Using in silico tools to predict flame retardant metabolites for more informative exposomics-based approaches.

IF 3.6 Q2 TOXICOLOGY
Frontiers in toxicology Pub Date : 2023-10-16 eCollection Date: 2023-01-01 DOI:10.3389/ftox.2023.1216802
Breanne Kincaid, Przemyslaw Piechota, Emily Golden, Mikhail Maertens, Thomas Hartung, Alexandra Maertens
{"title":"Using <i>in silico</i> tools to predict flame retardant metabolites for more informative exposomics-based approaches.","authors":"Breanne Kincaid, Przemyslaw Piechota, Emily Golden, Mikhail Maertens, Thomas Hartung, Alexandra Maertens","doi":"10.3389/ftox.2023.1216802","DOIUrl":null,"url":null,"abstract":"<p><p><b>Introduction:</b> The positive identification of xenobiotics and their metabolites in human biosamples is an integral aspect of exposomics research, yet challenges in compound annotation and identification continue to limit the feasibility of comprehensive identification of total chemical exposure. Nonetheless, the adoption of <i>in silico</i> tools such as metabolite prediction software, QSAR-ready structural conversion workflows, and molecular standards databases can aid in identifying novel compounds in untargeted mass spectral investigations, permitting the assessment of a more expansive pool of compounds for human health hazard. This strategy is particularly applicable when it comes to flame retardant chemicals. The population is ubiquitously exposed to flame retardants, and evidence implicates some of these compounds as developmental neurotoxicants, endocrine disruptors, reproductive toxicants, immunotoxicants, and carcinogens. However, many flame retardants are poorly characterized, have not been linked to a definitive mode of toxic action, and are known to share metabolic breakdown products which may themselves harbor toxicity. As U.S. regulatory bodies begin to pursue a subclass- based risk assessment of organohalogen flame retardants, little consideration has been paid to the role of potentially toxic metabolites, or to expanding the identification of parent flame retardants and their metabolic breakdown products in human biosamples to better inform the human health hazards imposed by these compounds. <b>Methods:</b> The purpose of this study is to utilize publicly available <i>in silico</i> tools to 1) characterize the structural and metabolic fates of proposed flame retardant classes, 2) predict first pass metabolites, 3) ascertain whether metabolic products segregate among parent flame retardant classification patterns, and 4) assess the existing coverage in of these compounds in mass spectral database. <b>Results:</b> We found that flame retardant classes as currently defined by the National Academies of Science, Engineering and Medicine (NASEM) are structurally diverse, with highly variable predicted pharmacokinetic properties and metabolic fates among member compounds. The vast majority of flame retardants (96%) and their predicted metabolites (99%) are not present in spectral databases, posing a challenge for identifying these compounds in human biosamples. However, we also demonstrate the utility of publicly available <i>in silico</i> methods in generating a fit for purpose synthetic spectral library for flame retardants and their metabolites that have yet to be identified in human biosamples. <b>Discussion:</b> In conclusion, exposomics studies making use of fit-for-purpose synthetic spectral databases will better resolve internal exposure and windows of vulnerability associated with complex exposures to flame retardant chemicals and perturbed neurodevelopmental, reproductive, and other associated apical human health impacts.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"5 ","pages":"1216802"},"PeriodicalIF":3.6000,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10613991/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in toxicology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3389/ftox.2023.1216802","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: The positive identification of xenobiotics and their metabolites in human biosamples is an integral aspect of exposomics research, yet challenges in compound annotation and identification continue to limit the feasibility of comprehensive identification of total chemical exposure. Nonetheless, the adoption of in silico tools such as metabolite prediction software, QSAR-ready structural conversion workflows, and molecular standards databases can aid in identifying novel compounds in untargeted mass spectral investigations, permitting the assessment of a more expansive pool of compounds for human health hazard. This strategy is particularly applicable when it comes to flame retardant chemicals. The population is ubiquitously exposed to flame retardants, and evidence implicates some of these compounds as developmental neurotoxicants, endocrine disruptors, reproductive toxicants, immunotoxicants, and carcinogens. However, many flame retardants are poorly characterized, have not been linked to a definitive mode of toxic action, and are known to share metabolic breakdown products which may themselves harbor toxicity. As U.S. regulatory bodies begin to pursue a subclass- based risk assessment of organohalogen flame retardants, little consideration has been paid to the role of potentially toxic metabolites, or to expanding the identification of parent flame retardants and their metabolic breakdown products in human biosamples to better inform the human health hazards imposed by these compounds. Methods: The purpose of this study is to utilize publicly available in silico tools to 1) characterize the structural and metabolic fates of proposed flame retardant classes, 2) predict first pass metabolites, 3) ascertain whether metabolic products segregate among parent flame retardant classification patterns, and 4) assess the existing coverage in of these compounds in mass spectral database. Results: We found that flame retardant classes as currently defined by the National Academies of Science, Engineering and Medicine (NASEM) are structurally diverse, with highly variable predicted pharmacokinetic properties and metabolic fates among member compounds. The vast majority of flame retardants (96%) and their predicted metabolites (99%) are not present in spectral databases, posing a challenge for identifying these compounds in human biosamples. However, we also demonstrate the utility of publicly available in silico methods in generating a fit for purpose synthetic spectral library for flame retardants and their metabolites that have yet to be identified in human biosamples. Discussion: In conclusion, exposomics studies making use of fit-for-purpose synthetic spectral databases will better resolve internal exposure and windows of vulnerability associated with complex exposures to flame retardant chemicals and perturbed neurodevelopmental, reproductive, and other associated apical human health impacts.

