Necroptosis contributes to deoxynivalenol-induced activation of the hypothalamic-pituitary-adrenal axis in a piglet model

The mycotoxin deoxynivalenol (DON) is highly prevalent in cereals as an immune stressor. The hypothalamic-pituitary-adrenal (HPA) axis is activated during periods of stress, and the organism is accompanied by inflammation. Necroptosis is a newly identified type of cell death. However, the relationship between necroptosis and HPA axis activation induced by DON is rarely reported. Our study aimed to explore the role played by necroptosis in HPA activation in a stress of piglet model produced by DON. Our results indicated that both feeding with a contaminated-DON diet (4 ppm) and DON injection at 0.8 mg/kg BW increased the concentration of plasma corticotropin-releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH) and the mRNA expression of adrenal steroidogenic acute regulatory protein (StAR). Furthermore, the mRNA expression of pro-inflammatory cytokines and factors related to necroptosis in the hypothalamus, pituitary gland, and adrenal gland were increased. As an inhibitor of necroptosis, necrostatin-1 (Nec-1) inhibited necroptosis through decreasing mRNA expression of necroptosis signal factors in the HPA axis. Nec-1 also reduced the mRNA levels of pro-inflammatory cytokines in the HPA axis. Meanwhile, the activation of the HPA axis was inhibited by Nec-1 as shown by the decrease of plasma CRH and ACTH concentrations and the mRNA expressions of hypothalamus CRH and pituitary POMC. These findings indicated that as a result of necroptosis, the HPA axis was activated by DON. In light of these findings, necroptosis could be considered as an intervention target that alleviates HPA axis activation and stress responses.