The contact allergen dinitrochlorobenzene (DNCB) and respiratory allergy in the Th2-prone Brown Norway rat.

All LMW respiratory allergens known to date can also induce skin allergy in test animals. The question here was if in turn skin allergens can induce allergy in the respiratory tract. Respiratory allergy was tested in Th2-prone Brown Norway (BN) rats by dermal sensitization with the contact allergen dinitrochlorobenzene (DNCB; 1%, day 0; 0.5%, day 7) and a head/nose-only inhalation challenge of 27mg/m3 of DNCB (15 min, day 21), using a protocol that successfully identified chemical respiratory allergens. Skin allergy to DNCB was examined in BN rats and Th1-prone Wistar rats in a local lymph node assay followed by a topical patch challenge of 0.1% DNCB. Sensitization of BN rats via the skin induced DNCB-specific IgG in serum, but not in all animals, and an increased number of CD4+ cells in the lung parenchyma. Subsequent inhalation challenge with DNCB did not provoke apneas or allergic inflammation (signs of respiratory allergy) in the BN rats. However, microarray analysis of mRNA isolated from the lung revealed upregulation of the genes for Ccl2 (MCP-1), Ccl4 (MIP-1beta), Ccl7 and Ccl17. Skin challenge induced considerably less skin irritation and allergic dermatitis in the BN rat than in the Wistar rat. In conclusion, the Th2-prone BN rat appeared less sensitive to DNCB than the Wistar rat; nevertheless, DNCB induced allergic inflammation in the skin of BN rats but even a relatively high challenge concentration did not induce allergy in the respiratory tract, although genes associated with allergy were upregulated in lung tissue.

Quercetin, but not its glycosidated conjugate rutin, inhibits azoxymethane-induced colorectal carcinogenesis in F344 rats.

The effect of the flavonoid quercetin and its conjugate rutin was investigated on (biomarkers of) colorectal cancer (CRC). Male F344 rats (n = 42/group) were fed 0, 0.1, 1, or 10 g quercetin/kg diet or 40 g rutin/kg diet. Two wk after initial administration of experimental diets, rats were given 2 weekly subcutaneous injections with 15 mg/kg body wt azoxymethane (AOM). At wk 38 post-AOM, quercetin dose dependently (P < 0.05) decreased the tumor incidence, multiplicity, and size, whereas tumor incidences were comparable in control (50%) and rutin (45%) groups. The number of aberrant crypt foci (ACF) in unsectioned colons at wk 8 did not correlate with the tumor incidence at wk 38. Moreover, at wk 8 post-AOM, the number and multiplicity of ACF with or without accumulation of beta-catenin were not affected by the 10 g quercetin/kg diet. In contrast, another class of CRC-biomarkers, beta-catenin accumulated crypts, contained less beta-catenin than in controls (P < 0.05). After enzymatic deconjugation, the plasma concentration of 3'-O-methyl-quercetin and quercetin at wk 8 was inversely correlated with the tumor incidence at wk 38 (r = -0.95, P

Evaluation of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin, and D-mannitol.

As part of the international evaluation program coordinated by ILSI/HESI, the potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/-.p53+/- mice for short term carcinogenicity assays was evaluated. For comparison also wild-type C57BL/6 mice (WT) were included in these studies. Four test compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa-/-.p53+/- mice and WT mice for 39 weeks. The model compounds investigated were haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test compounds were administered as admixture to rodent diet at levels up to 25 mg/kg diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10% for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival was not affected with any of the test compounds. Haloperidol, reserpine and D-mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/-.p53+/- mice, showing low and comparable tumor incidences in controls and high-dose animals. The results obtained with phenacetin may be designated equivocal in Xpa-/-.p53+/- mice, based on the occurrence of a single rare tumor in the target organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a high incidence of karyomegaly. These results are in agreement with the currently known carcinogenic potential of the 4 test compounds in humans.