Convergent disruption of GABAergic and IGF-1R signaling underlies growth inhibition induced by dibutyl phthalate and its alternative dibutyl adipate in zebrafish

Dibutyl phthalate (DBP) and dibutyl adipate (DBA) are commonly used plasticizers that may pose risks to aquatic organisms. This study investigated whether DBP and DBA disrupt larval growth through convergent neuroendocrine pathways using zebrafish (Danio rerio) as an in vivo model. Embryos were continuously exposed to DBP or DBA for 96 h, and growth-related morphological, transcriptional, and protein-level endpoints were assessed. DBP significantly reduced larval body length and increased locomotor activity, accompanied by decreased growth hormone (GH), insulin-like growth factor-1 (IGF-1), and gamma-aminobutyric acid-A (GABA) receptor alpha 2 protein levels, as well as marked suppression of gh1, igf1, gad2, gabrb2, and gabrg2 expression. DBA produced qualitatively similar but consistently weaker effects, primarily affecting growth endpoints and selected neuroendocrine markers. Continuous co-exposure with the GABAA receptor antagonist bicuculline or the IGF-1 receptor inhibitor picropodophyllin (PPP) did not further exacerbate growth inhibition or IGF signaling suppression compared with DBP or DBA exposure alone, revealing a non-additive interaction pattern. These results indicate that DBP- and DBA-induced growth inhibition converges on shared GABAergic and IGF-1R-dependent signaling pathways rather than arising from independent additive toxicity, providing mechanistic insight into plasticizer-induced developmental toxicity.