Latent carcinogenicity of early-life exposure to dichloroacetic acid in mice.

Environmental exposures occurring early in life may have an important influence on cancer risk later in life. Here, we investigated carryover effects of dichloroacetic acid (DCA), a small molecule analog of pyruvate with metabolic programming properties, on age-related incidence of liver cancer. The study followed a stop-exposure/promotion design in which 4-week-old male and female B6C3F1 mice received the following treatments: deionized water alone (dH2O, control); dH2O with 0.06% phenobarbital (PB), a mouse liver tumor promoter; or DCA (1.0, 2.0 or 3.5g/l) for 10 weeks followed by dH2O or PB (n = 20-30/group/sex). Pathology and molecular assessments were performed at 98 weeks of age. In the absence of PB, early-life exposure to DCA increased the incidence and number of hepatocellular tumors in male and female mice compared with controls. Significant dose trends were observed in both sexes. At the high dose level, 10 weeks of prior DCA treatment induced comparable effects (≥85% tumor incidence and number) to those seen after continuous lifetime exposure. Prior DCA treatment did not enhance or inhibit the carcinogenic effects of PB, induce persistent liver cytotoxicity or preneoplastic changes on histopathology or alter DNA sequence variant profiles within liver tumors compared with controls. Distinct changes in liver messenger RNA and micro RNA profiles associated with prior DCA treatment were not apparent at 98 weeks. Our findings demonstrate that early-life exposure to DCA may be as carcinogenic as life-long exposures, potentially via epigenetic-mediated effects related to cellular metabolism.

Kidney toxicogenomics of chronic potassium bromate exposure in f344 male rats.

BACKGROUND: Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by-product, is a nephrotoxic compound and rodent carcinogen. To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure, the gene expression in kidneys from chronically exposed male F344 rats was investigated. METHODS: Male F344 rats were exposed to KBrO3 in drinking water for 52 and 100 wk. Kidneys were removed, frozen, and stored at -80°C, then used for Affymetrix microarray analysis. Gene expression patterns were examined using a non-carcinogenic (20 ppm) and carcinogenic dose (400 ppm) at 52 wk, and compared to 100 wk high dose (400 ppm) and adenoma gene expression. RESULTS: Statistical analysis revealed 144, 224, 43, and 994 genes out of 15866 from the 52 wk low, 52 wk high, 100 wk high, and adenomas respectively, were differentially expressed when compared to control kidneys. Gene ontology classification of the 52 wk high dose showed alterations of gene transcripts involved in oxidative stress, lipid metabolism, kidney function/ion transport, and cellular function. In a comparison of kidney development gene expression, alterations were seen in the adenomas but not in the 52 wk bromate-treated kidneys. However, the normal kidney from the high dose group resembled the adenoma expression pattern with early kidney development genes being up-regulated and adult phase genes being down-regulated. Moreover, eight genes were identified which could serve as biomarkers of carcinogenic exposure to bromate. The most promising of these was Pendrin, or Slc26a4, a solute carrier of chloride and iodide active in the kidney, thyroid, and inner ear. All these tissues are targets of KBrO3 toxicity. Expression array results were verified with quantitative real-time rtPCR. CONCLUSIONS: These data demonstrate that the 400 ppm carcinogenic dose of KBrO3 showed marked gene expression differences from the 20 ppm non-carcinogenic dose. Comparison of kidney development gene expression showed that the adenoma patterns were more characteristic of embryonic than adult kidneys, and that the normal kidney from the high dose group resembled the adenoma-like gene expression pattern. Taken together, the analysis from this study identifies potential biomarkers of exposure and illuminates a possible carcinogenic mode of action for KBrO3.

Vehicle and mode of administration effects on the induction of aberrant crypt foci in the colons of male F344/N rats exposed to bromodichloromethane.

Bromodichloromethane (BDCM) and tribromomethane given by corn oil gavage were previously found to induce neoplasia in the large intestine of rats. Our chronic bioassay of BDCM administered in drinking water failed to produce colon neoplasia in male F344/N rats. We recently reported that BDCM induces aberrant crypt foci (ACF), putative precursor lesions in the development of colon cancer, when included in the drinking water of male rats. To investigate whether ACF induced by BDCM could be promoted by corn oil (CO), male F344/N rats were exposed to 0.7 g BDCM/L in drinking water or 50 mg BDCM/kg body weight by oral gavage in CO. Animals exposed to drinking water, CO, or 15 mg/kg azoxymethane (AOM) (ip) constituted the negative, vehicle, and positive controls. After 26 wk, colons were examined for ACF. A significant decrease in water consumption was observed in both the positive controls and BDCM-treated animals; however, no difference was noted in final body weight. The administration of CO to AOM-exposed animals produced a significant increase in total ACF when compared to AOM alone. BDCM produced a significant increase in ACF when compared to control, but no difference was noticed between BDCM exposure by oral CO gavage and control. Additionally, no difference was noted between BDCM exposure by drinking water and by oral CO gavage. This study demonstrates that the formation of ACF is independent of the route of BDCM exposure (drinking water vs. oral corn oil gavage), with both routes producing similar ACF values of 1.33 +/- 0.49 and 1.5 +/- 0.51 ACF/colon.