Low dosage exposure of deoxynivalenol and copper synergistically enhanced the intestinal toxicity

Deoxynivalenol (DON) pollution remains a significant safety concern for humans and animals due to its widespread occurrence in grains and feedstuffs. Copper (Cu) plays a vital role as a trace element in maintaining biological functions in humans and animals. Nevertheless, the risks of DON and Cu co-exposure and the underlying mechanisms of intestinal toxicity remain unclear. Herein, IPEC-J2 cells and a mouse intestinal organoid model were used to evaluate the combined toxic effects of co-exposure to DON and Cu. Co-exposure to DON and Cu at low doses has significant synergistic toxic effects, which disrupt the intestinal barrier and significantly inhibit intestinal organoid development. Mechanistically, co-treatment with DON and Cu alters the levels of apoptosis and ferroptosis related proteins, and consequently activates apoptosis and ferroptosis in mouse intestinal organoids and IPEC-J2 cells. These activations are driven by DON + Cu exposure-induced mtROS accumulation, disrupted MMP and mPTP, and inhibited the expression of mitochondrial antioxidant proteins. Pretreatment with the mtROS-targeted scavenger MitoQ effectively assuaged DON + Cu exposure-caused mitochondrial injury and subsequently attenuated the apoptosis and ferroptosis. Overall, our research revealed the synergistic toxicity of DON + Cu exposure and confirmed the potential mechanism of DON + Cu exposure-induced intestinal toxicity, which will provide valuable insights into their potential combined toxic effects on humans and animals.