Disruption of spindle checkpoint function in rats following 28 days of repeated administration of renal carcinogens.

We previously reported that 28-day exposure to hepatocarcinogens that facilitate cell proliferation specifically alters the expression of G1/S checkpoint-related genes and proteins, induces aberrant early expression of ubiquitin D (UBD) at the G2 phase, and increases apoptosis in the rat liver, indicating G1/S and spindle checkpoint dysfunction. The present study aimed to determine the time of onset of carcinogen-specific cell-cycle disruption after repeated administration of renal carcinogens for up to 28 days. Rats were orally administered the renal carcinogens nitrofurantoin (NFT), 1-amino-2,4-dibromoantraquinone (ADAQ), and 1,2,3-trichloropropane (TCP) or the non-carcinogenic renal toxicants 1-chloro-2-propanol, triamterene, and carboxin for 3, 7 or 28 days. Both immunohistochemical single-molecule analysis and real-time RT-PCR analysis revealed that carcinogen-specific expression changes were not observed after 28 days of administration. However, the renal carcinogens ADAQ and TCP specifically reduced the number of cells expressing phosphorylated-histone H3 at Ser10 in both UBD(+) cells and proliferating cells, suggestive of insufficient UBD expression at the M phase and early transition of proliferating cells from the M phase, without increasing apoptosis, after 28 days of administration. In contrast, NFT, which has marginal carcinogenic potential, did not induce such cellular responses. These results suggest that it may take 28 days to induce spindle checkpoint dysfunction by renal carcinogens; however, induction of apoptosis may not be essential. Thus, induction of spindle checkpoint dysfunction may be dependent on carcinogenic potential of carcinogen examined, and marginal carcinogens may not exert sufficient responses even after 28 days of administration.

The inhibition of 2,3-dichloro-1-propanol on T cell in vitro and in vivo.

2,3-Dichloro-1-propanol (2,3-DCP) is a member of a group of chemicals known as chloropropanols. Currently, immunotoxicity of 2,3-DCP has not been reported. In the present study, we studied its inhibitory effects on T cell both in vivo and in vitro. The results showed that 2,3-DCP markedly inhibited ConA-induced splenocyte proliferation, Th1 and Th2 cytokine production, CD4(+) T cell populations, and the ratio of CD4(+)/CD8(+) T cells and cell cycle arrest in vitro. In addition, 2,3-DCP markedly suppressed DNFB-induced T-cell-mediated delayed-type hypersensitivity (DTH) reaction in mice. Furthermore, Western blot was used to study how 2,3-DCP affects signal transduction mechanisms. The data revealed that 2,3-DCP could down regulate activation of ConA-induced NF-κB and NFAT signal transduction pathways. These observations indicated that 2,3-DCP exhibited negative regulatory effects by directly suppressing T-cell-mediated immune responses in vitro and in vivo.

Studies on hepatic function in the male langur (presbytis entellus entellus) following the administration of alpha-chlorohydrin.

1. ALPHA-Chlorohydrin, an inhibitor of spermatogenesis in langur (Presbytis entellus entellus) has been studied to ascertain whether any disturbance of liver function occurred in long term treatment with this compound. 2. Serum aminotransferase remained within normal limits while oral administration of alpha-chlorohydrin (13 mg/kg) were being taken. In subcutaneous treatment, the serum-aminotransferases were being raised during the period of administration, but returned to normal after cessation of drug administration. 3. The alkaline phosphatase levels were in normal range. 4. alpha-Chlorohydrin administration elevated the liver and plasma cholesterol levels. 5. The compound is a hypoglycaemic agent. A "sweet contraceptive" is an attractive proposition.

Mechanism of action of alpha-chlorhydrin on the testes and caput epididymidis of rat, gerbil (Meriones hurrianae), bat and mouse.

Chronic administration of alpha-chlorhydrin caused lesions of rat, gerbil and bat testicles selectively. The seminiferous epithelium became systematically depleted of spermatogenic elements. alpha-Chlorhydrin did not produce lesion of the caput epididymidis. Sloughing of the epithelial lining did not occur. No obstruction of the lumen of the epididymal duct was seen. The growth of androgen-dependent organs, i.e. seminal vesicles, epididymis and levator ani muscles was suppressed. alpha-Chlorhydrin caused no response directly on the epididymides. Subcutaneous or oral administration of alpha-chlorhydrin for a period of 3-5 weeks caused no response in the testes and epididymides of the mouse.

PIP: The mechanism of action of alpha-chlorhydrin on the testes and caput epididymidis of rat, gerbil (Meriones hurrianae), bat, and mouse was investigated. Chronic administration (rat: 25 mg/kg/day for 24 days; gerbil: 20 mg/kg/day for 50 days; mouse: 30 mg/kg/day for 18 days; bat: 75 mg/kg/day for 12 days) of alpha-chlorhydrin caused lesions selectively. Seminiferous epithelium became systematically depleted of spermatogenic elements. No lesion of the caput epididymidis was produced, no sloughing of the epithelial lining occurred, and no obstruction of the lumen of the epididymal duct was seen. The growth of androgen-dependent organs was suppressed. No direct response on the epididymides was seen. Sc or oral administration of alpha-chlorhydrin for a period of 3-5 weeks caused no response in the testes and epididymides of the mouse.