Dietary protein and chronic toxicity of 1,2-dimethylhydrazine fed to mice.
1,2-Dimethylhydrazine-HCl (DMH-2HCl) is derived from the natural toxin cycasin, and is extensively used to induce cancers in experiments with rodents. We examined the toxicity of DMH-2HCl, incorporated into purified diets varying in protein, to determine concentrations compatible with long-term survival in B6C3H1 mice. Initial studies showed single-dose oral LD50 values (95% confidence intervals) of 26 (18-32) mg DMH-2HCl/kg body weight for males, and 60 (53-65) for females. A 6-wk study was performed with diets containing 10 or 40% soybean protein with doses of 0, 11.25, 22.5, 45, 90, and 180 mg DMH-2HCl/kg diet. All mice fed the highest dose were removed from the study due to severe toxicity. Declines in food consumption and body weight occurred in both sexes, accelerated with increasing log(DMH) dose, and were substantially more severe in groups fed 10% protein. A 5-mo study was subsequently performed with male mice fed 10 or 40% protein diets containing doses of 0, 15, 30, or 45 mg DMH-2HCl/kg diet. In this longer study, dose-related declines of food intake and body weight were also more pronounced with 10% protein. Histopathologic examination of samples from 29 organs/tissues revealed hepatic changes most commonly, and these were more severe at higher DMH levels. Lesions ranged from focal centrilobular hepatocellular necrosis to severe toxic hepatitis, associated with lobular disorganization and hepatocellular hypertrophy. Frequent dose-dependent lesions were also found in kidneys, adrenals, and heart. Renal changes included focal subcapsular fibrosis with atrophy, and hyperplasia of the tubular epithelium. Adrenal cortical hypertrophy was noted at the two highest DMH doses. Focal cardiac myocytolysis was also noted at high DMH doses. Renal damage occurred only rarely in the absence of liver pathology, and adrenal hypertrophy only rarely without renal damage. Cardiac myocytolysis was found in 14% of mice without hepatic, renal, or adrenal damage, but in 62% of those with lesions in each of those organs. No evidence of gastrointestinal toxicity was observed. Hepatic, renal, and adrenal lesions were more frequent and severe in mice fed the low-protein diet. The protective effect of high protein was DMH-dose dependent. The lower doses in these studies could be used to investigate effects of diet, cocarcinogens, or chemopreventative agents on carcinogenesis resulting from chronic, low-level dietary exposure to DMH.
Visek
W J
WJ
Department of Internal Medicine, University of Illinois, Urbana 61801.
Clinton
S K
SK
Imrey
P B
PB
Thursh
D R
DR
Truex
C R
CR
Alster
J M
JM
Anderson
P A
PA
Mabry
F J
FJ
Nandkumar
S
S
Simon
J
J
D019813:1,2-Dimethylhydrazine; D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004044:Dietary Proteins / Q000008:administration & dosage*; D004127:Dimethylhydrazines / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D012727:Sex Characteristics; D013737:Testis / Q000187:drug effects
D002273:Carcinogens; D004044:Dietary Proteins; D004127:Dimethylhydrazines; D019813:1,2-Dimethylhydrazine