Academic journal article Environmental Health Perspectives

Genomic Profiling Reveals an Alternate Mechanism for Hepatic Tumor Promotion by Perfluorooctanoic Acid in Rainbow Trout

Academic journal article Environmental Health Perspectives

Genomic Profiling Reveals an Alternate Mechanism for Hepatic Tumor Promotion by Perfluorooctanoic Acid in Rainbow Trout

Article excerpt

BACKGROUND: Perfluorooctanoic acid (PFOA) is a potent hepatocarcinogen and peroxisome proliferator (PP) in rodents. Humans are not susceptible to peroxisome proliferation and are considered refractory to carcinogenesis by PPs. Previous studies with rainbow trout indicate they are also insensitive to peroxisome proliferation by the PP dehydroepiandrosterone (DHEA), but are still susceptible to enhanced hepatocarcinogenesis after chronic exposure.

OBJECTIVES: In this study, we used trout as a unique in vivo tumor model to study the potential for PFOA carcinogenesis in the absence of peroxisome proliferation compared with the structurally diverse PPs clofibrate (CLOF) and DHEA. Mechanisms of carcinogenesis were identified from hepatic gene expression profiles phenotypically anchored to tumor outcome.

METHODS: We fed aflatoxin [B.sub.1] or sham -initiated animals 200-1,800 ppm PFOA in the diet for 30 weeks for tumor analysis. We subsequently examined gene expression by cDNA array in animals fed PFOA, DHEA, CLOF, or 5 ppm 17[beta]-estradiol ([E.sub.2] a known tumor promoter) in the diet for 14 days.

RESULTS: PFOA (1,800 ppm or 50 mg/kg/day) and DHEA treatments resulted in enhanced liver tumor incidence and multiplicity (p <0.0001), whereas CLOF showed no effect. Carcinogenesis was independent of peroxisome proliferation, measured by lack of peroxisomal [beta]-oxidation and catalase activity. Alternately, both tumor promoters, PFOA and DHEA, resulted in estrogenic gene signatures with strong correlation to [E.sub.2] by Pearson correlation (R = 0.81 and 0.78, respectively), whereas CLOF regulated no genes in common with [E.sub.2]

CONCLUSIONS: These data suggest that the tumor promoting activities PFOA in trout are due to novel mechanisms involving estrogenic signaling and are independent of peroxisome proliferation.

KEY WORDS: clofibrate, dehydroepiandrosterone, estradiol, hepatocarcinogenesis, microarray, perfluorooctanoic acid, peroxisome proliferation, rainbow trout. Environ Health Perspect 116:1047-1055(2008). doi:10.1289/ehp.11190 available via [Online 9 May 2008]

Perfluorooctanoic acid (PFOA) is a member of a class of perfluorinated compounds that are used widely in consumer products and industrial applications including surfactants, lubricants, textile coatings, food packaging, and flame retardants. PFOA is also a degrada-tion product of other fluoropolymers that is highly resistant to further metabolic and environmental breakdown. Because of its widespread occurrence and chemical stability, there are increasing concerns about the environmental persistence and accumulation of PFOA measured in terrestrial and aquatic biota and in human serum (Calafat et al. 2007; Houde et al. 2006; Prevedouros et al. 2006). Estimation of PFOA half-lives in serum varies broadly, depending on species and sex, and ranges from days in rats (Vanden Heuvel et al. 1991) and cynomolgus monkeys (Butenhoff et al. 2004) to almost 4 years in occupationally exposed humans (Olsen et al. 2007). Although some perfluorinated chemicals have been voluntarily removed from the market by manufacturers over concerns related to environmental occurrence and stability, PFOA is still produced commercially, and its potential risk to humans continues to be evaluated (U.S. Environmental Protection Agency 2006).

PFOA is a potent peroxisome proliferator (PP) similar to other perfluorinated chemicals (Sohlenius et al. 1992). Overall, PPs comprise a structurally diverse group of nongenotoxic carcinogens including certain hypolipidemic drugs [clofibrate (CLOF), ciprofibrate], industrial plasticizers (phthalates), herbicides (phenoxyacetic acids), and organic solvents (trichloroethylene). PPs are known to cause hepatomegaly, altered cholesterol homeostasis, increased number and size of peroxisomes, and increased [beta]-oxidation and oxidation of fatty acids in peroxisomes and microsomes, respectively, in susceptible animal models (Moody et al. …

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