Chemical-Specific Metabolic Disruption during Early Zebrafish Development is Modulated by the Microbiome

Environmental contaminants such as per- and polyfluoroalkyl substances, bisphenols, and agricultural fungicides are increasingly recognized as metabolic disruptors, yet how individual chemicals perturb metabolic pathways during early development remains incompletely understood. Here, we used targeted and untargeted metabolomics and pathway analysis in zebrafish embryos to characterize metabolic disruption induced by perfluorooctanesulfonic acid (PFOS), boscalid (BOS), and bisphenol F (BPF). Each compound elicited a distinct metabolic fingerprint, indicating chemical-specific patterns of metabolic stress rather than a uniform response across toxicants. Comparative analysis demonstrated divergence in central metabolic pathways, including mitochondrial metabolism, amino acid and nucleotide turnover, redox balance, and tryptophan metabolism. PFOS induced the most extensive metabolic perturbation, whereas BOS and BPF produced more restricted but distinct metabolic profiles. Comparison of germ-free and conventionally colonized embryos showed that host microbial status modulated the magnitude, but not the direction, of chemical-induced metabolic changes. These metabolic alterations align with exposure-specific transcriptional network modules, supporting distinct chemical modes of action. Together, these findings demonstrate that early life exposure to PFOS, BOS, and BPF results in chemically distinct metabolic stress phenotypes during development and illustrate how integrated metabolomic profiling can resolve compound-specific metabolic effects while accounting for contextual modifiers such as host microbial status.