The importance of biological realism in dioxin risk assessment models.
The importance of biological realism in dioxin risk assessment models.
复制标题
生物现实主义在二恶英风险评估模型中的重要性。
DOI：
10.1111/j.1539-6924.1994.tb00068.x
复制
发表时间：
1994
期刊：
影响因子：
--
通讯作者：
C. Portier
中科院分区：
文献类型：
--
作者：
M. Kohn;G. Lucier;C. Portier
建立了TCDD致雌性大鼠肝癌的机理数学模型，探讨了Ah、雌激素和EGF受体在TCDD致肝癌中的可能关系。每个模型生成的剂量-反应曲线的生物标志物肝蛋白CYP 1A 1，CYP 1A 2，和残留的质膜EGF受体的表达，随后暴露于TCDD。响应曲线的形状强烈依赖于这些蛋白质的组成型表达的假设机制。假设肝脏Ah受体水平恒定，计算肝脏CYP 1A 1对总肝脏TCDD的S形剂量反应。然而，列入诱导的Ah受体TCDD在生理上现实的剂量测定模型产生的CYP 1A 1的线性低剂量反应。这种行为被计算产生的净效应的亚线性响应的CYP 1A 1 mRNA的浓度的Ah-TCDD复合物和蛋白质浓度的mRNA水平的超线性响应，说明了生物现实主义的重要性，在剂量-反应建模。剂量测定模型还计算了TCDD对肝脏雌二醇浓度的影响，以及对EGF受体结合能力的影响，并提出了TCDD促进肿瘤的可能机制。将模型中的循环雌二醇水平设置为雄性大鼠的典型值，表明EGF受体反应和两性肿瘤发展差异的可能来源。
Mechanistic mathematical models of hepatocarcinogenesis in the female rat were constructed to investigate possible relationships among the Ah, estrogen, and EGF receptors in TCDD hepatocarcinogenicity. Each model generates dose-response curves for the expression of biomarker liver proteins CYP1A1, CYP1A2, and residual plasma membrane EGF receptor consequent to exposure to TCDD. The shapes of the response curves were strongly dependent on the assumed mechanisms of constitutive expression of these proteins. Assuming a constant level of the hepatic Ah receptor, a sigmoidal dose-response of hepatic CYP1A1 to total liver TCDD was computed. However, inclusion of induction of the Ah receptor by TCDD in a physiologically realistic dosimetric model produced a linear low-dose response of CYP1A1. This behavior was computed to arise from the net effect of sublinear response of CYP1A1 mRNA to the concentration of the Ah-TCDD complex and supralinear response of the protein concentration to the mRNA level, illustrating the importance of biological realism in dose-response modeling. The dosimetric model also computed effects of TCDD on the hepatic estradiol concentration and consequent effects on the binding capacity of the EGF receptor and suggests plausible mechanisms for tumor promotion by TCDD. Setting circulating estradiol levels in the model to values typical of the male rat indicated possible sources of the differences in the responses of the EGF receptor and in development of tumors in the two sexes.
登录
查看更多内容
雌激素 2- 和 4- 羟化酶活性、儿茶酚雌激素形成以及对仓鼠肾中雌激素致癌的影响。
影响因子：
11.2
作者：
Li,SA;Klicka,JK;Li,JJ
通讯作者：
Li,JJ
Ah 受体-配体结合的动力学和平衡研究：使用[125I]2-碘-7,8-二溴二苯并-对二恶英。
影响因子：
3.6
作者：
Bradfield,CA;Kende,AS;Poland,A
通讯作者：
Poland,A
二恶英可诱导人角质形成细胞中的转化生长因子-α。
DOI：
--
发表时间：
1991
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Choi,EJ;Toscano,DG;Ryan,JA;Riedel,N;ToscanoJr,WA
通讯作者：
ToscanoJr,WA
DOI：
10.1073/pnas.81.23.7407
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
MADHUKAR, BV;BREWSTER, DW;MATSUMURA, F
通讯作者：
MATSUMURA, F