Susceptibility to Childhood Asthma Modified by the Interactive Effects of Polycyclic Aromatic Hydrocarbons Exposure and Genetic Polymorphisms of the Aryl Hydrocarbon Receptor Signaling Pathway - Functional Analysis Based on Lipid Metabolism

Sep 29, 2026

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Exposure to polycyclic aromatic hydrocarbons (PAHs) is linked to childhood asthma, yet the involved gene–environment mechanisms within the aryl hydrocarbon receptor (AHR) signaling pathway remain unclear. This study tested how PAH exposure interacts with AHR-pathway SNPs to shape childhood asthma risk and used metabolomics to characterize molecular pathways. Among 370 children, multiple PAH serum levels and CYP1A1 rs4646421 were associated with asthma, with rs4646421-mediated lipid metabolites supporting a functional role via CYP1A1 expression.

LanguageEnglish

CategoryHealthcare

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Tao et al. Respiratory Research (2026) 27:3 [https://doi.org/10.1186/s12931-025-03428-x](https://doi.org/10.1186/s12931-025-03428-x) Respiratory Research RESEARCH Open Access Susceptibility to childhood asthma modified by the interactive effects of polycyclic aromatic hydrocarbons exposure and genetic polymorphisms ofthe aryl hydrocarbon receptor signaling pathway: functional analysis based on lipid metabolism Xuna Tao 1†, Xinfeng Xu 1†, Xinyao Jiang 1, Mingcong Chen2, Yuling Bao3, Shuyuan Cao 1, Lei Li 1, Sheng Yang4* and Qian Wu 1* Abstract Exposure to polycyclic aromatic hydrocarbons (PAHs) is linked to the development of childhood asthma, but little is known about PAH exposure-single nucleotide polymorphisms (SNPs) involved in the aryl hydrocarbon receptor (AHR) signaling pathway interactions on childhood asthma. This study aimed to investigated the effects of PAH exposure interactions with SNPs in the AHR signaling pathway on childhood asthma and characterized the molecular pathway of asthma genetic risk based on the metabolome. A total of 370 children were included in the current study. Serum fluoranthene, benz(a)anthracene, chrysene, benzo(k)fluoranthene and benzo(a) pyrene levels were significantly associated with childhood asthma. SNP genotyping analysis revealed that CYP1A1 rs4646421 was significantly associated with childhood asthma (OR: 2.404, 95% CI: 1.542–3. 747) in Chinese children. Generalized multifactor dimensionality reduction analysis showed significant interactions between PAH exposure and rs4646421, increasing the risk of childhood asthma. Expression quantitative trait loci analysis showed that the rs4646421-AA genotype was significantly associated with the increased expression of CYP1A1 . Mediation analysis identified six serum lipid metabolites associated with rs4646421 that mediated the effect of the rs4646421-AA genotype on childhood asthma. To verify the potential biological function of rs4646421, a model of CYP1A1-overexpressing human bronchial epithelial cells was constructed. The results showed that CYP1A1 overexpression †Xuna Tao and Xinfeng Xu co-first authors have equal contributions to the work. *Correspondence: Sheng Yang [yangsheng@njmu.edu.cn](yangsheng@njmu.edu.cn)[ ](yangsheng@njmu.edu.cn)Qian Wu [wuqian@njmu.edu.cn](wuqian@njmu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. downregulated serine pal mitoyl transferase expression by decreasing AHR/ARNT2 levels, and subsequently reduced C16-ceramide synthesis and upregulated the expression of inflammatory factors associated with asthma in the human bronchial epithelial cells. This study provided the evidence of the interactions between PAH exposure and CYP1A1 rs4646421 in increasing childhood asthma susceptibility in Chinese, suggesting that rs4646421 played a functional role in childhood asthma by affecting the expression

FAQs

Which PAH exposures were associated with childhood asthma in this study?

Serum fluoranthene, benz(a)anthracene, chrysene, benzo(k)fluoranthene, and benzo(a)pyrene levels showed significant associations with childhood asthma.

What genetic variant was linked to childhood asthma susceptibility?

CYP1A1 rs4646421 was significantly associated with childhood asthma risk in Chinese children, with increased odds reported for carriers.

How did the study connect rs4646421 with asthma through biological mechanisms?

Interactions between PAH exposure and rs4646421 increased asthma risk; eQTL and mediation analyses indicated CYP1A1 expression changes and mediation by specific serum lipid metabolites, supported by functional cell model results.

Sep 29, 2026

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