Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts, 686 North Pleasant Street, Amherst, MA, 01003, USA.
Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts, 686 North Pleasant Street, Amherst, MA, 01003, USA.
Chemosphere. 2021 Jan;262:128362. doi: 10.1016/j.chemosphere.2020.128362. Epub 2020 Sep 18.
Targeted methods that dominated toxicological research until recently did not allow for screening of all molecular changes involved in toxic response. Therefore, it is difficult to infer if all major mechanisms of toxicity have already been discovered, or if some of them are still overlooked. We used data on 591,084 unique chemical-gene interactions to identify genes and molecular pathways most sensitive to chemical exposures. The list of identified pathways did not change significantly when analyses were done on different subsets of data with non-overlapping lists of chemical compounds indicative that our dataset is saturated enough to provide unbiased results. One of the most important findings of this study is that almost every known molecular mechanism may be affected by chemical exposures. Predictably, xenobiotic metabolism pathways, and mechanisms of cellular response to stress and damage were among the most sensitive. Additionally, we identified highly sensitive molecular pathways, which are not widely recognized as major targets of toxicants, including lipid metabolism pathways, longevity regulation cascade, and cytokine-mediated signaling. These mechanisms are relevant to significant public health problems, such as aging, cancer, metabolic and autoimmune disease. Thus, public health field will benefit from future focus of toxicological research on identified sensitive mechanisms.
直到最近，主导毒理学研究的靶向方法还不能筛选出所有与毒性反应相关的分子变化。因此，很难推断是否已经发现了所有主要的毒性机制，或者是否还有一些机制被忽视了。我们使用了 591084 个独特的化学-基因相互作用数据，来确定对化学暴露最敏感的基因和分子途径。当在具有不重叠的化学化合物列表的不同数据子集上进行分析时，确定的途径列表没有发生显著变化，这表明我们的数据集已经足够饱和，可以提供无偏的结果。这项研究的一个重要发现是，几乎每一个已知的分子机制都可能受到化学暴露的影响。可以预见的是，外源物质代谢途径和细胞对压力和损伤的反应机制是最敏感的。此外，我们还确定了一些高度敏感的分子途径，这些途径尚未被广泛认为是有毒物质的主要靶点，包括脂质代谢途径、长寿调控级联和细胞因子介导的信号转导。这些机制与重大的公共卫生问题有关，如衰老、癌症、代谢和自身免疫性疾病。因此，毒理学研究未来将集中在已确定的敏感机制上，这将使公共卫生领域受益。
