U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Chemical Characterization and Exposure Division, Research Triangle Park, NC, USA.
Agilent Technologies, Santa Clara, CA, USA.
Environ Int. 2022 Sep;167:107385. doi: 10.1016/j.envint.2022.107385. Epub 2022 Jun 30.
Environmental health research has recently undergone a dramatic shift, with ongoing technological advancements allowing for broader coverage of exposure and molecular biology signatures. Approaches to integrate such measures are still needed to increase understanding between systems-level exposure and biology.
We address this gap by evaluating placental tissues to identify novel chemical-biological interactions associated with preeclampsia. This study tests the hypothesis that understudied chemicals are present in the human placenta and associated with preeclampsia-relevant disruptions, including overall case status (preeclamptic vs. normotensive patients) and underlying transcriptomic/epigenomic signatures.
A non-targeted analysis based on high-resolution mass spectrometry was used to analyze placental tissues from a cohort of 35 patients with preeclampsia (n = 18) and normotensive (n = 17) pregnancies. Molecular feature data were prioritized for confirmation based on association with preeclampsia case status and confidence of chemical identification. All molecular features were evaluated for relationships to mRNA, microRNA, and CpG methylation (i.e., multi-omic) signature alterations involved in preeclampsia.
A total of 183 molecular features were identified with significantly differentiated abundance in placental extracts of preeclamptic patients; these features clustered into distinct chemical groupings using unsupervised methods. Of these features, 53 were identified (mapping to 40 distinct chemicals) using chemical standards, fragmentation spectra, and chemical metadata. In general, human metabolites had the largest feature intensities and strongest associations with preeclampsia-relevant multi-omic changes. Exogenous drugs were second most abundant and had fewer associations with multi-omic changes. Other exogenous chemicals (non-drugs) were least abundant and had the fewest associations with multi-omic changes.
These global data trends suggest that human metabolites are heavily intertwined with biological processes involved in preeclampsia etiology, while exogenous chemicals may still impact select transcriptomic/epigenomic processes. This study serves as a demonstration of merging systems exposures with systems biology to better understand chemical-disease relationships.
环境健康研究最近发生了重大转变，持续的技术进步使得对暴露和分子生物学特征的更广泛的覆盖成为可能。为了增加对系统水平暴露和生物学之间的理解，仍需要采用整合这些措施的方法。
我们通过评估胎盘组织来识别与子痫前期相关的新的化学-生物学相互作用，以此来解决这一差距。本研究检验了一个假设，即在人类胎盘中存在被研究较少的化学物质，并且这些化学物质与子痫前期相关的紊乱有关，包括整体病例状态（子痫前期患者与血压正常的患者）和潜在的转录组/表观遗传组学特征。
采用基于高分辨率质谱的非靶向分析方法，分析了 35 例子痫前期（n=18）和血压正常（n=17）妊娠患者的胎盘组织。根据与子痫前期病例状态的关联和化学物质鉴定的置信度，对分子特征数据进行优先确认。评估了所有分子特征与涉及子痫前期的 mRNA、microRNA 和 CpG 甲基化（即多组学）特征改变之间的关系。
在子痫前期患者的胎盘提取物中鉴定出 183 种具有显著差异丰度的分子特征；这些特征使用无监督方法聚类成不同的化学分组。其中，使用化学标准品、碎片谱和化学元数据鉴定出 53 种特征（映射到 40 种不同的化学物质）。总体而言，人类代谢物的特征强度最大，与子痫前期相关的多组学变化的关联最强。外源性药物次之，与多组学变化的关联较少。其他外源性化学物质（非药物）最少，与多组学变化的关联最少。
这些全局数据趋势表明，人类代谢物与子痫前期病因学中涉及的生物学过程紧密交织在一起，而外源性化学物质可能仍然会影响特定的转录组/表观遗传组学过程。本研究展示了将系统暴露与系统生物学相结合，以更好地理解化学-疾病关系。
