Activation of peroxisome proliferator-activated receptor alpha enhances apoptosis in the mouse liver.

Chronic exposure to peroxisome proliferators (PPs) leads to increased incidence of liver tumors in rodents. Liver tumor induction is thought to require increased hepatocyte proliferation and suppression of apoptosis. Transcript profiling showed increased expression of proapoptotic genes and decreased expression of antiapoptotic genes in the livers of mice exposed to the PP WY-14,643 (WY).

The transcriptional response to a peroxisome proliferator-activated receptor alpha agonist includes increased expression of proteome maintenance genes.

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARalpha in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARalpha-null mice. Primary hepatocytes from wild-type but not PPARalpha-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat.

Zonal distribution of cell proliferation in the liver of untreated B6C3F1 and C57BL mice.

To determine the lobular distribution of hepatocellular proliferation, S-phase response was measured in untreated adult male B6C3F1 and C57BL mice at ages 11, 14, and 23 weeks. The percentage of cells in S-phase (labeling index, LI) was evaluated using immunohistochemical detection of 5-bromo-2'-deoxyuridine (BrdU). The BrdU was delivered either by a single ip injection 2 hr prior to sacrifice or via an osmotic minipump implanted subcutaneously for 3 or 7 days.

Evaluation of potential modes of action of inhaled ethylbenzene in rats and mice.

Potential factors underlying the tumorigenic activity of ethylbenzene (EB) were examined in F344 rats and B6C3F1 mice inhaling 750 ppm EB vapor 6 h/day, 5 days/week, for one or four weeks. Target tissues (kidneys of rats and livers and lungs of mice) were evaluated for changes in organ weights, mixed function oxygenases (MFO), glucuronosyl transferase activities, S-phase DNA synthesis, apoptosis, alpha2u-globulin deposition, and histopathology. In male rats, kidney weight increases were accompanied by focal increases in hyaline droplets, alpha2u-globulin, degeneration, and S-phase synthesis in proximal tubules.

Tumor induction in mouse liver: di-isononyl phthalate acts via peroxisome proliferation.

Recently several chronic toxicity/carcinogenicity studies of di-isononyl phthalate (DINP) have been reported. These studies defined effect levels for liver tumors in male and female F344 rats at dietary levels exceeding 700 mg/kg/day; the no effect levels were 359 mg/kg/day in males and 442 mg/kg/day in females. Similar results were found in male B6C3F1 mice, but in female mice a significant increase in liver tumors was found at 336 mg/kg/day, making 112 mg/kg/day the NOAEL for liver tumors in that sex and species.