Methylparaben Induces Gut Microbiota–Dependent Neurotoxicity in Zebrafish

The neurotoxic effects of parabens have been previously proposed, however, the mechanisms driving its neurotoxicity remain largely uncharacterized. To better understand and identify the underlying mechanistic effects, methylparaben (MeP), the most common paraben produced, was exposed to embryonic zebrafish (Danio rerio) at environmentally relevant concentrations. Nontargeted and targeted metabolomics revealed that MeP primarily disrupted neurotransmitter-related metabolic pathways, leading to altered levels of gut microbiota associated neuroactive metabolites, suggesting impairment of neurobehavioral regulatory functions. Concurrently, MeP exposure significantly reduced locomotor activity, providing behavioral evidence for its neurotoxic effects. Comparisons between germ-free and conventionally reared zebrafish demonstrated that the absence of gut microbiota markedly alleviated MeP-induced neurotoxicity, as evidenced by weaker perturbations in neurotransmitter profiles and swimming behavior. Further, stable isotope-assisted high-resolution mass spectrometry revealed that gut microbes could reverse phase II detoxification through deconjugation reactions, regenerating MeP and enhancing systemic exposure. Overall, this study first reveals that MeP induces neurotoxicity through gut microbiota-mediated metabolic remodeling and biotransformation, providing new insights into the ecological risks of parabens.