W3 AM Toxicogenomics in Environmental Studies
Wednesday, 16 November 2005: 8:00 AM - 11:40 AM in Ballroom 3

(TIL-1117-832028) Possible mechanism for hepatic tumor promotion by perfluorooctanoic acid in rainbow trout: A toxicogenomic approach.

Tilton, S^{1, 2}, Orner, G^{1, 2}, Benninghoff, A¹, Hendricks, J¹, Williams, D^{1, 2}, ¹ Environmental and Molecular Toxicology, Marine and Freshwater Biomedical Sciences Center² Linus Pauling Institute, Oregon State University, Corvallis, OR, USA

ABSTRACT- Perfluorooctanoic acid (PFOA), a perfluorinated carboxylate, is considered a peroxisome proliferator (PP) in rat hepatocarcinogenesis studies. A marked species difference to peroxisome proliferation has been documented such that rodents are highly responsive and primates are relatively resistant. Previous studies with rainbow trout have shown that they are also insensitive to peroxisome proliferation by the PP, dehydroepiandrosterone (DHEA), but are still susceptible to enhanced hepatocarcinogenesis after chronic exposure. In this study, we determined whether PFOA is also a tumor promotor in trout and then examined hepatic gene expression profiles using a rainbow trout oligonucleotide microarray to further investigate possible mechanisms of action. Fish were initiated as fry to the hepatocarcinogen, aflatoxin B₁, and then fed 200-1800 ppm PFOA in the diet for 30 weeks. Two structurally diverse PPs, 1800 ppm clofibrate and DHEA, were included for comparison. PFOA (1800 ppm) and DHEA treatments resulted in enhanced liver tumor incidence and multiplicity while clofibrate showed no effect. Carcinogenesis seemed independent of peroxisome proliferation as no induction of peroxisomal -oxidation and catalase activity were observed. Alternately, plasma VTG was elevated in fish fed PFOA and DHEA suggesting that estrogenic mechanisms may play a role. We exposed juvenile trout to similar doses of PFOA, DHEA and clofibrate along with 5 ppm 17-estradiol (E2; a known tumor promotor) in the diet for 14 days to compare hepatic gene expression patterns. Both tumor promotors, PFOA and DHEA, showed strong correlation with gene expression patterns by E2 with Pearson correlation (r) values of 0.79 and 0.71, respectively. Of interest were upregulated genes known to be important for estrogen receptor signaling and vitellogenesis. In comparison, clofibrate regulated no genes in common with E2 and had a Pearson correlation value of 0.11. Overall, these data suggest a possible alternative mechanism for tumor enhancement by PFOA in a model that is relatively resistant to peroxisomal proliferation. Supported by NIH grants ES03850 and ES07060.

Key words: rainbow trout, microarray, estrogen, perfluorooctanoic acid