Benzotriazole Ultraviolet Stabilizer UV-PS Exposure Induces Immune Hyperactivation and Metabolic Reprogramming in Drosophila in a Microbiota-Dependent Manner

Abstract Benzotriazole ultraviolet stabilizers (BUVSs) have raised ecological safety concerns due to their environmental persistence and bioaccumulation. Among them, 2-(2H-benzotriazol-2-yl)-4-tert-butylphenol (UV-PS) is frequently detected in various environments and biological media, with its aryl hydrocarbon receptor agonistic activity suggesting potential toxicity. However, its chronic toxic effects and underlying mechanisms remain unclear. This study employed male fruit fly (Drosophila melanogaster) as a model organism to explore chronic toxicity of UV-PS via a 14 day dietary exposure at 1–1000 μg/L. The results demonstrated that UV-PS induced phenotypic alterations in Drosophila, including weight loss, metabolic reprogramming, compromised intestinal barrier integrity, impaired locomotor activity, and decreased survival rates. Transcriptomic analysis revealed that response to oxidative stress and immune activation constitute the early molecular responses of toxic effects. Microbiome profiling further indicated that UV-PS altered gut microbial community structure, leading to shifts in specific bacterial family abundances that significantly correlated with immune pathway activation. In vitro S2 cells and in vivo germ-free fly experiments further confirmed that gut microbiota was essential for oxidative stress and immune hyperactivation. These findings provide novel evidence that UV-PS-induced chronic toxicity in male Drosophila involves a gut-immune-metabolic axis. Our work offers valuable insights into risk assessments of BUVSs.