Benzo[a]pyrene induces metabolic alterations and associated effects on cholesterol and vitamin D-related pathways in zebrafish embryos

Benzo[ a ]pyrene (BaP), a highly toxic polycyclic aromatic hydrocarbon, is classified as a Group 1 carcinogen. Although BaP-induced carcinogenicity, oxidative stress, and developmental toxicity are well established, the mechanisms linking xenobiotic-induced stress responses to endocrine-metabolic dysfunction remain poorly understood. Here, we combined high-resolution magic angle spinning (HR-MAS) NMR-based metabolite profiling with targeted mRNA expression analysis to characterize BaP-induced toxicity in intact zebrafish embryos. BaP exposure caused developmental abnormalities, including reduced hatching success and survival rates, and induced widespread reactive oxygen species (ROS) accumulation in multiple organs, including the liver and brain. HR-MAS NMR revealed metabolic reprogramming involving lipid, amino acid, and energy metabolism, with alterations associated with mitochondrial function. These changes were accompanied by altered expression of genes involved in xenobiotic detoxification, antioxidant defense, mitochondrial homeostasis, and neurodevelopmental regulation. Notably, altered expression of cyp2r1 and dhcr7 suggested changes in pathways related to cholesterol and vitamin D metabolism. Together these findings indicate that BaP exposure induces coordinated oxidative, transcriptional, and metabolic responses in developing zebrafish and provide a systems-level view of BaP toxicity. The observed alterations in cholesterol- and vitamin D-related pathways further suggest that endocrine-metabolic processes may contribute to the response to environmental toxicant exposure.