Short-term tributyltin exposure initiates lipid-centered molecular programs linked to early neurotoxicity in zebrafish.

Tributyltin (TBT) is a persistent environmental contaminant with well-established endocrine-disrupting and obesogenic properties; however, the earliest molecular events linking short-term exposure to functional toxicity remain poorly resolved. In particular, it is unclear whether brief exposure during sensitive developmental windows is sufficient to initiate coordinated molecular programs with downstream neurofunctional consequences. Here, we investigated the effects of a short-term (24 h), environmentally relevant TBT exposure in zebrafish eleutheroembryos by integrating untargeted lipidomics and transcriptomics with neurotransmitter profiling and behavioral assessment. Such exposure was sufficient to disrupt lipid homeostasis, oxidative balance, and neurofunction, suggesting that aquatic organisms are far more sensitive to TBT than previously recognized. This work highlights the value of lipid-centered multi-omics integration for identifying mechanistic pathways affected by endocrine disruptors beyond classical assays. Lipidomics revealed a coordinated reorganization of lipid homeostasis, including depletion of fatty acids, sterols, and glycerophospholipids together with accumulation of glycerolipids, indicating early disruption of lipid metabolic balance. These lipid shifts were supported by transcriptomic reprogramming of lipid-related gene networks, identifying lipid-centered hub genes that explained the observed abundance patterns. Moreover, gene expression dysregulation was consistent with epigenomics and transcriptomics data from a longer exposure window (2-5 dpf), underscoring the robustness of early TBT alterations on lipid homeostasis, in addition to other RXR-related processes such as neurotoxicity and signaling disruption. Importantly, lipid-centered molecular alterations were accompanied by disruption of monoaminergic neurotransmitter profiles and transient behavioral impairments, linking early metabolic dysregulation to neurofunctional toxicity. Overall, this study demonstrates that short-term, environmentally relevant TBT exposure is sufficient to initiate lipid-centered molecular programs during early development, with measurable neurochemical and behavioral consequences.