Molecular Mechanisms of Perfluorooctanoate-Induced Hepatocyte Apoptosis in Mice Using Proteomic Techniques

The stability of perfluorooctanoate
(PFOA) coupled with its wide
use cause serious concerns regarding its potential risk to human health.
The molecular mechanisms of PFOA-induced hepatotoxicity relevant to
human health was investigated using both in vivo (mouse model) and
in vitro (human hepatocyte cells, HL-7702) techniques. Both male and
female Balb/c mice were administered PFOA at 0.05, 0.5, or 2.5 mg/kg-d
for 28-d, with serum PFOA concentrations after exposure being found
at environmentally relevant levels. Liver samples were examined for
histology and proteomic change using iTRAQ and Western Blotting, showing
dose-dependent hepatocyte apoptosis and peroxisome proliferation.
At high doses, genotoxicity resulting from ROS hypergeneration was
due to suppression of Complex I subunits in the electron transport
chain and activation of PPARα in both genders. However, at 0.05
mg/kg-d, Complex I suppression occurred only in females, making them
more sensitive to PFOA-induced apoptosis. In vitro assays using HL-7702
cells confirmed that apoptosis was also induced through a similar
mechanism. The dose/gender-dependent toxicity mechanisms help to explain
some epidemiological phenomena, i.e., liver cancer is not often associated
with PFOA exposure in professional workers. Our results demonstrated
that a proteomic approach is a robust tool to explore molecular mechanisms
of toxic chemicals at environmentally relevant levels.