Exploring the role of hepatic lipid droplets in mouse liver toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin: sequestration, biochemical alterations and gene regulation

Dioxins are highly toxic and persistent environmental pollutants. The liver, with its complex enzymatic system, plays a crucial role in their detoxification. Hepatic lipid droplets (LDs) are specialized organelles with diverse biological functions, yet their role in dioxin toxicity remains poorly understood. This study investigates the impact of TCDD, the most potent dioxin congener, on the biochemical properties and functionality of hepatic LDs in exposed mice. Female and male BALB/c mice (12-14 weeks old) received a single oral dose of 15-25 µg/kg bw, designated as TCDD₁₅-F, TCDD₁₅-M, TCDD₂₅-F, and TCDD₂₅-M. TCDD exposure induced a dose-dependent increase in liver weight, suggesting hepatomegaly. The number of hepatic LDs and their protein composition increased, with greater hydroxylation enzymatic activity observed in males. HPLC analysis confirmed that hepatic LDs in both sexes accumulated and stored TCDD, raising concerns about potential long-term effects. Moreover, gene expression analysis revealed significant alterations in hepatotoxicity markers (Ahr, Arnt, Cyp1a1, Gsta1, Gsta3), oxylipin biosynthesis genes (Lox15, Cox2), and LD formation genes (Plin5, Cidec, Ppara, Pparg) in a dose-, time-, and sex-dependent manner. These findings offer insight into how lipophilic pollutants are sequestered and metabolized, aiding strategies to reduce dioxin toxicity and treat related liver disorders.