Urinary synthetic phenolic antioxidants exposure and plasma microRNA signatures: A profile and functional analysis in a Chinese population-based study

Synthetic phenolic antioxidants (SPAs), recognized as contaminants of emerging concern, have been implicated in potential adverse health outcomes. Nevertheless, their epigenetic effects, particularly on plasma microRNAs (miRNAs) in humans, remain poorly characterized. This study aimed to investigate the associations between urinary concentrations of SPAs and plasma miRNA profiles, and further explore their potential biological functions. We quantified nine urinary SPAs in 142 Chinese adults by ultraperformance liquid chromatography-tandem mass spectrometry. Multivariate linear regression was employed to assess single-chemical relation, while multi-chemical associations were evaluated using two-way orthogonal partial least-squares analysis and weighted quantile sum regression. To explore the potential origin of SPA-related plasma miRNAs, we analyzed associations between miRNA levels in plasma and leukocytes. Leveraging leukocyte mRNA sequencing data and public databases, we performed pathway enrichment analysis to identify the pathways associated with SPA-associated miRNAs. We found that urinary 4-tert-Octylphenol and 2,6-di-tert-butyl-4-hydroxy-4-methyl-2,5-cyclohexadienone were significantly associated with 2 and 7 plasma miRNAs, respectively (False discovery rate < 0.10). Furthermore, mixed exposure to SPAs was associated with five miRNAs (miR-3135b, miR-769-5p, miR-548 k, miR-3188, miR-7705) in both two models. Notably, miR-769-5p and miR-3135b demonstrated consistent associations across all analytical approaches. The positive associations between plasma levels of miR-769-5p, miR-548 k, and miR-3188 and their corresponding intra-leukocyte levels ( P < 0.05) suggested that leukocytes might serve as a potential source of these miRNAs. Functional analyses identified that SPA-related miRNAs were involved in pathways related to neurotoxicity and cancers, which may inform future environmental risk assessments and support the development of evidence-based strategies for reducing population exposure to SPAs. • This study identified plasma miRNAs linked to multiple SPAs in urine. • 4-tOP and BHT-quinol were individually associated with 2 and 7 plasma miRNAs. • Multiple SPAs exposure was associated with 5 plasma miRNAs by O2PLS and WQS models. • MiR-769-5p and miR-3135b consistently associated with SPAs across various models. • SPA-associated miRNAs enriched in neurotoxicity and digestive/reproductive cancers.