title: Promotion of hepatocarcinogenesis by perfluoroalkyl acids in rainbow trout.
abstract: 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.
authors: Department of Animal, Dairy and Veterinary Sciences and Graduate Program in Toxicology, Utah State University, Logan, Utah 84322, USA. abby.benninghoff@usu.edu
authors: Abby D
authors: AD
authors: Benninghoff
authors: Gayle A
authors: GA
authors: Orner
authors: Clarissa H
authors: CH
authors: Buchner
authors: Jerry D
authors: JD
authors: Hendricks
authors: Aaron M
authors: AM
authors: Duffy
authors: David E
authors: DE
authors: Williams
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity; D017738:Alkanesulfonic Acids / Q000633:toxicity; D000818:Animals; D002210:Caprylates / Q000633:toxicity; D015197:Carcinogenicity Tests; D003043:Cocarcinogenesis; D003652:Decanoic Acids / Q000633:toxicity; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D005466:Fluorocarbons / Q000737:chemistry / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006845:Hydrocarbons, Fluorinated / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D017686:Oncorhynchus mykiss; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D003652:Decanoic Acids; D052244:Endocrine Disruptors; D005466:Fluorocarbons; D006845:Hydrocarbons, Fluorinated; C033729:fluorotelomer alcohols; D008769:Methylnitronitrosoguanidine; C036567:perfluorodecanoic acid; C018959:hexadecafluoro-nonanoic acid; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid; D016604:Aflatoxin B1