身体内的羟基代谢物被认为是新兴污染物（ECs）和乳腺癌暴露的潜在生物标志物，但它们的形成机制没有得到足够的关注。此外，代谢转化期间代谢产物的负面影响很大程度上仍然未知。在本研究中，我们采用密度泛函计算结合人肝微粒体体外孵育来探索人体中防腐剂甲基对羟基苯甲酸酯（MPB）的生物转化。我们的结果表明，MPB的羟基代谢产物（OH-MPB）在实验中被观察到，并揭示了分子水平上的形成机制。也就是说，羟基代谢物是通过从MPB的苯酚羟基中选择性地进行氢剥夺，随后通过OH反弹途径生成的，而不是直接在苯环上进行羟基化。ECs上的羟基基团数量的增加可以改善代谢反应。这在没有羟基基团和具有多个羟基基团的ECs代谢中得到了证实。此外，毒性评估表明，与原始MPB相比，羟基代谢物对胃肠系统和肝脏具有更大的负面影响。半醌产物对心血管系统有潜在的损害作用，环氧物对血液和胃肠系统有毒性。这些发现加深了我们对人体健康中对对羟基甲苯酸酯类物质的生物转化的认识，特别是通过提供半醌和环氧物可能产生的潜在影响的健康警告。版权所有 © 2023作者。由Elsevier Ltd.出版。保留所有权利。

Hydroxylated metabolites in the living body are considered as a potential biomarker of exposure to emerging contaminations (ECs) and breast cancer, but their formation mechanism has not received enough attention. Besides, the adverse impacts of metabolites during the metabolic transformation of ECs largely remain unknown. In this study, we employed a density functional calculation combing with in-vitro incubation of human liver microsomes to explore the bio-transformation of preservative methylparaben (MPB) in human bodies. Our results showed that hydroxylated metabolites of MPB (OH-MPB) were observed experimentally, while a formation mechanism was revealed at the molecular level. That is, hydroxylated metabolite was exclusively formed via the hydrogen abstraction from the phenolic hydroxyl group of MPB followed by the OH-rebound pathway, rather than the direct hydroxylation on the benzene ring. The increasing of hydroxyl groups on ECs could improve the metabolisms. This was confirmed in the metabolism of ECs without hydroxyl group and with multiple-hydroxyl groups, respectively. Furthermore, toxicity assessments show that compared to parent MPB, the hydroxylated metabolites have increased negative impacts on the gastrointestinal system and liver. A semiquinone product exhibits potential damage in the cardiovascular system and epoxides are toxic to the blood and gastrointestinal system. The findings deepen our insight into the biotransformation of parabens in human health, especially by providing health warnings about the potential impacts caused by semiquinone and epoxides.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.