Abstract Image

Abstract Image

Abstract Image

使用计算机工具预测阻燃剂代谢产物,以获得更多基于暴露组学的信息。
引言:人类生物样本中外源性物质及其代谢产物的阳性鉴定是暴露组学研究的一个组成部分,但化合物注释和鉴定方面的挑战继续限制了全面鉴定总化学暴露的可行性。尽管如此,采用代谢物预测软件、QSAR结构转换工作流和分子标准数据库等计算机工具,可以帮助在非目标质谱研究中识别新化合物,从而评估更广泛的化合物库对人类健康的危害。这一策略尤其适用于阻燃化学品。人们普遍接触阻燃剂,有证据表明其中一些化合物是发育神经毒性物质、内分泌干扰物、生殖毒性物质、免疫毒性物质和致癌物质。然而,许多阻燃剂的特性很差,与确切的毒性作用模式没有联系,并且已知它们共享代谢分解产物,这些产物本身可能具有毒性。随着美国监管机构开始对有机卤素阻燃剂进行基于亚类的风险评估,很少考虑潜在有毒代谢物的作用,也很少考虑扩大人类生物样本中母体阻燃剂及其代谢分解产物的识别范围,以更好地了解这些化合物对人类健康的危害。方法:本研究的目的是利用公开的计算机工具来1)表征所提出的阻燃剂类别的结构和代谢命运,2)预测首次通过的代谢物,3)确定代谢产物是否在母体阻燃剂分类模式中分离,以及4)评估质谱数据库中这些化合物的现有覆盖范围。结果:我们发现,美国国家科学、工程和医学院(NASEM)目前定义的阻燃剂类别在结构上是多样化的,成员化合物之间预测的药代动力学特性和代谢命运变化很大。绝大多数阻燃剂(96%)及其预测代谢产物(99%)不存在于光谱数据库中,这对在人类生物样本中识别这些化合物构成了挑战。然而,我们也证明了公开可用的硅方法在生成阻燃剂及其代谢物的适合用途的合成光谱库方面的实用性,这些阻燃剂及其代谢产物尚未在人类生物样品中鉴定。讨论:总之,利用适合用途的合成光谱数据库进行暴露组学研究,将更好地解决与复杂暴露于阻燃化学品以及扰乱神经发育、生殖和其他相关顶端人类健康影响相关的内部暴露和脆弱性窗口。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
3.80
自引率
0.00%
发文量
0
审稿时长
13 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信