Toxic effects of environmentally relevant copper and cadmium Co-exposure on goats: Rumen–liver axis dysregulation and multi-omics mechanisms

Heavy metal contamination in pasture ecosystems poses a significant threat to ruminant health. This study investigated the toxicological effects and potential underlying mechanisms of co-exposure to copper (Cu) and cadmium (Cd) at environmental concentrations in goats, with a focus on the rumenliver axis. Thirty-two male goats were randomly assigned to four groups (CON, Cu, Cd, and Cu+Cd) and subjected to a 55-day feeding trial, including a 10-day adaptation period and a 45-day experimental period. Cu/Cd exposure led to significant accumulation of toxic metals in the rumen and liver, disrupting mineral homeostasis by reducing the levels of essential elements such as Fe, Zn, and Ca. Cu/Cd exposure also altered the rumen microbial composition, with a marked reduction in key phyla (Firmicutes, Fusobacteriota, Desulfobacterota) and genera (Streptococcus, Bacteroides), which correlated with shifts in hepatic metabolites involved in amino acid, lipid, and nitrogen metabolism. Furthermore, Cu/Cd exposure compromised rumen barrier integrity by downregulating the expression of tight junction proteins and increasing the expression of inflammatory markers. In the liver, histopathological analysis revealed cellular damage, apoptosis, and inflammatory infiltration. Proteomic and metabolomic analyses further revealed disturbances in pathways related to energy metabolism, detoxification, and amino acid processing. Correlation analysis between the rumen microbiota and liver metabolites revealed strong microbemetabolite interactions, suggesting that Cu/Cd-associated systemic metabolic disorders may be linked to alterations in the rumenliver axis. In conclusion, Cu/Cd co-exposure exerts toxic effects on goats, which are associated with mineral imbalance, microbial dysbiosis, barrier dysfunction, and hepatic metabolic disruption, providing novel insights into heavy metal-induced pathophysiological responses in ruminants.