Tilton Susan C, Orner Gayle A, Benninghoff Abby D, Carpenter Hillary M, Hendricks Jerry D, Pereira Cliff B, Williams David E
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA.
Environ Health Perspect. 2008 Aug;116(8):1047-55. doi: 10.1289/ehp.11190.
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.
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.
We fed aflatoxin B(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 17beta-estradiol (E(2), a known tumor promoter) in the diet for 14 days.
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(2) by Pearson correlation (R = 0.81 and 0.78, respectively), whereas CLOF regulated no genes in common with E(2).
These data suggest that the tumor-promoting activities of PFOA in trout are due to novel mechanisms involving estrogenic signaling and are independent of peroxisome proliferation.
全氟辛酸（PFOA）是啮齿动物体内一种强效的肝癌致癌物和过氧化物酶体增殖剂（PP）。人类对过氧化物酶体增殖不敏感，被认为对PP诱导的致癌作用具有抗性。先前对虹鳟鱼的研究表明，它们对PP脱氢表雄酮（DHEA）诱导的过氧化物酶体增殖也不敏感，但在长期接触后仍易发生肝癌。
在本研究中，我们使用鳟鱼作为独特的体内肿瘤模型，研究与结构多样的PPs氯贝丁酯（CLOF）和DHEA相比，PFOA在无过氧化物酶体增殖情况下的致癌潜力。从与肿瘤结果表型相关的肝脏基因表达谱中确定致癌机制。
我们给黄曲霉毒素B1处理组或假启动组动物喂食含200 - 1800 ppm PFOA的饲料30周，用于肿瘤分析。随后，我们通过cDNA芯片检测了喂食含PFOA、DHEA、CLOF或5 ppm 17β - 雌二醇（E2，一种已知的肿瘤促进剂）饲料14天的动物的基因表达。
PFOA（1800 ppm或50 mg/kg/天）和DHEA处理导致肝脏肿瘤发生率和多发性增加（p < 0.0001），而CLOF无此作用。通过缺乏过氧化物酶体β - 氧化和过氧化氢酶活性来衡量，致癌作用与过氧化物酶体增殖无关。另外，两种肿瘤促进剂PFOA和DHEA均导致雌激素基因特征，与E2通过Pearson相关性具有强相关性（分别为R = 0.81和0.78），而CLOF与E2没有共同调控的基因。
这些数据表明，PFOA在鳟鱼中的肿瘤促进活性是由于涉及雌激素信号传导的新机制，且与过氧化物酶体增殖无关。
