DIFFERENTIAL TOXICITY OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN C57BL/6J MICE CONGENIC AT THE AH LOCUS
DIFFERENTIAL TOXICITY OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN C57BL/6J MICE CONGENIC AT THE AH LOCUS
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DOI：
10.1016/0272-0590(90)90175-j
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发表时间：
1990-07-01
期刊：
影响因子：
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通讯作者：
HARRIS, MW
中科院分区：
文献类型：
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作者：
BIRNBAUM, LS;MCDONALD, MM;HARRIS, MW
本文研究了2，3，7，8-四氯二苯并-对二恶英(TCDD)对雄性C57BL/6J小鼠的急性毒性。野生型小鼠(ahb/b；“b/”b)一次性口服0、50、100、200、300和400微克TCDD/kg，而同源小鼠(Ahd/d、“d/d”)单次注射0、400、800、1600、2400和3200微克TCDD/kg。每天对小鼠进行检查，每周称两次体重，那些存活下来的小鼠在治疗后35天处死。对B/b和d/d小鼠的LD_(50)分别为159和3351微克/公斤。平均死亡时间为22天，与剂量和基因无关。在治疗5天后，两种菌株的体重增加都有所减少，并且在剂量为gtoreq时出现。B/b小鼠为100微克/公斤，d/d小鼠为1600微克/公斤。D/d剂量是b/b小鼠的8-24倍，与剂量相关的肝脏重量(绝对重量和相对体重)增加，胸腺、脾、睾丸和附睾脂肪垫重量减少。在两个菌株中都观察到了与剂量相关的节段性中性粒细胞增加。血清化学值显示8~24倍。与b/b小鼠相比，d/d小鼠需要更大剂量的TCDD来升高山梨醇脱氢酶、丙氨酸氨基转移酶和5‘-核苷酸酶，降低总胆固醇和酯化胆固醇。对总胆汁酸、血清甘油三酯、血糖或酯化胆固醇几乎没有影响。在肝脏中，两种菌株都以剂量相关的方式出现肝细胞肿大、脂肪改变和胆管增生，胸腺和脾萎缩也是如此。在急性中毒剂量下，睾丸生发上皮坏死和胃粘膜下层出现水肿。这些损害也发生在剂量的8-24倍。D/D小鼠大于B/B小鼠。因此，毒性谱与Ah位点上的等位基因无关，但引起各种急性反应所需的相对剂量约为8-24倍。与携带两个拷贝的“b”基因的野生型动物相比，携带“d”等位基因纯合的同源小鼠的风险更大。
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 .mu.g TCDD/kg po while congenic mice (Ahd/d, "d/d") received a single dose of 0, 400, 800, 1600, 2400, and 3200 .mu.g 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 .mu.g/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 .gtoreq. 100 .mu.g/kg in b/b mice and 1600 .mu.g/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 8-24 .times. 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 on esterified 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 8-24.times. greater in d/d than in b/b mice. Thus, the spectum of toxicity is independent of the allele at the Ah locus, but the relative dose needed to bring about various acute responses is approximately 8-24.times. greater in congenic mice homozygous for the "d" allele than for the wild type animals carrying two copies of the "b" gene.