The cell surface marker CD34 marks mouse hair follicle bulge cells, which have attributes of stem cells, including quiescence and multipotency. Using a CD34 knockout (KO) mouse, we tested the hypothesis that CD34 may participate in tumor development in mice because hair follicle stem cells are thought to be a major target of carcinogens in the two-stage model of mouse skin carcinogenesis. Following initiation with 200 nmol 7,12-dimethylbenz(a)anthracene (DMBA), mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Under these conditions, CD34KO mice failed to develop papillomas. Increasing the initiating dose of DMBA to 400 nmol resulted in tumor development in the CD34KO mice, albeit with an increased latency and lower tumor yield compared with the wild-type (WT) strain. DNA adduct analysis of keratinocytes from DMBA-initiated CD34KO mice revealed that DMBA was metabolically activated into carcinogenic diol epoxides at both 200 and 400 nmol. Chronic exposure to TPA revealed that CD34KO skin developed and sustained epidermal hyperplasia. However, CD34KO hair follicles typically remained in telogen rather than transitioning into anagen growth, confirmed by retention of bromodeoxyuridine-labeled bulge stem cells within the hair follicle. Unique localization of the hair follicle progenitor cell marker MTS24 was found in interfollicular basal cells in TPA-treated WT mice, whereas staining remained restricted to the hair follicles of CD34KO mice, suggesting that progenitor cells migrate into epidermis differently between strains. These data show that CD34 is required for TPA-induced hair follicle stem cell activation and tumor formation in mice. [Cancer Res 2007;67(9):4173-81]
A mycotoxin-producing strain of Fusarium moniliforme was isolated from southern leaf blight-damaged corn seed. A water-soluble toxin, subsequently purified from the fungus, had an oral median lethal dose of 4.0 milligrams per kilogram in 1-day-old cockerels. The toxin also produced plant growth-regulating and phytotoxic effects on plant systems. Physical and chemical data presented for the toxin suggest a structurally new toxin. The trivial name "moniliformin" has been assigned to the toxin.
No. 5 MOUSE COLON TUMOR MODEL 9 Corbett et al. 2661* Dosage conversion: to convert mg/kg in the mouse to mg/m* in humans, multiply by 3. That is, a dose of 5 mg/kg in the mouse is equal to 15 mg/m' in humans. (c, OI
Benzophenone, an aryl ketone, is used primarily as a photoinitiator and fragrance enhancer. Groups of 50 male and 50 female F344 rats and B6C3 F1 mice were fed diets containing 0, 312, 625, and 1, 250 ppm benzophenone for 105 weeks. Survival of males exposed to 1, 250 ppm benzophenone was significantly less than that of controls. There was a positive trend in the incidence of renal tubule adenoma in male rats; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Increased incidences of mononuclear cell leukemia were observed in male rats exposed to 312 or 625 ppm benzophenone and in female rats exposed to 625 ppm benzophenone. Liver lesions observed included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of rats. In mice, survival of all exposed groups was generally similar to that of the control groups. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1, 250 ppm groups. In female mice, the incidences of hepatocellular adenoma in the 625 and 1,250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. The incidences of kidney nephropathy in exposed groups of female mice, as well as the severity of nephropathy in exposed groups of males, were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1, 250 ppm mice. Rare histiocytic sarcomas were observed in female rats and mice in the 625 and 1,250 ppm groups.Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginal increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F 1 mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F 1 mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F 1 mice may have been related to benzophenone exposure.
Because the paired lobes (ventral, dorsal, lateral, and anterior) of the rat prostate have not been consistently sampled in many carcinogenicity and toxicity studies, comparison among different investigations has been compromised. The lack of specific site identification for prostatic lesions further lessens the value of incidences reported. We present here the lobe-specific incidences and degree of severity of background prostatic, seminal vesicular, and ampullary glandular lesions in 1768 control Fischer-344 rats from 35 recent National Toxicology Program 2-year carcinogenicity and toxicity studies conducted in 4 laboratories. The dorsal and lateral lobes were combined and considered the dorsolateral lobe where inflammation, epithelial degeneration, mucinous cysts, and edema were observed. Inflammation in the dorsolateral lobes was significantly associated with pituitary gland adenoma whose prolactin was suggested to play an important role in pathogenesis of prostatic inflammation. Epithelial degeneration, epithelial hyperplasia, inflammation, edema, and adenoma were conspicuous in the ventral lobes. Inflammation and edema occurred in the anterior lobes (coagulating glands). Inflammation, dilatation, epithelial hyperplasia, edema, and adenoma were observed in the seminal vesicles. Inflammation was also present in the ampullary glands. We suggest an optimal embedment and trimming method in rat prostate and seminal vesicle to ensure adequate, consistent sampling.
The concomitant administration of 20 micrograms 17 beta-estradiol and 4 mg progesterone/injection (5 days/week) over a 40-day treatment period beginning 10 days after methylnitrosourea (MNU) treatment was as effective as ovariectomy in inhibiting mammary cancers (an 84% reduction from non-hormone treated rats). The primary action of the hormones must have been directed at preneoplastic cells since the hormones were not given until 10 days after MNU (a direct-acting carcinogen with a short half-life).
Naphthalene administered by inhalation at concentrations of 10, 30, or 60 ppm for 6 hours per day, 5 days per week for 105 weeks caused nonneoplastic and neoplastic effects in nasal respiratory and olfactory regions of male and female F344/N rats. Non-neoplastic nasal effects were characterized by an increase in the incidence and severity of a complex group of lesions, including atypical hyperplasia, atrophy, chronic inflammation, and hyaline degeneration of olfactory epithelium; hyperplasia, squamous metaplasia, hyaline degeneration, and goblet cell hyperplasia of the respiratory epithelium; and hyperplasia and squamous metaplasia of mucosal glands. Neoplastic effects were characterized by the induction of two types of rare primary nasal tumors, olfactory neuroblastomas and respiratory epithelial adenomas. The incidences of olfactory neuroblastomas in males at 0 ppm, 10 ppm, 30 ppm, and 60 ppm were, respectively, 0%, 0%, 8%, and 6%, whereas in females they were 0%, 4%, 6%, and 24%. The incidences of respiratory epithelial adenomas in males at 0 ppm, 10 ppm, 30 ppm, and 60 ppm were, respectively, 0%, 12%, 17%, and 31% and in females 0%, 0%, 8%, and 4%. The olfactory neuroblastomas and respiratory epithelial adenomas were considered carcinogenic effects related to naphthalene exposure based on their relatively high incidence in exposed rats, their absence in concurrent control rats and NTP historical controls, and their rare spontaneous occurrence in rats of any strain.
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