Xylene exposure, miR-181b-5p and miR-106b-5p alterations, and type 2 diabetes mellitus: Exploring relationship, mediation, and mechanism

Xylene is a widely encountered volatile organic compound, while little is known about its relationship with type 2 diabetes mellitus (T2DM) as well as possible roles of miR-181b-5p and miR-106b-5p, which are multifunctional microRNAs observed to be implicated in glucose metabolism, and the possible mechanisms. These uncharted territories warrant further investigation. In this case-control study of 138 newly developed T2DM adult patients and 138 matched healthy controls, urinary xylene exposure biomarkers (2-methyl hippuric acid [2MHA]; 3-methyl hippuric acid [3MHA]; 2MHA+3MHA [ΣUXYM]) and plasma miR-181b-5p/miR-106b-5p were measured. Relationships among xylene exposure biomarkers, miR-181b-5p/miR-106b-5p, and T2DM were estimated by generalized linear or logistic models. Potential roles of miR-181b-5p/miR-106b-5p in xylene-T2DM relationship were explored by mediation analyses. Network toxicology and molecular docking were performed to explore the hypothesis-generating pathway linking xylene and T2DM. We observed 2MHA (odds ratio=3.12; 95% confidence interval [CI]: 1.86∼5.24), 3MHA (2.12; 1.45∼3.10), ΣUXYM (2.33; 1.54∼3.54), miR-181b-5p (1.51; 1.25∼1.83), and miR-106b-5p (1.72; 1.42∼2.10) were positively related to T2DM odds. 2MHA was positively related to miR-181b-5p (β=0.40; 95% CI: 0.02∼0.78) and miR-106b-5p (0.56; 0.14∼0.98), which further accounted for 10.25% and 17.75% of the 2MHA-T2DM association, respectively. Peroxisome proliferator-activated receptor (PPAR) signaling pathway was enriched in the xylene-T2DM link, with potential molecular targets (estrogen receptor 1 [ESR1], etc.) identified. Target relationships between miR-181b-5p/miR-106b-5p and PPAR/ESR1 were predicted. Conclusively, exposure of general adults to xylene was positively associated with T2DM, which was partially explained by miR-181b-5p and miR-106b-5p, and PPAR signaling pathway and targets like ESR1 might be involved in the possible mechanisms.