Integrated multi-omics analysis uncovers Zearalenone-induced ovarian and intestinal inflammation is mediated by the tumor necrosis factor-α.

As a widely encountered foodborne mycotoxin, Zearalenone (ZEN) has the potential to accumulate along the food chain, posing threats to public health and safety. However, the precise mechanisms by which ZEN causes tissue damage remain incompletely understood. Here, we established in vivo (40 μg/kg) and in vitro (30 μM) models to elucidate the underlying processes of ZEN-induced damage to the ovary and intestine. Our results demonstrated that, following ZEN exposure, pro-inflammatory signaling factors, including NLR family pyrin domain containing 3 (NLRP3) and Interleukin 6 (IL6), were significantly elevated in both ovarian and intestines. Metagenomic analysis revealed dysbiosis of the gut microbiota, which was closely associated with tumor necrosis factor (TNF)-α signaling pathway. Transcriptomic results further indicated that inflammatory response are intricately linked to TNF signaling pathway. Additionally, the Tnf-α knockout mouse model showed a marked resistance to ZEN-induced ovarian and intestinal injuries. In vitro, RNA interference targeting TNF-α attenuated the inflammatory response in IPEC-J2 cells. Moreover, dysregulated expression of the hormone synthesis genes, including KISS-1 metastasis suppressor (Kiss1) and gonadotropin releasing hormone 1 (Gnrh1), was observed, suggesting that ZEN-induced microbial dysbiosis and ovary damage may be interconnected through hormonal disruption. In summary, our results emphasize the role of TNF-α in causing ovarian and intestinal damage after ZEN exposure.