Kenji Tokumo

Dose response effects of 2-acetylaminofluorene on DNA damage, cytotoxicity, cell proliferation and neoplastic conversion in rat liver

This study measured the effect of precise doses of 2-acetylaminofluorene (AAF) in inducing DNA damage, functional changes and neoplastic conversion in rat liver. Groups of male F344 rats at 9 weeks of age were exposed to cumulative doses of 0.5 or 2.0 mmol AAF per kg body weight given by gavage daily 5 days per week over an 8-week period and maintained with no further exposure for up to 8 weeks. Administration of AAF resulted in the formation of N-deoxyguanosin-(8-yl)-2-aminofluorene in liver DNA in relationship to dose. In centrilobular hepatocytes the zone of glutamine synthetase-expressing cells was reduced by exposure. By 8 weeks, but not at 4 weeks, the higher of the two doses of AAF provoked an increase in cell proliferation measured by immunohistochemical incorporation of bromodeoxyuridine. Altered hepatocellular foci expressing the placental form of glutathione transferase were induced by the high dose of AAF at 4 weeks, but not at the low dose. At 8 weeks the incidence of foci at the high dose was 79 times that induced by the low dose. These foci were highly proliferative. In animals exposed to AAF for 8 weeks and maintained for 4 weeks with no exposure, DNA adducts decreased by 80% and cell proliferation subsided by 80%, although the glutamine synthetase zone remained diminished. After discontinuation of AAF, the number of foci diminished by 50% and their proliferation subsided by 80% at 4 weeks, indicating a phenotypic reversion of many foci. With this protocol of administration of precise doses of AAF, we have established non-linearity of effects and a lack of correlation between DNA adduct formation and induction of cellular lesions. We suggest that doses in the range of those reported can be used to study the contribution of epigenetic and genotoxic effects in carcinogenesis and to study threshold events.

Cell proliferation induced in the kidneys and livers of rats and mice by short term exposure to the carcinogen p-dichlorobenzene

Cell proliferation in the kidneys and livers of rats and mice exposed short-term to p-dichlorobenzene (p-DCB) was evaluated by immunohistochemical measurement of bromodeoxyuridine (BrdU) incorporation into nuclei of DNA-synthesizing cells. p-DCB was given by gavage at two doses up to 600 mg/kg body weight for 4 days. The cumulative fraction of proliferating cells was increased in the proximal tubule epithelial cells of male rats at the high dose, but not at the low dose nor in females at either dose using gamma-glutamyl transferase reaction to identify tubular cells. Also, no increase in cell proliferation was found in mouse kidneys. The fractions of proliferating cells in the livers of rats and mice of both sexes were also increased. The increased cell proliferation in only male rat kidney and in the livers of mice of both sexes correlates with the reported carcinogenic effects of p-DCB in those tissues. However, the finding that p-DCB also induced cell proliferation in the livers of rats of both sexes, which were not a site of p-DCB-induced tumors in bioassays, and in female mice at the low dose, which was not affected by an increase in tumors, reveals a lack of concordance and indicates that acute induction of cell proliferation is not sufficient to lead to carcinogenesis.

Serotonin-containing EC cells in normal human gastric mucosa and in gastritis. Immunohistochemical, electron microscopic and autoradiographic studies.

Serotonin-containing EC cells in human fetal, infantile and adult stomachs both normal and affected by gastritis, were studied by immunohistochemical, electron microscopic and autoradiographic methods. EC cells were sparse in fetal and infantile stomachs, while they occurred in the lower half of the gastric mucosa in adult stomachs showing no atrophic changes and their distribution density was higher than that of D cells. With the progress of chronic gastritis, the number of EC cells gradually decreased, but intestinal type of EC cells appeared in intestinalized gastric mucosa, often showing hyperplasia. Most of EC cells showed argyrophil reaction, but only about 10-20% of them were positive with argentaffin. Epithelial cells with3H-TdR labeled nuclei were frequently detected in the gastric mucosa where EC cells were sparse or almost absent. Electron microscopically, EC cells had typical electron dense granules in both the normal gastric mucosa and in the intestinal metaplastic glands, but the number of secretory granules was greater in the latter than in the former. These findings suggested that EC cells are preferentially present in the gastric mucosa with a small number of labeled nuclei and have morphological heterogeneity.

Unusual Manifestation of Malignant Lymphoma of the Esophagus

Primary malignant lymphoma of the esophagus is very rare. We encountered three cases of esophageal malignant lymphoma, showing unusual manifestations radiologically and endoscopically. In all cases, the upper gastrointestinal series showed smooth swelling of folds resembling varices. Esophagoscopy showed smooth and soft longitudinal protruding lesions. A computed tomographic scan showed marked thickening of the esophageal wall. These cases were diagnosed by endoscopic giant forceps biopsy specimens as small-cell, diffuse type malignant lymphoma. We report the unusual manifestation of malignant lymphoma characterized by marked thickening of the esophageal wall.