In silico Toxizitätsvorhersage der hitzebedingten Lebensmittelkontaminanten 3-MCPD, 2-MCPD und 2-MCPD-Dipalmitat und anschließende vergleichende proteomische Analyse substanzinduzierter molekularer Veränderungen in Leber, Niere, Hoden und Herz der Ratte

The detection of numerous Maillard reaction and lipid oxidation products in a variety of processed food such as grilled meat, coffee, edible plant oils and heated cereals did put a lot of pressure on federal consumer protection authorities. Due to the lack of sufficient data regarding toxicological characteristics, an adequate risk assessment for numerous heat-induced food contaminants is not possible. Therefore the possibilities of in silico predictions regarding the endpoints mutagenicity and cancerogenicity based on (quantitative) structure activity relationship (QSAR) was examined for more than 800 substances. For this approach, five software tools for mutagenicity prediction and three carcinogenicity prediction tools were used, all of them beeing freely available. The combination of the software tool output yielded a mutagenicity score or carcinogenicity score, which can be seen as a kind of putative toxicity index. A subsequent inquiry revealed good correlation between in silico prediction and available experimental data. For the substances 3-monochloro-1,2-propanediol (3-MCPD) and 2-monochloro-1,3-propanediol (2-MCPD), which were found amongst the top 10 rated compounds regarding the endpoint mutagenicity, a proteomic approach using a subacute 28-day toxicity study on male Wistar rats was issued to find out more about their toxicological characteristics. Despite their structural similarities, there was only small commonality of deregulated proteins between the chloropropanoles. Regardless of this, 2-MCPD and 3-MCPD showed similar toxic effects. The mechanism behind remains unrevealed. In addition, it was shown that 2-MCPD esterified with palmitic acid caused similar effects on the organs focused on in the current study indicating a release of free 2-MCPD. Possible synergistic effects based on real life mixtures of the substances examined in this study demand their discovery.在烤肉、咖啡、食用植物油及加热谷物等各类加工食品中检出大量美拉德反应（Maillard reaction）产物与脂类氧化产物，给联邦消费者保护主管部门带来了极大的监管压力。由于缺乏足够的毒理学特征数据，无法对众多热诱导食品污染物开展充分的风险评估。因此，本研究针对800余种物质，探究了基于（定量）构效关系（quantitative structure activity relationship，QSAR）开展致突变性与致癌性终点的计算机模拟（in silico）预测的可行性。本研究共使用5款致突变性预测软件工具与3款致癌性预测工具，所有工具均免费对外开放。整合各软件的输出结果可得到致突变性评分或致癌性评分，可视为一种推定毒性指数。后续验证结果显示，计算机模拟预测结果与现有实验数据具有良好的相关性。针对在致突变性终点评分位列前十的3-氯-1,2-丙二醇（3-monochloro-1,2-propanediol，3-MCPD）与2-氯-1,3-丙二醇（2-monochloro-1,3-propanediol，2-MCPD），本研究采用蛋白质组学方法，对雄性Wistar大鼠开展为期28天的亚急性毒性实验，以进一步探究二者的毒理学特征。尽管二者结构相似，但两种氯丙醇类物质间的差异表达蛋白仅存在少量共通性。即便如此，2-MCPD与3-MCPD仍表现出相似的毒性效应，其背后的作用机制尚未阐明。此外，研究发现与棕榈酸酯化的2-MCPD对本研究关注的脏器可产生相似效应，提示结合态2-MCPD可释放出游离的2-MCPD。本研究涉及的物质在真实场景中多以混合物形式存在，其潜在的协同效应仍有待进一步发掘。