Paraquat induced depression-related neurobehavioral abnormalities in zebrafish: Linkage between hepatic SAM biosynthesis and cerebral m⁶A methylation.

Abstract

Accumulating epidemiological and toxicological evidence implicates the herbicide paraquat (PQ) as an environmental risk factor for depressive neuropsychiatric disorders. In this study, we demonstrated that PQ exposure induces depression-associated neurobehavioral abnormalities in adult zebrafish. Subsequent examination revealed that chronic PQ exposure markedly suppressed hepatic biosynthesis of S-adenosylmethionine (SAM), selectively downregulated methyltransferase METTL16 expression, and reduced global cerebral N⁶-methyladenosine (m⁶A) abundance. Integrative analyses combining cerebral MeRIP-seq and transcriptome sequencing data further identified pervasive perturbations in the m⁶A epitranscriptomic landscape and transcriptional profiles of functional genes enriched in synaptic plasticity, neurotransmission and depression-associated signaling cascades. Notably, exogenous SAM supplementation effectively ameliorated impaired brain m⁶A methylation and PQ-evoked depression-related behavioral phenotypes. Collectively, our findings support inter‑organ crosstalk linking impaired hepatic SAM metabolism to reduced cerebral m⁶A abundance. The consequent epitranscriptomic disruption underpins PQ-associated neurobehavioral abnormalities, pointing to SAM as a promising candidate therapeutic agent against depressive disorders induced by environmental toxicants.