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Objective <p>The influence of aromatic hydrocarbons (PAHs) structure on activating the aryl hydrocarbon receptor (AhR) was investigated.</p> Methods <p>In silico and in vitro assays were conducted using 20 PAHs and their halogenated and nitro derivatives as targets based on AhR activation as the initial molecular event.</p> Results <p>All PAHs can bind to AhR, and their binding ability is related to their molecular weight, as reflected by the Gibbs free energy of high molecular weight (HMW) PAHs binding to AhR is generally lower than that of low-molecular weight PAHs. Compared with the parent PAHs, substituent modification significantly enhances their binding affinity to AhR. Moreover, the conformational stability of the complex formed by HMW PAHs and their halogenated and nitro derivatives with AhR is higher, likely stabilized by key interactions with Phe12, Ile42, and Phe68. Their energetic contributions and key roles were further confirmed by free energy decomposition and amino acid mutation. Subsequently, studies in HepG2 cells confirmed that stronger binding activates AhR signaling, reflected by oxidative stress levels and the upregulation of CYP1A1 and CYP1B1. These results demonstrate that AhR activation is closely related to molecular structure.</p> Conclusion <p>These findings support toxicity risk assessment based on the structure–affinity–toxicity logical relationship and provide detailed molecular sites for studying the mechanism of action of PAHs on AhR, which may facilitate the development of AhR-targeted antagonists or modulators for mitigating PAH-induced toxicity.</p>

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Assessment of the toxicity of different PAHs and their derivatives via their binding ability to AhR in molecular details

  • 期刊论文

  • 发表日期：

    2026年4月20日

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  • Weiwei Zhu,
  • Yuxin Chen,
  • Xuanyu Hong,
  • Yi Chen,
  • Wei Chen,
  • Zedong Ouyang,
  • Shiheng Gui,
  • Ruifang Fan

摘要

Objective

The influence of aromatic hydrocarbons (PAHs) structure on activating the aryl hydrocarbon receptor (AhR) was investigated.

Methods

In silico and in vitro assays were conducted using 20 PAHs and their halogenated and nitro derivatives as targets based on AhR activation as the initial molecular event.

Results

All PAHs can bind to AhR, and their binding ability is related to their molecular weight, as reflected by the Gibbs free energy of high molecular weight (HMW) PAHs binding to AhR is generally lower than that of low-molecular weight PAHs. Compared with the parent PAHs, substituent modification significantly enhances their binding affinity to AhR. Moreover, the conformational stability of the complex formed by HMW PAHs and their halogenated and nitro derivatives with AhR is higher, likely stabilized by key interactions with Phe12, Ile42, and Phe68. Their energetic contributions and key roles were further confirmed by free energy decomposition and amino acid mutation. Subsequently, studies in HepG2 cells confirmed that stronger binding activates AhR signaling, reflected by oxidative stress levels and the upregulation of CYP1A1 and CYP1B1. These results demonstrate that AhR activation is closely related to molecular structure.

Conclusion

These findings support toxicity risk assessment based on the structure–affinity–toxicity logical relationship and provide detailed molecular sites for studying the mechanism of action of PAHs on AhR, which may facilitate the development of AhR-targeted antagonists or modulators for mitigating PAH-induced toxicity.