DDT is known as a nongenotoxic hepatocarcinogen and has been shown to induce microsomal enzymes and GGT-positive foci and to inhibit gap junctional intercellular communication (GJIC) in the rodent liver. In consideration of these findings, we examined time-related changes in potential factors including hepatic enzyme induction, oxidative stress, cell proliferation, and GJIC in a 4-week and a 2-year feeding studies of p,p'-DDT with F344 rats. Consequently, hepatic microsomal P450 isozymes such as CYP2B1 and CYP3A2 were induced from the beginning of treatment in a dose-dependent manner. Measurement of oxidative stress markers revealed significant increases in lipid peroxide and 8-hydroxydeoxyguanosine at dose levels that induced hepatocellular tumors. Cell proliferation was enhanced within 3 days at any dose level, but returned to normal after 7 days and no significant changes thereafter. GJIC was inhibited throughout the study from the beginning to the end of treatment. Histologically, eosinophilic foci appeared earlier than controls and increased in number and size prior to development of hepatocellular tumors. These results indicate that DDT may induce eosinophilic foci as a result of oxidative DNA damage and leads them to neoplasia in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.

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In order to prepare background data for toxicity studies, reproductive organs of a total of 106 purpose-bred female cynomolgus monkeys 2.0 to 9.0 years of age were surveyed for the sequence of events during reproductive cycles. Based on histological features, these animals were classified into groups according to the six phases of the reproductive cycle in addition to a group at the immature stage. Follicular phases were characterized by development of follicles and luteal phases by development of functional corpus luteum. Proliferation of endometrial glands started at the follicular phase and reached the maximum at the luteal phase. Features in the menstrual phase were almost the same as those in the follicular phases except for the shedding of superficial surface of endometrium. The percentage of animals in the phases of follicular development was 51%, and those in luteal development 46%, indicating roughly equal duration of both phases of the reproductive cycle. Absolute and relative weights of the ovaries and uterus were lowest in early follicular phase and gradually increased and reached the maximum in the early luteal phase, then decreased to the level of the early follicular phase. The difference in weight between the bigger and smaller ovaries, remarkable between 5.0 to 5.5 years of age, was at the maximum in the early luteal phase. The absolute weight of the ovaries and uterus increased rapidly and reached its peak between 5.0 to 5.5 years of age and remained unchanged thereafter, although the body weight gradually increased up to 9.0 years of age.

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Effects of shark cartilage proteoglycan (SCPG), which has heat-stable inhibitory activities against matrix metalloproteinase (MMP)-2 and -9 in vitro, on pancreatic carcinogenesis were studied in a rapid production model for pancreatic duct adenocarcinomas (PCs) in hamsters. Female Syrian golden hamsters received a diet containing 0% (group 1), 0.2% (group 2) or 0.4% (group 3) of SCPG for 50 days after initiation with N-nitrosobis(2-oxopropyl)amine followed by augmentation pressure. The number of PCs were 3.1 ± 2.0 in group 1 and 1.4 ± 0.9 in group 3, and total ductal lesions including hyperplasia, atypical hyperplasia and PCs were 9.7 ± 4.0 and 5.6 ± 2.7, respectively, the differences being significantly different (P < 0.05). These results were confirmed in a repeat experiment (P < 0.01). Gelatin zymography revealed that oral administration of SCPG did not affect the expression and activation of MMP-2 and MMP-9 in either serum or PC tissue. These results suggest that inhibition of pancreatic carcinogenesis by SCPG might involve a mechanism different from other synthetic-MMPs inhibitors.

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Mono-(2-ethylhexyl) phthalate (MEHP) is known to cause germ cell apoptosis in the testis of rats as a consequence of Sertoli cell damage. In the present study, a single dose of 2,000 mg/kg body weight MEHP was orally administered to Fischer 344 rats and the molecular apoptosis pathway was surveyed. Histopathological examination, TUNEL assay and immunohistochemical analysis of cleaved caspase-3 were performed to assess the reproducibility of apoptosis. In addition, immunohistochemical analysis and RT-PCR to determine the parameters of the apoptosis pathway were performed. Histopathological examination showed that from 6 to 12 hours after MEHP treatment there was detachment of germ cells that had eosinophilic cytoplasm and pyknotic nuclei. A TUNEL assay detected a significant increase in TUNEL-positive cells at 12 hours after treatment. Immunohistochemistry showed some of the cytoplasm of germ cells was positive for cleaved caspase-3 at 12 hours after treatment. In immunohistochemistry of the Fas/Fas ligand (FasL) apoptosis pathway, the cytoplasm of germ cells was found to be occasionally positive for Fas at 12 hours after treatment, and the expression of the Fas gene in RT-PCR had significantly increased at 12 hours after treatment. RT-PCR of the mitochondrial apoptosis pathway revealed a significant increase in the expression of Bax and Bcl-2 genes in the treated group at 12 hours after treatment. These results strongly suggest that both the Fas/FasL and mitochondrial pathways are involved in germ cell apoptosis induced by MEHP.

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Spontaneous hepatocellular intracytoplasmic inclusions were observed in a 4-year old male cynomolgus monkey used in a toxicity study. Histopathological findings of the inclusions revealed an eosinophilic ground glass appearance. The inclusions were positive for periodic acid Schiff and colloidal iron under diastase or hyaluronidase treatment, and they included microvacuoles which stained positive in oil red O. Ultrastructurally, the inclusions consisted of many lipid droplets with granular substances and disintegration of organelles, but there were had no limiting membrane around the inclusions. Any abnormal findings such as necrosis, inflammation or virus particles were not detected. Our case was considered to be a kind of a disease categorized under metabolic diseases with unknown mechanisms, and it might provide information as a historical control in the assessment of monkey toxicity studies.

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