Associations of per- and perfluoroalkyl substances with serum alanine and aspartate aminotransferase levels and the potential mediating role of cytokines in children

Evidence on the association of per- and perfluoroalkyl substances (PFAS) with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in children, and the underlying mechanisms are still unknown. This study aims to examine the associations of PFAS with ALT and AST, and the mediating role of cytokines in healthy children. A panel study was carried out using three repeated measurements of 11 plasma PFAS, serum ALT and AST, and 48 cytokines among 134 children in Wuhan, China. Linear mixed-effect models, Bayesian kernel machine regression, and weighted quantile sum regression were used to explore the individual and combined associations of PFAS with ALT and AST. The mediating function of cytokines in these associations was assessed using causal mediation analysis. Perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluoroundecanoic acid (PFUnDA), and perfluorododecanoic acid (PFDoDA) were found to have dose-response relationships with elevated ALT. PFAS mixture was associated with increased ALT in two mixed exposure models, with PFHxS identified as the major contributor. Such associations of PFAS and ALT were more evident in children who were overweight or obese and consumed fish ≥1 day/week. An integrated analysis revealed a group of children with elevated ALT levels, characterized by high PFAS exposure and increased cytokine levels. Four cytokines, including CCL 4, CCL27, IL-2Rα, and IL-9, were found to be associated with elevated levels of PFNA, PFHxS, PFUnDA, and ALT. Among them, CCL27 and IL-9 mediated 8.96 % and 12.06 % of the association of PFHxS with ALT, respectively. Our findings suggested that PFAS exposure was positively associated with ALT, and CCL27 and IL-9 might partially mediate PFAS-associated increased ALT among children.