Exposure to per- and polyfluoroalkyl substances, neonicotinoid insecticides, benzotriazoles and benzothiazoles: Associations with human non-alcoholic fatty liver disease

Evidence of the joint association between exposure to multiple environmental chemicals and non-alcoholic fatty liver disease (NAFLD) is scarce. In this study, 281 participants from Zhuhai, China (138 patients with NAFLD vs. 143 healthy participants) were recruited to explore the associations of 40 per- and polyfluoroalkyl substances (PFAS), 11 neonicotinoid insecticides (NEOs), and 8 benzotriazoles (BTRs) and benzothiazoles (BTHs) with the risk of NAFLD. Perfluorooctane sulfonate (PFOS) and its emerging alternatives (6:2 chlorinated polyfluorinated ether sulfonate [6:2 Cl-PFESA] and 8:2 fluorotelomer sulfonic acid [8:2 FTSA]), NEO metabolites (m-NEOs), BTR, and BTH were the predominant PFAS, NEOs, BTRs and BTHs, respectively. The total median concentrations of PFAS (20.4 ng/mL vs. 7.16 ng/mL) and NEOs (7.24 ng/mL vs. 6.23 ng/mL) in NAFLD group were significantly higher than those in healthy group. Sex differences in PFAS exposure have been observed among patients with NAFLD. 8:2 FTSA and short-chain PFAS were more predominant in female patients with NAFLD, whereas other emerging (i.e., 6:2 and 8:2 Cl-PFESA) and legacy PFAS (i.e., PFOS and long-chain perfluoroalkyl carboxylic acids) easily accumulated in male patients with NAFLD. The results of the multiple linear regression analysis indicated a significant positive association between PFOS and alanine transaminase (ALT) in serum samples from patients with NAFLD (β = 23.2, 95% confidence intervals (CI): 7.82, 38.5). Conversely, negative correlations were observed between 5-hydroxy-imidacloprid (5-OH-IMI) and γ-glutamyl transpeptidase (GGT) (β = −2.73, 95% CI: −5.29, −0.18), as well as between tolyltriazole (TTR) and total bilirubin (TBIL) (β = −0.70, 95% CI: −1.33, −0.08) and direct bilirubin (DBIL) (β = −0.59, 95% CI: −0.98, −0.20). The Bayesian kernel machine regression model revealed a positive joint effect of exposure to PFAS and NEO on elevated NAFLD outcomes, suggesting that exposure to PFAS and NEO might exacerbate the severity of NAFLD. This study fills the knowledge gap between multi-pollutant exposure and NAFLD risk.