RELATIVE SENSITIVITIES OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN-INDUCED CYP1A-1 AND CYP1A-2 GENE-EXPRESSION AND IMMUNOTOXICITY IN FEMALE B6C3F1 MICE
RELATIVE SENSITIVITIES OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN-INDUCED CYP1A-1 AND CYP1A-2 GENE-EXPRESSION AND IMMUNOTOXICITY IN FEMALE B6C3F1 MICE
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DOI：
10.1006/faat.1994.1146
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发表时间：
1994-11-01
期刊：
影响因子：
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通讯作者：
SAFE, S
中科院分区：
文献类型：
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作者：
NARASIMHAN, TR;CRAIG, A;SAFE, S
风险评估的改进要求通过确定目标组织剂量更好地将暴露与反应联系起来。在雌性B6C3F1小鼠体内，基于3个数量级的给药和靶组织剂量，比较了几种反应的相对敏感度。给药24小时后，在心、脾、肾、子宫、胸腺、肺和肝脏中检测到[H-3]TCDD，其中肝、子宫和肺中浓度最高。在5到25 ng/kg的剂量下，与胞浆和核亚细胞部分相关的肝脏[H-3]TCDD水平从占总肝脏水平的12%上升到62%，然后在更高的剂量下下降。在酶诱导研究中使用的两个最低剂量，5和10 ng/kg时，与[H-3]TCDD特异性结合的核受体复合体的水平分别为2.3和2.5fmol/mg蛋白。当剂量为25~100 ng/kg(即3.6~4.2fmol/mg蛋白)时，核内AhR复合体水平略高，而在500、1000和5000 ng/kg剂量下(分别为8.0、39.3和92.8fmol/mg蛋白)，核内AhR水平呈剂量依赖性增加。[H-3]TCDD对大鼠肝脏Cypla-1、Cypla-2基因表达及乙氧基间苯二酚O-脱乙基酶(EROD)活性的影响同时测定脾抗体空斑形成细胞(PFC)对绵羊红细胞的反应，后者在给药后第9天测定。在低于任何其他标记物的剂量(25 ng/kg)下观察到显著的肝脏CyplA-1诱导，随后在100 ng TCDD/kg和较高剂量下观察到每脾或每10(6)个细胞表达的EROD和PFC的诱导。当剂量大于或等于1000 ng/kg时，Cypla-2显著高于对照组。在所分析的变量中，PFCS/10(6)细胞的ED50值最低，与对照组(91+/-92 ng/kg)没有统计学差异。当剂量分别为736+/-132和1630+/-431 ng/kg时，Cypla-2和Cypla-1mRNA水平分别增加50%。由于PFC/脾反应的变异性和EROD活性的次极值诱导，无法计算这些反应的ED50值。分析表明，免疫抑制反应(当脾细胞数量归一化时)可能被低至90 ng TCDD/kg体重的剂量所抑制。在较高剂量(分别为1630或736 ng/kg)时，观察到Cypla-1或Cypla-2增加了50%。这表明，与所研究的其他变量相比，TCDD剂量较低时，免疫抑制反应会受到抑制。(C)1994年毒理学学会。
Improvements in risk assessment require better linkage of exposure to response by the determination of target tissue dose. The relative sensitivity of several responses in female B6C3F1 mice was compared on the basis of administered and target tissue dose spanning 3 orders of magnitude. Twenty-four hours after administration, [H-3]TCDD was detected in the heart, spleen, kidney, uterus, thymus, lung, and liver, and the highest concentrations were noted in the liver, uterus, and lung. At doses from 5 to 25 ng/kg, hepatic [H-3]TCDD levels associated with the cytosolic and nuclear subcellular fractions increased from 12 to 62% of the total liver levels and then decreased at higher doses. At the two lowest doses used in the enzyme induction study, 5 and 10 ng/kg, the levels of specifically bound nuclear Ah receptor complex liganded with [H-3]TCDD were 2.3 and 2.5 fmol/mg protein. Slightly higher levels of nuclear Ah receptor complex were observed at doses between 25 and 100 ng/kg (i.e., 3.6 to 4.2 fmol/mg protein) and a steep dose-dependent increase in nuclear Ah receptor levels was noted at doses of 500, 1000, and 5000 ng/kg (8.0, 39.3, and 92.8 fmol/mg protein, respectively). The dose-dependent effects of [H-3]TCDD on hepatic Cypla-1 and Cypla-2 mRNA levels, ethoxyresorufin O-deethylase (EROD) activity. and the splenic antibody plaque forming cell (PFC) response to sheep red blood cells were also determined; the latter response was determined 9 days after administration of TCDD. Statistically significant induction of hepatic Cypla-1 was observed at lower doses (25 ng/kg) than any other marker, followed by induction of EROD and PFCs expressed per spleen or per 10(6) cells which was observed at 100 ng TCDD/kg and at higher doses. Cypla-2 was elevated significantly relative to control at doses greater than or equal to 1000 ng/kg. The ED50 value for PFCs/10(6) cells was the lowest of the variables analyzed and was not statistically significantly different from control(91 +/- 92 ng/kg). A 50% increase in Cypla-2 and Cypla-1 mRNA levels was observed at doses of 736 +/- 132 and 1630 +/- 431 ng/kg, respectively. Due to variability in response in PFCs/spleen and the submaximal induction of EROD activity, ED50 values could not be calculated for these responses. The analyses indicate that the immunosuppressive response (when normalized for the number of spleen cells) may be depressed by administered doses as low as 90 ng TCDD/kg body weight. A 50% increase in Cypla-1 or Cypla-2 was observed at higher administered doses (1630 or 736 ng/kg, respectively). This suggests that the immunosuppressive response is depressed at lower doses of TCDD than the other variables studied. (C) 1994 Society of Toxicology.