Journal
ENVIRONMENTAL HEALTH PERSPECTIVES
Volume 117, Issue 4, Pages 545-551Publisher
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/ehp.11728
Keywords
extracellular receptor kinase; gap-junctional intercellular communication; mitogen-activated protein kinase; perfluorooctanoate; perfluoropentanoate; phosphatidylcholine-specific-phospholipase C; tumor promotion
Funding
- National Institute of Environmental Health Sciences (NIEHS) [R01 ES013268-01A2]
- Ministry of Education, Science, Sports, and Culture of Japan [11694334]
- Grants-in-Aid for Scientific Research [11694334] Funding Source: KAKEN
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BACKGROUND: Perfluoroalkanoates, (e.g., perfluorooctanoate (PFOA)I, are known peroxisome proliferators that induce hepatomegaly and hepatocarcinogenesis in rodents, and are classic non-genotoxic carcinogens that inhibit in vitro gap-junctional intercellular communication (GJIC). This inhibition of GJIC is known to be a function of perfluorinated carbon lengths ranging from 7 to 10. OBJECTIVES: The aim of this study was to determine if the inhibition of GJIC by PFOA but not perfluoropentanoate (PFPeA) observed in F344 rat liver cells in vitro also occurs in F344 rats in vivo and to determine mechanisms of PFOA dysregulation of GJIC using in vitro assay systems. METHODS: We used an incision load/dye transfer technique to assess GJIC in livers of rats exposed to PFOA and PFPeA. We used in vitro assays with inhibitors of cell signaling enzymes and antioxidants known to regulate GJIC to identify which enzymes regulated PFOA-induced inhibition of GJIC. RESULTS: PFOA inhibited GJIC and induced hepatomegaly in rat livers, whereas PFPeA had no effect on either end point. Serum biochemistry of liver enzymes indicated no cytotoxic response to these compounds. In vitro analysis of mitogen-activated protein kinase (MAPK) indicated that PFOA, but not PFPeA, can activate the extracellular receptor kinase (ERK). Inhibition of GJIC, in vitro, by PFOA depended on the activation of both ERK and phosphatidylcholine-specific phospholipase C (PC-PLC) in the dysregulation of GJIC in an oxidative-dependent mechanism. CONCLUSIONS: The in vitro analysis of GJIC, an epigenetic marker of tumor promoters, can also predict the in vivo activity of PFOA, which dysregulated GJIC via ERK and PC-PLC.
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