Bryant P L, Schmid J E, Fenton S E, Buckalew A R, Abbott B D
Environmental Sciences and Engineering Department, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Toxicol Sci. 2001 Jul;62(1):103-14. doi: 10.1093/toxsci/62.1.103.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure produces hydronephrosis and cleft palate in mice. These responses are correlated with disruption of expression of epidermal growth factor (EGF) receptor ligands, primarily EGF and transforming growth factor-alpha (TGF-alpha), and altered epithelial cell proliferation and differentiation. This research examined the role of these growth factors in TCDD-induced teratogenicity by using wild type (WT) and knockout (-/-) mice that do not express EGF, TGF-alpha, or both EGF and TGF-alpha. Pregnant females were weighed on GD 12 and dosed by gavage with either corn oil or TCDD at 24 microg/kg, 5 ml/kg. On GD 17.5, the maternal parameters evaluated included body weight, body weight gain, liver weight (absolute and adjusted for body weight). The number of implantations, live and dead fetuses, early or late resorptions, the proportion of males, fetal body weight, fetal absolute and relative liver weight, placenta weight, incidence of cleft palate, and the severity and incidence of hydronephrosis were recorded. TCDD did not affect maternal weight gain, fetal weight, or survival, but maternal and fetal liver weights and liver-to-body weight ratios were increased in all genotypes. The WT and TGF-alpha (-/-), but not the EGF (-/-) and EGF + TGF-alpha (-/-) fetuses, developed cleft palate after exposure to 24 microg TCDD/kg. Hydronephrosis was induced by TCDD in all genotypes, with the incidence in EGF + TGF-alpha (-/-) fetuses comparable to that of the WT. The incidence and severity of this defect was substantially increased in EGF (-/-) and TGF-alpha (-/-). In conclusion, this study demonstrated that expression of EGF influences the induction of cleft palate by TCDD. Also, EGF and TGF-alpha are not required for the induction of hydronephrosis, but when either is absent the response of the fetal urinary tract to TCDD is enhanced.
2,3,7,8-四氯二苯并-对-二恶英（TCDD）暴露可导致小鼠出现肾积水和腭裂。这些反应与表皮生长因子（EGF）受体配体表达的破坏相关，主要是EGF和转化生长因子-α（TGF-α），并改变了上皮细胞的增殖和分化。本研究通过使用不表达EGF、TGF-α或同时不表达EGF和TGF-α的野生型（WT）和基因敲除（-/-）小鼠，研究了这些生长因子在TCDD诱导的致畸作用中的作用。在妊娠第12天对怀孕母鼠称重，并通过灌胃给予玉米油或24微克/千克、5毫升/千克的TCDD。在妊娠第17.5天，评估的母体参数包括体重、体重增加、肝脏重量（绝对重量和根据体重调整后的重量）。记录植入数、活胎和死胎数、早期或晚期吸收数、雄性比例、胎儿体重、胎儿绝对和相对肝脏重量、胎盘重量、腭裂发生率以及肾积水的严重程度和发生率。TCDD不影响母体体重增加、胎儿体重或存活率，但所有基因型的母体和胎儿肝脏重量以及肝体重比均增加。野生型和TGF-α（-/-）胎儿在暴露于24微克TCDD/千克后出现腭裂，但EGF（-/-）和EGF + TGF-α（-/-）胎儿未出现。TCDD在所有基因型中均诱导肾积水，EGF + TGF-α（-/-）胎儿的发生率与野生型相当。在EGF（-/-）和TGF-α（-/-）中，这种缺陷的发生率和严重程度显著增加。总之，本研究表明EGF的表达影响TCDD诱导的腭裂。此外，诱导肾积水不需要EGF和TGF-α，但当其中任何一种缺失时，胎儿泌尿道对TCDD的反应会增强。
