cells. Furthermore, the degree of inhibition increased with increasing chain length (33).…”

Transcellular chaperone signaling: an organismal strategy for integrated cell stress responses

“…Gap junctions have also gained attention for a phenomenon called the radiation-induced bystander effect, in which non-irradiated cells exhibit similar effects to irradiated cells as a result of signals received from nearby irradiated cells via gap junctions (Azzam et al, 2004;Azzam and Little, 2004;Mitchell et al, 2004b;Mitchell et al, 2004a). In this process, gap junctional intercellular communication may also be involved in a range of cellular stress responses including ionizing radiation and oxidative stress (Upham et al, 1998), UV radiation (Provost et al, 2003) and HS (Hamada et al, 2003). Thus, between cells in close proximity, gap junctions may have an important role in the exchange of signaling molecules for proteostasis communication.…”