Differential toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6J mice congenic at the Ah Locus.
The acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in male C57BL/6J mice differing only at the Ah locus. Wild type mice (Ahb/b, "b/b") were treated once with 0, 50, 100, 200, 300, and 400 micrograms TCDD/kg po while congenic mice (Ahd/d, "d/d") received a single dose of 0, 400, 800, 1600, 2400, and 3200 micrograms TCDD/kg. Mice were checked daily, weighed twice a week, and those that survived, killed 35 days post-treatment. The LD50 values were 159 and 3351 micrograms/kg for b/b and d/d mice, respectively. Mean time to death was 22 days and was independent of dose and genotype. Decrease in body weight gain was noted in both strains 5 days after treatment and occurred at doses greater than or equal to 100 micrograms/kg in b/b mice and 1600 micrograms/kg in d/d mice. Dose-related increases in liver weight (both absolute and relative to body weight) and decreases in thymus, spleen, testes, and epididymal fat pad weights were observed at 8-24-fold higher doses in d/d than in b/b mice. A dose-related increase in segmented neutrophils was observed in both strains. Serum chemistry values indicated that 8-24X greater doses of TCDD were needed to elevate sorbitol dehydrogenase, alanine aminotransferase, and 5'-nucleotidase and to decrease total and esterified cholesterol in d/d than in b/b mice. Few effects were seen on total bile acids, serum triglycerides, glucose, or nonesterified cholesterol. In the liver, hepatocellular cytomegaly, fatty change, and bile duct hyperplasia occurred in both strains in a dose-related manner, as did thymic and splenic atrophy. Necrosis of germinal epithelium in the testes and edema in the stomach submucosa occurred at acutely toxic doses. These lesions also occurred at doses 8-24X greater in d/d than in b/b mice. Thus, the spectrum of toxicity is independent of the allele at the Ah locus, but the relative dose needed to bring about various acute responses is approximately 8-24X greater in congenic mice homozygous for the "d" allele than for the wild type animals carrying two copies of the "b" gene.
Birnbaum
L S
LS
Division of Toxicology and Research Testing, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
McDonald
M M
MM
Blair
P C
PC
Clark
A M
AM
Harris
M W
MW
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D004147:Dioxins / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D001189:Aryl Hydrocarbon Hydroxylases