Metabolic Disruption Early in Life is Associated With Latent Carcinogenic Activity of Dichloroacetic Acid in Mice.

Early-life environmental factors can influence later-life susceptibility to cancer. Recent evidence suggests that metabolic pathways may mediate this type of latency effect. Previously, we reported that short-term exposure to dichloroacetic acid (DCA) increased liver cancer in mice 84 weeks after exposure was stopped. Here, we evaluated time course dynamics for key events related to this effect. This study followed a stop-exposure design in which 28-day-old male B6C3F1 mice were given the following treatments in drinking water for up to 93 weeks: deionized water (dH2O, control); 3.5 g/l DCA continuously; or 3.5 g/l DCA for 4-52 weeks followed by dH2O. Effects were evaluated at eight interim time points. A short-term biomarker study was used to evaluate DCA effects at 6, 15, and 30 days. Liver tumor incidence was higher in all DCA treatment groups, including carcinomas in 82% of mice previously treated with DCA for only 4 weeks. Direct effects of DCA in the short-term study included decreased liver cell proliferation and marked mRNA changes related to mitochondrial dysfunction and altered cell metabolism. However, all observed short-term effects of DCA were ultimately reversible, and prior DCA treatment did not affect liver cell proliferation, apoptosis, necrosis, or DNA sequence variants with age. Key intermediate events resulting from transient DCA exposure do not fit classical cytotoxic, mitogenic, or genotoxic modes of action for carcinogenesis, suggesting a distinct mechanism associated with early-life metabolic disruption.

Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a gamma-dominant PPAR alpha/gamma agonist: lack of evidence for urolithiasis as an inciting event.

Naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was tested for carcinogenicity in F344 rats in a 2-year study. Changes in urine composition and urothelial morphology were characterized in a companion 18-month investigative study. A significant increase in neoplasms of the bladder occurred only in females of the high-dose group (14/60) in the carcinogenicity study. Trends toward increased cell proliferation in the urothelium were noted in both sexes at all time points evaluated in the 18-month study. Group means for urothelial mitogenesis were increased statistically significantly only in high-dose females at 12 and 18 months. Urothelial hyperplasia occurred in high-dose females at 18 months. Morphologic changes in the urothelium at earlier time points were limited to hypertrophy and decreased immunolabeling of the superficial cells for cytokeratin 20 (a marker of terminal differentiation in urothelial cells) in both males and females. No treatment-related changes in urinary parameters, including urinary sediments, were associated with the occurrence of urothelial proliferation. Urinary pH was unaffected by treatment in both males and females, but expected diurnal changes were demonstrated. Collectively, these data indicate that naveglitazar was associated with hypertrophic and proliferative effects on the urothelium, but a link with changes in urinary parameters was not demonstrated.

Sub-chronic dietary toxicity of potassium perfluorooctanesulfonate in rats.

Perfluorooctanesulfonate (PFOS) is a widely disseminated persistent compound found at low (part-per-billion) concentrations in serum and liver samples from humans and fish-eating wildlife. This study investigated the hypotheses that early hepatocellular peroxisomal proliferation and hepatic cellular proliferation are factors in chronic liver response to dietary dosing, that lowering of serum total cholesterol is an early clinical measure of response to treatment, and that liver and serum PFOS concentrations are proportional to dose and cumulative dose after sub-chronic treatment. PFOS was administered in diet as the potassium salt at 0, 0.5, 2.0, 5.0, and 20 parts per million (ppm) to Sprague Dawley rats for 4 or 14 weeks. At 4 weeks, effects included decreased serum glucose and an equivocal (

Promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17beta-estradiol in male Sprague-Dawley rats.

The determination of differences in hormonal regulation of tumor promotion-related response to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) between males and females may identify factors contributing to the female-specific hepatocarcinogenicity of TCDD in rats. In the current study, diethylnitrosamine-initiated male Sprague-Dawley rats were exposed to TCDD or corn oil vehicle in the presence and absence of 17beta-estradiol (E2), and cell proliferation and development of preneoplastic altered hepatic foci (AHF) were determined. After 30 weeks of exposure, gamma-glutamyltranspeptidase (GGT)-positive AHF and the number of placental glutathione-s-transferase (PGST)-positive AHF were significantly higher in TCDD-treated rats than in control rats. Both the number and volume fraction of GGT-positive AHF were significantly lower in rats cotreated with E2 regardless of TCDD exposure compared with corresponding non-E2-treated groups and were unaffected by TCDD. In contrast, the number of PGST-positive AHF was significantly higher in E2-treated rats in the absence of TCDD treatment. In addition, whereas E2 had no effect on the volume fraction of PGST-positive foci, the levels in rats cotreated with both E2 and TCDD were significantly higher than in controls. No differences were observed in cell proliferation between TCDD-treated and control rats, although cell proliferation was lower in rats exposed to E2 compared with placebo controls. The weaker potency of tumor promotion and lack of induction of cell replication and DNA damage in male rats likely explain the female-specific hepatocarcinogenicity of TCDD in chronic bioassays.