Comparative Hepatotoxicity of Novel PFOA Alternatives (Perfluoropolyether Carboxylic Acids) on Male Mice

As novel alternatives
to perfluorooctanoic acid (PFOA), perfluoropolyether
carboxylic acids (multiether PFECAs, CF3(OCF2)nCOO–, n = 2–4) have been detected in various environmental matrices;
however, public information regarding their toxicities remains unavailable.
To compare the hepatotoxicity of multiether PFECAs (e.g., PFO2HxA,
PFO3OA, and PFO4DA) with PFOA, male mice were exposed to 0.4, 2, or
10 mg/kg/d of each chemical for 28 d, respectively. Results demonstrated
that PFO2HxA and PFO3OA exposure did not induce marked increases in
relative liver weight; whereas 2 and 10 mg/kg/d of PFO4DA significantly
increased relative liver weight. Furthermore, PFO2HxA and PFO3OA demonstrated
almost no accumulation in the liver or serum; whereas PFO4DA was accumulated
but with weaker potential than PFOA. Exposure to 10 mg/kg/d of PFO4DA
led to 198 differentially expressed liver genes (56 down-regulated,
142 up-regulated), with bioinformatics analysis highlighting the urea
cycle disorder. Like PFOA, 10 mg/kg/d of PFO4DA decreased the urea
cycle-related enzyme protein levels (e.g., carbamoyl phosphate synthetase
1) and serum ammonia content in a dose-dependent manner. Both PFOA
and PFO4DA treatment (highest concentration) caused a decrease in
glutamate content and increase in both glutamine synthetase activity
and aquaporin protein levels in the brain. Thus, we concluded that
PFO4DA caused hepatotoxicity, as indicated by hepatomegaly and karyolysis,
though to a lesser degree than PFOA, and induced urea cycle disorder,
which may contribute to the observed toxic effects.