低剂量、亚慢性下黄曲霉毒素B_(1)和微囊藻毒素LR诱导雄性野生型C57BL/6小鼠肝损伤/肝癌联合效应研究

Studies on the Combined Effects of Aflatoxin B_(1) and Microcystin LR on Liver Injury/Liver Cancer in Male Wild-type C57BL/6 Mice at Low Dose and Sub-chronic Condition

目的:本文旨在预测和评价低剂量、亚慢性下共暴露黄曲霉毒素B_(1)(AFB_(1))和微囊藻毒素LR(MC-LR)诱导肝癌以及肝损伤联合效应的强度及趋势,阐述膳食暴露场景下AFB_(1)+MC-LR诱导联合肝毒性效应发生的可能性及阈值空间,为制修订限量标准等科学管控措施提供依据。方法:基于雄性野生型C57BL/6小鼠,采用CI模型模拟结合合理外推,预测低剂量、亚慢性下AFB_(1)+MC-LR诱发小鼠肝癌的联合风险,同时结合5项典型生化靶标在血清及肝脏表达,初探肝损伤联合效应及规律。结果:当共暴露组AFB_(1)+MC-LR在0~20 mg/kg体重范围,小鼠肝癌CI指数概率在0~1.5范围,表明患癌风险主要表现为弱拮抗、弱协同或加和效应,其中弱加和和弱协同效应概率相对更高;等发生率比的共暴露组,血清和肝脏中5项生化指标总体表达均略高于单一组(P<0.05)。主成分分析证实协同效应概率相对更高;而非等发生率比的共暴露组,血清中除总胆红素(TBIL)、甲胎蛋白(AFP)外,共暴露组中任意单一组剂量变化会影响联合毒性表达(P<0.05),而肝脏共暴露组中单一组剂量变化会极显著影响联合效应表达(P<0.001)。结论:低剂量、亚慢性下AFB_(1)+MC-LR诱导肝癌及早期肝损伤主要呈现弱协同效应,单一毒素含量变化可能会显著影响肝损伤联合效应,在标准制定及监管中应得到重视。

Objective:This paper aimed to evaluate the probability of liver cancer combination and intensity of combined liver injury induced by AFB_(1)+MC-LR at low dose and sub-chronic conditions,and to promote the understanding the threshold and occurrence possibility of liver toxicity co-exposure to AFB_(1)+MC-LR at dietary scenarios,the results were helpful for risk control(e.g.MRLs setting).Methods:Based on the male wild-type C57BL/6 mice,CI model combined with scenarios extrapolating was used to predict the combined risk of hepatoma induced by AFB_(1)+MC-LR at low dose and sub-chronic condition.And then,according to the expression of 5 typical targets in serum and liver,the combined effects of liver injury were explored.Results:Within dose range of 0-20 mg/kg bw,the CI index was in the range of 0-1.5,which showed the probability of additive/synergistic effect was relatively higher.With the equal effect ratio,the overall expression of combined group related with five indicators was slightly higher than that of single component in the serum and liver(P<0.05),which was also confirmed by principal component analysis,the probability of synergistic effect was relatively higher than antagonistic and simple additive effects.With unequal effect ratio,except TBIL and AFP in serum,the change of any single component will affect the expression of combined toxicity(P<0.05),while the change of single dose in liver will significantly affect the expression of combined toxicity(P<0.001).Conclusion:The results showed that early liver injury induced by AFB_(1)+MC-LR was slight synergistic effect at low dose and sub-chronic condition,and the change of any single mycotoxin can affect the expression of combined liver injury in mixtures.It should be paid attention to in the standard making and supervision.