Histamine-Induced Multisystem Toxicity in Eriocheir sinensis and Its Potential Ecological Implications

With the global expansion of aquaculture, histamine, an emerging contaminant derived from microbial decarboxylation of histidine in aquafeed, poses a hidden threat to aquatic ecosystems owing to its obscure sources. This study employed Eriocheir sinensis (E. sinensis) as a model to clarify histamine’s ecological risks and toxic mechanisms. A 5-day oral gavage trial with four histamine doses (0, 50, 100, 200 μg/g body weight) was performed on 160 male crabs (initial weight: 20.0 ± 0.5 g) allocated to four replicate tanks of 10 individuals each. The results showed histamine significantly increased crab autotomy rate in a dose-dependent manner (p < 0.05), disturbed neuroendocrine factors, damaged hepatopancreas microstructure and reduced digestive-enzyme activities (p < 0.05). It triggered hepatopancreatic oxidative stress-related apoptosis and altered the expression of mitogen-activated protein kinase (MAPK) associated genes, with significant up-regulation of pro-apoptotic genes and down-regulation of BCL2 (p < 0.05). Metabolomics showed distinct metabolic perturbations; arachidonic-acid metabolism was markedly enriched at 200 μg/g histamine (p < 0.05). Combined reverse virtual screening, molecular docking and RNAi analyses support the involvement of the histamine H2 receptor (H2R) in crustacean histamine toxicity, and H2R silencing significantly alleviated histamine-induced tissue damage (p < 0.05). Collectively, histamine exerts multi-system toxicity in E. sinensis principally via H2R, disrupting the neuroendocrine–immune network, impairing hepatopancreatic integrity and disturbing metabolic homeostasis. This study provides novel insights into the toxic mechanism of histamine in crustaceans, and offers valuable implications for feed safety evaluation, nutritional risk control, and healthy aquaculture management.