Transcriptome and metabolome analysis reveal the effects of Tb (III) exposure on zebrafish (Danio rerio) embryonic development

Rare earth elements (REEs) represent emerging environmental contaminants with increasing global concern due to intensive mining activities. This study employed an integrated transcriptomic-metabolomic approach, coupled with an in-depth computational network analysis, to elucidate the systemic toxicity of terbium (Tb³⁺) in zebrafish embryos exposed to environmentally relevant concentrations (0.25-10.0 mg/L). Tb³⁺ exposure induced dose-dependent developmental toxicity, including growth retardation, hyperactive locomotion, and cardiovascular dysfunction. We have performed multi-omics network analysis and identified four critical, high-centrality metabolic hubs that orchestrate this toxicity, including Guanosine monophosphate (GMP), Gamma-Aminobutyric acid (GABA), Linoleic acid, and Prostaglandin E1 (PGE1). Mechanistically, we identified a "Nucleotide-Neuro" axis, where the disruption of the GMP hub was statistically co-regulated (r > 0.86, p < 0.0001) with the downregulation of grin neurotransmitter receptor genes was identified. Furthermore, PGE1 was confirmed to have high connectivity to multiple pathways, statistically linking to key genes in calcium signaling ( camk2d2 ) and lipid energy metabolism ( pnpla3 ). The study also revealed a severe oxidative damage, which was characterized by the concurrent transcriptional suppression of the key defense enzymes CAT and ALDH7A1 despite a high substrate load from the Linoleic acid (lipid peroxidation) hub. These mechanistic insights establish comprehensive toxicity framework for Tb³⁺ and provide scientific foundations for environmental risk assessment of REEs contamination in aquatic ecosystems. • Environmentally relevant Tb³⁺ concentrations (2.0-10.0 mg/L) induce delayed hatching, reduced body length, and teratogenesis in zebrafish embryos. • Growth retardation and malformations are mechanistically linked to a synergistic impairment of both bioenergetic pathways (PGE1- pnpla3 axis) and nucleotide biosynthesis (the GMP hub). • A "Nucleotide-Neuro" axis was identified, where GMP hub disruption is statistically co-regulated ( p < 0.0001) with grin neurotransmitter receptor gene expression. • Cardiovascular dysfunction is mechanistically linked to the PGE1 hub, which is statistically correlated with key genes in both calcium signaling ( camk2d2 ). • Tb³⁺ induces a oxidative damage by suppressing the key detoxification enzyme CAT and ALDH7A1 despite high substrate load from lipid peroxidation.