The relationship of organophosphate flame retardants with hyperuricemia and gout via the inflammatory response: An integrated approach

Evidence regarding the relationships between organophosphate flame retardants (OPFRs) and hyperuricemia and gout as well as the underlying mechanisms remains scarce, but some evidence indicates that inflammation might play a key role. Using an integrated approach, we aim to elucidate the associations of urinary metabolite OPFRs (m-OPFRs) with hyperuricemia and gout. Cross-sectional analyses using data from the National Health and Nutrition Examination Survey were performed to reveal the associations. Adults with complete data on five m-OPFRs with high detection frequencies and outcomes were enrolled. We used multivariate logistic regression, restricted cubic spline (RCS), and Bayesian kernel machine regression (BKMR) methods to account for single, nonlinear, and joint effects. The mediating effect of the inflammatory response was also estimated. Moreover, adverse outcome pathways (AOPs) based on network analysis were further constructed to reveal the underlying mechanism. Multivariate logistic models revealed that bis(2-chloroethyl) phosphate (BCEP) significantly increased risk of hyperuricemia (OR [95 % CI]: 1.165 [1.047, 1.296]) in the fully adjusted model. Elevated levels of bis(1-chloro-2-propyl) phosphate were associated with gout (OR [95 % CI]: 1.293 [1.015, 1.647]). No nonlinear relationship was observed in RCS. There was a positive association between mixed m-OPFRs and hyperuricemia risk in BMKR, with bis(1,3-dichloro-2-propyl) phosphate and BCEP being the main contributors (PIP > 0.5). We found that the inflammatory response significantly mediated the association between BCEP and hyperuricemia (P < 0.05). Network topology analysis identified seven genes and six phenotypes related to OPFR exposure and hyperuricemia. The AOP framework suggested that the inflammatory response, especially the activation of the TNF pathway, played a core role in the above relationships. Our results first revealed that individual and mixed OPFRs were associated with hyperuricemia, in which the inflammatory response plays an important role. Further longitudinal studies are warranted to consolidate or refute our main findings.