Abstract 3451: Cell proliferation and apoptosis during chloroform-induced hepatocarcinogenesis in male F-344/N rats

Abstract The carcinogenic potential of chlorinated organics is of direct importance in human risk assessment. Most drinking water chlorinated organics are disinfection by products (DBPs) of water chlorination and many test positive in rodent bioassays. Trihalomethanes (THMs) are the most prevalent DBPs generated in chlorinated drinking water and chloroform (TCM) is the THM in highest concentration in finished drinking water. Human exposure to TCM occurs through ingestion of drinking water, inhalation and dermal exposure. TCM is carcinogenic to the liver and kidney of rodents including male and female B6C3F1 mice and male F-344/N and Osborne-Mendel rats. The carcinogenic mechanism of TCM in the rodent is not completely understood. Four mechanisms have been proposed: 1) mutagenicity; 2) reparative hyperplasia; 3) altered gene expression; and 4) secondary genotoxicity. Here, histopathology, immunohistochemistry, and quantitative image analysis were used to examine reparative cell proliferation and altered gene expression as potential mechanisms of TCM-induced hepatocellular carcinogenesis in male F-344/N rats. Animals were exposed to concentrations of 803 + 5 or 1592 + 21 mg/L in the drinking water for 78 or 100 weeks. Distilled water was the vehicle control. The high TCM dose increased the prevalence (% of animals with a lesion) of hepatocellular neoplasia (carcinoma and adenoma) 17.5% vs. 5.1% (p<0.05) and marginally enhanced the prevalence of combined preneoplastic and neoplastic tumors (20.5% vs 7.7%; 0.05<p<0.1). Cell proliferation (proliferating cell nuclear antigen), apoptosis (terminal transferase assay) and expression of tumor associated markers, transforming growth factor alpha (TGF-α) and the p21 Ras oncogene were evaluated in normal liver, altered foci (AF), large foci of cellular alteration (LFCA) and adenomas (AD). PCNA, TGF-α, and p21 Ras increased significantly during TCM-induced neoplastic progression (p = 0.0021, 0.0105, and 0.0167, respectively). A significant change in apoptosis was not found during neoplastic progression, however, a progressive imbalance between cell proliferation and death occurred (p = 0.0022). The phenotype of hepatocellular lesions in rats receiving TCM in their drinking water differed from that of the “spontaneous” lesions arising in rats given distilled water, suggesting a different mechanistic origin. Taken together the data are consistent with a carcinogenic mechanism for TCM that includes adaptation to a hepatotoxic chemical and selection of resistant cells. (This abstract does not reflect the views of the EPA). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3451.