4,5-Dichloro-2-n-octyl-4-isothiazolin-3-one induces obesogenic effects by targeting fatty acid synthase

The widespread use of biocides to control biofouling has led to significant marine pollution. Among these, 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) has emerged as a prominent antifouling contaminant known to disrupt lipid metabolism in marine organisms. However, the chronic effects and underlying mechanisms of DCOIT-induced lipid dysregulation remain unclear. In this study, marine medaka embryos were exposed to environmentally relevant concentrations of DCOIT (0, 1, 3, and 10 μg/L) throughout their entire life cycle. Disturbances in lipid metabolism were systematically characterized by integrating histopathological, biochemical, transcriptional, proteomic, and lipidomic analyses. DCOIT exposure significantly increased whole-body fat content, induced fatty liver pathology, and promoted adipocyte hypertrophy, with more severe effects in males (10.6-fold enlargement of adipocyte size). Consistently, exposed livers accumulated excessive triglycerides (TG) and fatty acids in a sex-dependent manner. Lipidomic profiling further revealed that TG accumulation was significantly elevated only in male adipose, explaining the pronounced adipocyte hypertrophy. DCOIT also remodeled TG composition, characterized by increased palmitic acid (C16:0), the principal product of fatty acid synthase (FAS). Multifaceted approaches confirmed a strong binding affinity between DCOIT and FAS, establishing FAS as a key molecular target of DCOIT-induced lipid toxicity. This study provides the first evidence that DCOIT functions as a potent obesogen, significantly impairing the health and viability of marine teleosts.