Laboratoire d'Hématologie, Pavillon Lefevre, CHU Purpan, INSERM UMR 1037, Place Baylac, 31058 Toulouse Cedex, France.
Toxicology. 2013 Jun 7;308:74-87. doi: 10.1016/j.tox.2013.03.004. Epub 2013 Mar 22.
Consumers are exposed to a mixture of pesticides through their food intake. These compounds are considered risk factors for human health, and the impact of dietary exposure to low doses of pesticide mixtures remains poorly understood. For this study we developed a mouse model to mimic consumer exposure in order to compare the effect of pesticides both alone or combined at doses corresponding to their Acceptable Daily Intake value. Female mice were exposed to pesticides throughout gestation and lactation. After weaning pups were fed the same pesticide-enriched diet their mothers had received for an additional 11 weeks. A metabonomic approach using (1)H NMR-based analysis of plasma showed that exposure to each pesticide produced a specific metabolic fingerprint in adult offspring. Discriminant metabolites between groups were glucose or lactate, choline, glycerophosphocholine and phosphocholine. Interestingly, metabolite differences were observed as early as weaned animals that had not yet been directly exposed themselves. Studies of the hematopoietic system revealed that dietary exposure to one particular pesticide, endosulfan, produced a significant decrease in red blood cell and hemoglobin levels, consistent with hemolytic anemia. Moreover, cell signaling profiles of bone marrow progenitors were also clearly affected. Expression of cell signaling proteins such as P35, CDC27, FAK, P38 MAP kinase, calcineurin and caspase as well as proteins involved in the stability or structure of the cytoskeleton (vinculin, MAP2) was changed upon dietary exposure to pesticides. Finally, we found that dietary exposure to a mixture of pesticides had effects that differed and were often lesser or equal to that of the most efficient pesticide (endosulfan), suggesting that the effect of pesticide mixtures cannot always be predicted from the combined effects of their constituent compounds.
消费者通过食物摄入会接触到混合农药。这些化合物被认为是人类健康的风险因素，而饮食暴露于低剂量农药混合物的影响仍知之甚少。为此，我们开发了一种模拟消费者暴露的小鼠模型，以便比较单一农药以及在相当于其可接受日摄入量剂量下混合农药的作用。雌性小鼠在妊娠和哺乳期全程接触农药。断奶后，幼鼠被喂食其母亲在额外 11 周内接受的相同富含农药的饮食。使用基于 (1)H NMR 的血浆代谢组学分析方法表明，暴露于每种农药都会在成年后代中产生特定的代谢特征。组间差异代谢物为葡萄糖或乳酸、胆碱、甘油磷酸胆碱和磷酸胆碱。有趣的是，在尚未直接暴露的断奶动物中就已经观察到代谢物差异。对造血系统的研究表明，膳食接触一种特定的农药——硫丹，会导致红细胞和血红蛋白水平显著下降，与溶血性贫血一致。此外，骨髓祖细胞的细胞信号蛋白谱也明显受到影响。细胞信号蛋白如 P35、CDC27、FAK、P38 MAP 激酶、钙调神经磷酸酶和半胱天冬酶以及参与细胞骨架稳定性或结构的蛋白（纽蛋白、MAP2）的表达在膳食接触农药后发生改变。最后，我们发现膳食接触农药混合物的影响与单一最有效农药（硫丹）的影响不同，而且往往更小或相等，这表明农药混合物的影响不能总是从其组成化合物的综合效应来预测。
