EGF and TGF-α expression influence the developmental toxicity of TCDD:: Dose response and AhR phenotype in EGF, TGF-α, and EGF plus TGF-α knockout mice
EGF and TGF-α expression influence the developmental toxicity of TCDD:: Dose response and AhR phenotype in EGF, TGF-α, and EGF plus TGF-α knockout mice
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DOI：
10.1093/toxsci/71.1.84
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发表时间：
2003-01-01
影响因子：
3.8
通讯作者：
Schmid, JE
中科院分区：
文献类型：
--
作者：
Abbott, BD;Buckalew, AR;Schmid, JE
环境毒物2，3，7，8-四氯二苯并对二恶英（TCDD）可引起小鼠腭裂和肾积水。这些缺陷的病因分别涉及第二腭架和输尿管上皮细胞的过度增殖。这些效应与表皮生长因子受体（EGFR）、表皮生长因子（EGF）和转化生长因子-α（TGF-α）的表达改变相关。在这项研究中，TCDD的发育毒性在EGF，TGF-α，和双EGF + TGF-α基因敲除（-/-）和野生型（WT）小鼠中进行了检查。背景遗传学的影响，TCDD的反应性进行了检查，使用肝脏7-乙氧基试卤灵-O-脱乙基酶（EROD）的活性。在妊娠第12天，动物通过灌胃给予0、0.2、1、5、24、50、100或150 μ g TCDD/kg（5 ml/kg）体重。WT、EGF（-/-）和EGF + TGF-α（-/-）的混合遗传背景使这些小鼠相对于具有C57 BL背景的C57 BL/6 J和TGF-α（-/-）对TCDD的反应较低。这些结果表明，EGF和TGF-α是不需要的TCDD的反应，然而，可用于结合EGFR的特异性配体影响的TCDD的反应。EGF（-/-）小鼠对CP的反应较低，但对HN更敏感。TGF-α（-/-）小鼠对CP和HN诱导的敏感性与WT相似。EGF + TGF-α（-/-）小鼠的反应与WT相似，但在较高剂量下对CP的敏感性增加，表明反应可能由EGFR的替代配体介导，这些配体不是EGF或TGF-α的功能等同物。总之，EGFR途径在胚胎对TCDD的反应中是重要的机制。特异性配体赋予靶组织依赖性的敏感性或抗性。
The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate (CP) and hydronephrosis (HN) in mice. The etiology of these defects involves hyperproliferation of epithelial cells of the secondary palatal shelf and ureter, respectively. These effects correlate with altered expression of the epidermal growth factor receptor (EGFR), epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha). In this study, the developmental toxicity of TCDD was examined in EGF, TGF-alpha, and double EGF + TGF-alpha knockout (-/-) and wild type (WT) mice. The influence of background genetics in responsiveness to TCDD was examined using liver 7-ethoxyresorufin-O-deethylase (EROD) activity. Animals were dosed by gavage with 0, 0.2, 1, 5, 24, 50, 100, or 150 mug TCDD/kg (5 ml/kg) body weight on gestation day 12. The mixed genetic background of WT, EGF (-/-), and EGF + TGF-alpha (-/-) made these mice less responsive to TCDD relative to C57BL/6J and TGF-alpha (-/-), which have a C57BL background. These results show that EGF and TGF-a are not required for response to TCDD; however, the specific ligand available to bind EGFR affects the responsiveness to TCDD. EGF (-/-) mice are less responsive for CP, but more sensitive to HN. TGF-alpha (-/-) mice were similar to WT in sensitivity for induction of CP and HN. The responses of EGF + TGF-alpha (-/-) mice were like the WT except at higher doses where sensitivity to CP increased, suggesting that the responses may be mediated by alternative ligands for EGFR that are not functional equivalents of EGF or TGF-alpha. In conclusion, the EGFR pathway is mechanistically important in responses of the embryo to TCDD. Specific ligands confer sensitivity or resistance that are target tissue-dependent.