Academic journal article Environmental Health Perspectives

Structure-Activity-Dependent Regulation of Cell Communication by Perfluorinated Fatty Acids Using in Vivo and in Vitro Model Systems

Academic journal article Environmental Health Perspectives

Structure-Activity-Dependent Regulation of Cell Communication by Perfluorinated Fatty Acids Using in Vivo and in Vitro Model Systems

Article excerpt

BACKGROUND: Perfluoroalkanoates, [e.g., perfluorooctanoate (PFOA)], 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.

KEY WORDS: extracellular receptor kinase, gap-junctional intercellular communication, mitogen-activated protein kinase, perfluorooctanoate, perfluoropentanoate, phosphatidylcholine-specific-phospholipase C, tumor promotion. Environ Health Perspect 117:545-551 (2009). doi:10.1289/ehp.11728 available via http://dx.doi.org/ [Online 23 October 2008]

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Research on the environmental fate and toxicology of halogenated compounds has focused primarily on brominated and chlorinated organics, whereas fluorinated organics received less attention, partly because of the perception that these compounds, which are quite chemically inert, were also biologically inert (Key et al. 1997). However, perfluorinated fatty acids (PFFAs), such as perfiuorooctano-ate (PFOA) and perfluorooctane sulfonate (PFOS), are found in the environment and have been detected in the blood of animals throughout the world, including the seals of remote arctic regions, indicating widespread distribution (Kannan 2001; Tao 2006; Van de Vijver 2005). Significant levels of PFOA and PFOS have also been detected in the serum of humans, but there is evidence of a significant decline in body burdens of PFOS and PFOA over the last 5-10 years (Calafat et al. 2007). The values from the first National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2000 reported geometric means of 30.4 [micro]g PFOS/L and 5.4 [micro]g PFOA/L, and the second NHANES conducted between 2003 and 2004 reported geometric means of 20.7 [micro]g PFOS/L and 3.9 [micro]g PFOA/L (Calafat et al. 2007). Contamination of the environment is not limited to PFOA and PFOS but also includes short-chain perfluorinated alkano-ates, such as perfluorobutyrate, perfluoropentanoate (PFPeA), perfluorohexanoate, and perfluoroheptanoate (Skutlarek et al. 2006).

The acute toxicities of PFOA and PFOS in rodent systems are low (Hekster 2003; Kudo and Kawashima 2003). After the absorption of PFOA into the body, it is predominantly distributed in the liver and plasma and, to a lesser extent, the kidney and lungs (Kudo and Kawashima 2003). Thus, the chronic and short-term effects of PFOA in rats are found largely in the liver (Kennedy et al. 2004) and immune system (DeWitt et al. …

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