Previously, we reported that
perfluorooctanoic acid (PFOA) promotes
liver cancer in a manner similar to that of 17β-estradiol (E2) in rainbow trout. Also, other perfluoroalkyl
acids (PFAAs) are weakly estrogenic in trout and bind the trout liver
estrogen receptor. The primary objective of this study was to determine whether multiple PFAAs enhance hepatic
tumorigenesis in trout, an animal model that represents human insensitivity to peroxisome proliferation. A two-stage chemical
carcinogenesis model was employed in trout to evaluate PFOA,
perfluorononanoic acid (PFNA),
perfluorodecanoic acid (PFDA),
perfluorooctane sulfonate (PFOS), and
8:2 fluorotelomer alcohol (8:2FtOH) as complete
carcinogens or promoters of
aflatoxin B(1) (AFB(1))- and/or
N-methyl-N'-nitro-N-nitrosoguanidine (
MNNG)-induced
liver cancer. A custom trout
DNA microarray was used to assess hepatic transcriptional response to these dietary treatments in comparison with E2 and the classic peroxisome proliferator,
clofibrate (CLOF). Incidence, multiplicity, and size of liver
tumors in trout fed diets containing E2, PFOA, PFNA, and PFDA were significantly higher compared with AFB(1)-initiated animals fed control diet, whereas PFOS caused a minor increase in liver
tumor incidence. E2 and PFOA also enhanced
MNNG-initiated hepatocarcinogenesis. Pearson correlation analyses, unsupervised hierarchical clustering, and principal components analyses showed that the hepatic gene expression profiles for E2 and PFOA, PFNA, PFDA, and PFOS were overall highly similar, though distinct patterns of gene expression were evident for each treatment, particularly for PFNA. Overall, these data suggest that multiple PFAAs can promote
liver cancer and that the mechanism of promotion may be similar to that of E2.