Harnessing In Silico, In Vitro, and In Vivo Data to Understand the Toxicity Landscape of Polycyclic Aromatic Compounds (PACs)

Polycyclic
aromatic compounds (PACs) are compounds with a minimum
of two six-atom aromatic fused rings. PACs arise from incomplete combustion
or thermal decomposition of organic matter and are ubiquitous in the
environment. Within PACs, carcinogenicity is generally regarded to
be the most important public health concern. However, toxicity in
other systems (reproductive and developmental toxicity, immunotoxicity)
has also been reported. Despite the large number of PACs identified
in the environment, research attention to understand exposure and
health effects of PACs has focused on a relatively limited subset,
namely polycyclic aromatic hydrocarbons (PAHs), the PACs with only
carbon and hydrogen atoms. To triage the rest of the vast number of
PACs for more resource-intensive testing, we developed a data-driven
approach to contextualize hazard characterization of PACs, by leveraging
the available data from various data streams (in silico toxicity,
in vitro activity, structural fingerprints, and in vivo data availability).
The PACs were clustered on the basis of their in silico toxicity profiles
containing predictions from 8 different categories (carcinogenicity,
cardiotoxicity, developmental toxicity, genotoxicity, hepatotoxicity,
neurotoxicity, reproductive toxicity, and urinary toxicity). We found
that PACs with the same parent structure (e.g., fluorene) could have
diverse in silico toxicity profiles. In contrast, PACs with similar
substituted groups (e.g., alkylated-PAHs) or heterocyclics (e.g.,
N-PACs) with varying ring sizes could have similar in silico toxicity
profiles, suggesting that these groups are better candidates for toxicity
read-across analysis. The clusters/regions associated with certain
in silico toxicity, in vitro activity, and structural fingerprints
were identified. We found that genotoxicity/carcinogenicity (in silico
toxicity) and xenobiotic homeostasis and stress response (in vitro
activity), respectively, dominate the toxicity/activity variation
seen in the PACs. The “hot spots” with enriched toxicity/activity
in conjunction with availability of in vivo carcinogenicity data revealed
regions of either data-poor (hydroxylated-PAHs) or data-rich (unsubstituted,
parent PAHs) PACs. These regions offer potential targets for prioritization
of further in vivo assessment and for chemical read-across efforts.
The analysis results are searchable through an interactive web application
(https://ntp.niehs.nih.gov/go/pacs_tableau), allowing for alternative hypothesis generation.

多环芳香化合物（Polycyclic Aromatic Compounds, PACs）是指至少含有两个六元芳香稠环的化合物。这类化合物源于有机质的不完全燃烧或热解，广泛分布于各类环境介质中。在PACs的各类危害中，致癌性通常被视作最受关注的公共卫生议题，但现有研究也报道了其对其他生理系统的毒性效应，包括生殖发育毒性与免疫毒性。尽管环境中已鉴定出海量PACs，但针对其暴露水平与健康效应的研究，大多集中在一个相对狭窄的子集——仅由碳、氢元素构成的多环芳烃（Polycyclic Aromatic Hydrocarbons, PAHs）。
为了对剩余的大量PACs进行优先级排序，以开展资源消耗更高的验证性测试，我们开发了一种数据驱动的分析方法，通过整合多源数据（计算机模拟（in silico）毒性、体外活性、结构指纹以及体内数据可获得性）来表征PACs的危害特征。我们基于包含8类预测结果的计算机模拟毒性谱对PACs进行聚类，这8类毒性分别为：致癌性、心脏毒性、发育毒性、遗传毒性、肝毒性、神经毒性、生殖毒性及泌尿毒性。
研究发现，具有相同母核结构的PACs（如芴）可表现出截然不同的计算机模拟毒性谱；与之相反，取代基团相似的PACs（如烷基化PAHs）或不同环数的杂环PACs（如含氮PACs, N-PACs）却可呈现高度相似的计算机模拟毒性谱，这表明这类基团更适合作为毒性交叉参照分析的候选对象。
我们还识别出与特定计算机模拟毒性、体外活性及结构指纹相关的聚类区域。分析结果显示，PACs的毒性与活性差异主要由两部分主导：计算机模拟层面的遗传毒性/致癌性，以及体外实验层面的异生物质稳态与应激反应。结合体内致癌性数据的可获得性，我们发现富集毒性/活性的“热点区域”对应两类PACs：数据匮乏的羟基化PAHs，以及数据充足的未取代母核PAHs。这些区域可为后续体内评估的优先级确定以及化学物交叉参照研究提供潜在的靶向方向。
本分析的结果可通过交互式网络应用程序（https://ntp.niehs.nih.gov/go/pacs_tableau）进行检索，支持替代性研究假说的生成。