Correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in vascular endothelium with toxicity in early life stages of lake trout
Correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in vascular endothelium with toxicity in early life stages of lake trout
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DOI：
10.1006/taap.1996.8051
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发表时间：
1997-04-01
影响因子：
3.8
通讯作者：
Stegeman, JJ
中科院分区：
文献类型：
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作者：
Guiney, PD;Smolowitz, RM;Stegeman, JJ
脊椎动物在早期发育过程中暴露于2，3，7，8-四氯二苯并对二恶英（TCDD）会引起水肿和心血管功能障碍。本研究探讨细胞色素P4501 A（CYP 1A）诱导内皮细胞和其可能与死亡率由于水肿和血管效应的TCDD在湖鳟鱼的早期生命阶段。湖鳟鱼（Salvelinus namaycush）卵在受精后24-50小时注射0.2 μ l的50 mM磷脂酰胆碱脂质体或脂质体含有TCDD，得到7个剂量范围从11到176 pg TCDD/g卵。剂量的TCDD大于44 pg/g鸡蛋引起的水肿;卵黄囊，心包，脑膜水肿;颅面畸形;局部缺血;生长迟缓;和死亡率在囊鱼苗阶段的发展。CYP 1A的表达进行了评估，在四个发展阶段，通过免疫组化分析的单克隆抗体1-12-3硬骨鱼CYP 1A的个别鱼的连续切片。CYP 1A染色发生在许多器官的内皮细胞的TCDD暴露，但没有车辆暴露的胚胎在孵化前1周和囊鱼苗在孵化后2周。在任何剂量的TCDD下，检查的早期发育阶段的CYP 1A表达均为阴性。最强的反应发生在囊鱼苗在TCDD剂量大于sg pg TCDD/g鸡蛋，但在剂量低至22 pg TCDD/g鸡蛋检测。在孵化前胚胎和孵化后囊鱼苗中，内皮细胞的CYP 1A染色强度较低，而在其他细胞类型中染色强度较强。因此，血管系统是一个主要的初始网站TCDD在湖鳟鱼的早期生命阶段的影响，血管内皮细胞是一种细胞类型，独特的敏感性诱导CYP 1A在这些发展中的动物。根据CYP 1A免疫组化染色指数，TCDD诱导囊鱼苗内皮CYP 1A的ED 50为64-69 pg TCDD/g卵，与囊鱼苗发育阶段死亡率的剂量反应相似（LD 50 = 47 pg TCDD/g卵）。这里看到的相关性表明，CYP 1A或芳香烃受体（AhR）在内皮细胞可能与早期病变，导致TCDD诱导的血管紊乱，导致卵黄囊，心包，脑膜水肿，与湖鳟鱼囊鱼苗死亡率，但确切的机制仍有待确定。(C)北京：科学出版社.
Edema and cardiovascular dysfunction occur in vertebrates exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early development. This study examined cytochrome P4501A (CYP1A) induction in endothelium and its possible association with mortality due to the edema and vascular effects of TCDD in lake trout early life stages. Lake trout (Salvelinus namaycush) eggs were injected at 24-50 hr postfertilization with 0.2 mu l of 50 mM phosphatidylcholine liposomes or liposomes containing TCDD to give seven doses ranging from 11 to 176 pg TCDD/g egg. Doses of TCDD greater than 44 pg/g egg elicited hemorrhages; yolk sac, pericardial, and meningial edema; craniofacial malformations; regional ischemia; growth retardation; and mortality at the sac fry stage of development. Expression of CYP1A was assessed at four developmental stages, by immunohistochemical analysis of serial sections of individual fish with monoclonal antibody 1-12-3 to teleost CYP1A. CYP1A staining occurred in endothelial cells of many organs of TCDD-exposed but not vehicle-exposed embryos at 1 week prehatch and sac fry at 2 weeks posthatch. Earlier developmental stages examined were negative for CYP1A expression at any dose of TCDD. The strongest response occurred in sac fry at TCDD doses greater than sg pg TCDD/g egg but was detected at doses as low as 22 pg TCDD/g egg. CYP1A staining in endothelium appeared at lower doses and was stronger than that in other cell types, in both prehatch embryos and posthatch sac fry. Thus, the vascular system is a major initial site affected by TCDD in lake trout early life stages, and the vascular endothelium is a cell type uniquely sensitive to induction of CYP1A in these developing animals. Based on an index of immunohistochemical staining of CYP1A, endothelial CYP1A induction in sac fry by TCDD occurred with an ED50 of 64-69 pg TCDD/g egg, similar to the dose-response for mortality occurring during the sac fry stage of development (LD50 = 47 pg TCDD/g egg). The correlations seen here suggest that CYP1A or aryl hydrocarbon receptor (AhR) in the endothelium may be linked to early lesions that result in TCDD-induced vascular derangements leading to yolk sac, pericardial, and meningial edema that is associated with lake trout sac fry mortality, but the precise mechanism remains to be determined. (C) 1997 Academic Press.