The components of biphenyl induced urinary bladder calculus in the male rats were studied using HPLC coupled with mass spectrometry/mass spectrometry (LC-MS/MS), IR and inductive coupled plasma (ICP). Two peaks in the calculus components were detected by HPLC and LC-MS/MS. The peaks were identified as 4-hydroxybiphenyl sulfate (4-HBPSC) and 4, 4'-dihydroxybiphenyl sulfate (4, 4'-DHBPSC). 4-HBPSC was accounted for 54.6% and 4, 4'-DHBPSC was accounted for 1.5% by LC-MS/MS. 4-HBPSC was main component by these results and IR. Inorganic elements of urinary bladder calculus were accounted for 25% by ICP.
Two‐year Study of Carcinogenicity and Chronic Toxicity of Biphenyl in Rats: Yumi U meda , et al . Japan Bioassay Research Center, Japan Industrial Safety and Health Association— Carcinogenicity and chronic toxicity of biphenyl were examined in 50 male and 50 female F344 rats exposed to 0, 500, 1,500 or 4,500 ppm biphenyl in the diet for 105 weeks. Bladder tumors were found in the 4,500 ppm males, as evidenced by significantly increased incidence of carcinoma (24/50) and papilloma (10/50) of the transitional cells as well as one rarely observed case both of carcinoma and papilloma of the squamous cells. The survival rate of the 4500 ppm males significantly decreased, due to the bladder tumors and the hematuria accompanied by bladder calculi. The bladder calculi were found in 43 males in the 4,500 ppm group, but in only 8 females. Urinary pH significantly increased in the males, and occult blood was observed both in males and females in the 4,500 ppm group. The pre‐neoplastic lesions were hyperplasia of transitional epithelium (simple, nodular and papillary hyperplasia) in the bladder of the 4,500 ppm males. Incidences of calculus formation and transitional cell hyperplasia in the renal pelvis also significantly increased in the 4,500 ppm males and females. On the other hand, the incidences of the transitional cell hyperplasia and the calculus formation in the bladder and the renal pelvis were far lower in females than in males, and no bladder tumors were observed in the females. Causative factors of the bladder tumors and their male predominance were discussed with reference to the findings reported in the literature and the previous study of biphenyl metabolism.
The relationship between methylation and expression of rat pepsinogen 1 (Pg1) genes was investigated in various tissues. On Northern blotting with a Pg1 complementary DNA probe, Pg1 mRNA was detected only in the glandular stomach of normal rats. Methylation analysis with Msp1/HpaII and Hha1 revealed tissue specific methylation patterns of Pg1 genes with less methylated in the stomach than in other normal tissues not expressing the genes. During stomach development, there was a progressive increase in the Pg1 mRNA level that almost coincided with change in the mucosal pepsinogen level and progressive demethylation after the onset of transcription. Thus, there was an inverse correlation between methylation and expression of Pg1 genes, suggesting a role of DNA methylation in Pg1 gene regulation during normal differentiation, although not its primary role in gene activation. There was no detectable Pg1 mRNA in either primary or transplanted stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine. The methylation patterns of Pg1 genes were different from those of normal tissues that expressed the gene and of those that did not and no simple correlation was observed between methylation and expression of Pg1 genes. This result is consistent with a previous finding that DNA methylation is deranged in tumor cells.
To investigate the development of resistance to chloroform toxicity, a 4-week inhalation study was conducted in which BDF1 male mice were exposed to a low level of chloroform for an initial two-week period, and thereafter the exposure concentration was increased for a second two-week period. The animals were exposed to inhalation of chloroform vapor 6 hr per day, 5 days per week, with clinical observation and measurement of body weight conducted. These results demonstrate that pre-exposure to chloroform at a low dose level induced resistance to a higher dose of chloroform in male mice. This resistance was dependent on the pre-exposure concentration.
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