Bioaccumulative toxicity of butylated hydroxytoluene in Ruditapes philippinarum: Lipid metabolic disruption and...

The ubiquitous presence of synthetic phenolic antioxidants (SPAs) has raised growing concern over their potential ecological and health risks. However, their bioaccumulative toxicity and underlying mechanisms remain poorly understood. Here, this study elucidated the bioaccumulative toxicity of butylated hydroxytoluene (BHT) in the marine invertebrate Ruditapes philippinarum. BHT exhibited pronounced tissue-specific accumulation, accompanied by elevated TG and PL levels. PP-LFER modeling, Spearman's correlation, and LMM analyses, revealed a significant positive association between BHT accumulation and TG/PL contents, suggesting preferential accumulation of BHT in lipid droplets enriched in TG and enclosed by PL. MD simulations demonstrated that BHT interacts with DPPC membranes and its tert-butyl substituents impede transmembrane diffusion. Moreover, BHT may induce ER stress and modulate mTOR-SREBP1 and PPARα/β signaling, together with altered expression of lipid metabolism-related genes, implying disruption of lipid metabolic homeostasis and enhanced lipid deposition. Target prediction and molecular docking further indicated stable binding of BHT to key lipid metabolic regulators. Meanwhile, BHT may activate NF-κB-related signaling, potentially mediated by lipotoxic, neurotransmitter-immune, and oxidative stress pathways, contributing to low-grade inflammation. Collectively, this study provides new insights into SPA-associated lipid metabolic disruption and inflammatory risk in aquatic invertebrates, supporting their health risk assessment.