The ability of methyl-deficient, amino acid-defined diets to produce liver tumors was studied in rats treated both with and without initiating doses of diethylnitrosamine (DENA). Male, weanling F344 rats were fed a complete, amino acid-defined diet for one week. They were then injected once i.p. with one of 3 doses of DENA (20, 70 or 200 mg/kg body weight) and fed the complete diet for an additional week. Thirty animals from each dose group were then maintained for 76 weeks on the complete diet (Diet 1) or one of 4 methyl-deficient diets: Diet 2, devoid of methionine and choline; Diet 3, devoid of methionine only; Diet 4, devoid of choline only and Diet 5, devoid of methionine, choline, folic acid and vitamin B12. In Diets 2, 3 and 5 methionine was replaced by equimolar amounts of its metabolic precursor DL-homocystine. Control rats were injected i.p. with the saline vehicle and maintained for the 76-week period on Diets 1 and 2. Forty percent of the rats fed Diet 2, but receiving no DENA, developed hepatocellular carcinomas or cholangiomas. A 90-100% incidence of hepatocellular carcinomas was seen in all groups initiated with DENA and fed Diet 2. No malignant liver tumors developed in Diet 1 rats that had received 0 or 20 mg/kg DENA; however, hepatocellular carcinomas were noted in one-half of such animals receiving the 70 and 200 mg/kg doses. Liver metastases grew in the lungs of 60% of the tumor-bearing rats fed Diet 2; none were seen in the Diet 1-fed rats. The singly deficient Diets 3 and 4 enhanced liver tumor formation to DENA-initiated rats to a significantly lesser extent than did Diet 2. All DENA-initiated rats fed the severely deficient Diet 5, died within 23 experimental weeks with livers containing hepatocytes of atypical appearance and, particularly at the 2 higher dosages, a cirrhotic pseudonodular architecture. No hepatocellular carcinomas or cholangiomas were observed in Diet 5-fed rats. None of the diets tested appeared to enhance tumor formation in extrahepatic tissues. In fact, significant decreases were noted in the formation of spontaneous testicular interstitial cell tumors in Diet 2-fed rats and of pancreatic acinar tumors in rats fed Diets 2 and 3. Diet 2, devoid of both methionine and choline, also induced metaplasia of pancreatic acinar cells to hepatocyte-like cells and was associated with moderate to severe hyperplasia of the transitional epithelium lining the renal pelvis.(ABSTRACT TRUNCATED AT 400 WORDS)
Potentially preneoplastic hepatocellular hyperplastic foci and hepatocellular neoplasms were studied in weanling male B6C3F1 mice that received a single i.p. injection (80 mg/kg) of diethylnitrosamine (DEN) at 4 weeks of age, followed by oral administration of phenobarbital (PB) or di(2-ethylhexyl)-phthalate (DEHP) that began 2 weeks after DEN injection and continued for up to 6 months. PB was administered in drinking water at 500 p.p.m. and DEHP in the feed at 3000, 6000 or 12 000 p.p.m. Groups of mice were sacrificed at 2, 4 and 6 months after DEN exposure; formalin-fixed liver samples were evaluated histologically. Hepatocellular neoplasms and foci of hyperplasia were quantified with the aid of an image analysis computer. Few foci were seen at 2, 4 or 6 months in mice exposed to DEN, PB or DEHP alone, while numerous foci and neoplasms were seen in mice given DEHP or PB after DEN. Area-perimeter measurements for each hepatocellular focus or neoplasm transection revealed that foci and neoplasms in PB-exposed mice increased both in size (area and volume) and in number throughout the study. In DEHP-exposed mice the pattern of response was different in that the numbers of foci did not increase between 4 and 6 months, but the foci increased in mean diameter and volume throughout the experiment. Foci and tumors appeared earlier in mice given higher dietary levels of DEHP than in those given lower doses. By the end of the study the number of foci per unit volume of liver was similar in mice given any dose of DEHP, but their volume was dose-related. Hepatocellular foci and neoplasms in PB-exposed mice were composed predominantly of eosinophilic hepatocytes, while in DEHP-exposed mice, basophilic foci and neoplasms predominated; the latter were more malignant in appearance than neoplasms in PB-exposed mice. At 6 months, the neoplasms in high dose DEHP-exposed mice were significantly larger than those in PB exposed mice. Histochemistry, however, revealed similarities between lesions in mice exposed to PB or DEHP. PB given continuously for 6 months revealed no initiating activity of DEHP given once by gavage and followed by PB in drinking water. Both morphology and biology of hepatocellular foci and neoplasms, which develop in mice after a single exposure to a carcinogen with initiating activity, thus depend, in part, on the subsequent promoting agent. More than one process of tumor promotion, as characterized by a specific sequence of morphologic and biochemical changes, is possible for the mouse hepatocyte.
Experiments were conducted to study the acute inhalation toxicity of T-2 mycotoxin in both young adult and mature mice. For a 10-min aerosol exposure, the 24-hr LC50 of T-2 mycotoxin in young adult mice was 0.08 +/-0.04 mg T-2/liter air and that for mature mice was 0.325 +/-0.1 mg T-2/liter air. Deaths among mice exposed to the higher aerosol concentrations used in this study (i.e., 1.5 to 2.4 mg T-2/liter air) occurred in less than 5 hr. General clinical symptoms in these animals immediately postexposure were tremors, lethargy, stilted gait, and, in some animals, prostration. In experiments separate from the concentration-response studies, total deposition of T-2 aerosol and selective retention of T-2 in the respiratory tract and nasal turbinates were determined analytically from 3H-labeled T-2. When total deposition of T-2 was quantitated, there was excellent agreement between that amount of T-2 deposited and that amount of T-2 predicted from calculations based on aerosol size and animal minute volume. Based on the aerosol deposition data, the LD50 values of T-2 mycotoxins was 0.24 mg/kg for young adult mice and 0.94 mg/kg for mature mice. For mice, inhalation of T-2 mycotoxin is at least 10 times more toxic than systemic administration (LD50 approximately 4.5 mg/kg) and at least 20 times more toxic than dermal administration (LD50 greater than 10 mg/kg).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.