Integrative toxicopathological evaluation of aflatoxin B₁ exposure in F344 rats.
Integrative toxicopathological evaluation of aflatoxin B₁ exposure in F344 rats.
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DOI：
10.1177/0192623313477256
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发表时间：
2013
影响因子：
1.5
通讯作者：
Wang JS
中科院分区：
文献类型：
--
作者：
Qian G;Wang F;Tang L;Massey ME;Mitchell NJ;Su J;Williams JH;Phillips TD;Wang JS
在这项研究中，雄性F344大鼠经口暴露于0、50、250或1，000 μg/kg体重（BW）的单剂量黄曲霉毒素B1（AFB 1）或0、5、10、25或75 μg/kg BW的重复剂量，持续5周。生化和组织学的变化进行了评估，连同形成的黄曲霉毒素B1-赖氨酸加合物（AFB-Lys）和胎盘型谷胱甘肽S转移酶（GST-P+）阳性肝灶。在单次给药方案中，血清天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和碱性磷酸酶（ALP）显示出剂量相关性升高，在治疗后第3天观察到最大变化（>100倍）。250 μg/kg AFB 1组第3天出现胆管增生、坏死和GST-P+肝细胞，第1周出现肝GST-P+灶。在重复给药方案中，75 μg/kg AFB 1暴露3周后，胆管增殖和肝脏GST-P+病灶同时发生，4周后形成增殖病灶，5周后ALT、AST和CK显著升高。肝脏GST-P+病灶诱导时间和剂量相关的方式。血清AFB-Lys在低剂量（5-25 μg/kg）时呈一过性升高，在75 μg/kg剂量组2周后达到最大值。本研究结果表明，F344大鼠肝脏GST-P+细胞和病灶是AFB 1毒性作用的敏感生物标志物，并与胆管增生和生化改变相关。
In this study, male F344 rats were orally exposed to a single dose of aflatoxin B1 (AFB1) at 0, 50, 250, or 1,000 μg/kg body weight (BW) or repeated dose of 0, 5, 10, 25, or 75 μg/kg BW for up to 5 weeks. Biochemical and histological changes were assessed together with the formation of AFB1-lysine adduct (AFB-Lys) and liver foci positive for placental form glutathione S transferase (GST-P+). In single-dose protocol, serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) showed dose-related elevation, with maximal changes observed (>100-fold) at day 3 after treatment. Animals that received 250 μg/kg AFB1 showed concurrent bile duct proliferation, necrosis, and GST-P+ hepatocytes at 3 day, followed by liver GST-P+ foci appearance at 1 week. In repeated-dose protocol, bile duct proliferation and liver GST-P+ foci co-occurred after 3-week exposure to 75 μg/kg AFB1, followed by proliferation foci formation after 4 week and dramatic ALT, AST, and CK elevations after 5 weeks. Liver GST-P+ foci were induced temporally and in a dose-related manner. Serum AFB-Lys increased temporally at low doses (5–25 μg/kg), and reached the maximum after 2-week exposure at 75 μg/kg. This integrative study demonstrated that liver GST-P+ cells and foci are sensitive biomarkers for AFB1 toxic effect and correlated with bile duct proliferation and biochemical alterations in F344 rats.