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

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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 downregulated serine palmitoyl 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 of CYP1A1, thereby interfering with lipid metabolism. • Interactions between PAH exposure and CYP1A1 rs4646421 increased the risk of childhood asthma. • CYP1A1 rs4646421 conferred childhood asthma susceptibility by having biological effects on CYP1A1 expression. • Specific lipid metabolites mediated the interaction of PAH exposure-genetic risk effect on childhood asthma. • The overexpression of CYP1A1 perturbed the synthesis of C16-ceramide via an AHR-induced decrease in serine palmitoyl transferase expression.

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