Structure-activity-dependent regulation of cell communication by perfluorinated fatty acids using in vivo and in vitro model systems.
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.


OBJECTIVE
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.
Department of Pediatrics and Human Development, National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824, USA. upham@msu.edu
Brad L
BL
Upham
Joon-Suk
JS
Park
Pavel
P
Babica
Iva
I
Sovadinova
Alisa M
AM
Rummel
James E
JE
Trosko
Akihiko
A
Hirose
Ryuichi
R
Hasegawa
Jun
J
Kanno
Kimie
K
Sai
D000818:Animals; D002210:Caprylates / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005232:Fatty Acids, Volatile / Q000633:toxicity; D005466:Fluorocarbons / Q000633:toxicity*; D017629:Gap Junctions / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008297:Male; D020025:Peroxisome Proliferators / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D014631:Valerates / Q000633:toxicity
D002210:Caprylates; D002273:Carcinogens; D005232:Fatty Acids, Volatile; D005466:Fluorocarbons; D020025:Peroxisome Proliferators; D014631:Valerates; C023036:perfluorooctanoic acid; D048049:Extracellular Signal-Regulated MAP Kinases