Zearalenone (ZEA) is a mycotoxin produced by the fungi of Fusarium genera, which contaminates the cereals and food stuffs worldwide. Fusarium mycotoxins are considered as important metabolites related to animal and human health. Evidences indicate that ZEA has been found to be present in different food stuffs from developed countries like USA, Canada, France, Germany, Japan, etc. and developing nations like Egypt, Thailand, Iran, Croatia, Philippines, etc. The toxicokinetic studies reveal that following oral exposure of ZEA, the compound is absorbed through gastrointestinal tract (GIT), gets metabolized and distributed to different body parts. ZEA has been shown to cause reproductive disorders in laboratory animals. Although the toxicity of ZEA in humans have not been conclusively established nonetheless, limited evidences indicate that ZEA can cause hyper estrogenic syndrome. Though, ZEA causes low acute toxicity, but reports are available confirming the systemic toxicity caused by ZEA. There is no review available that addresses the occurrence, systemic toxicity and the probable mechanisms of ZEA toxicity. This review shall address the world-wide occurrence and in vivo & in vitro toxicity studies of ZEA over the past 20 years. The review shall also discuss the toxicokinetics of ZEA and metabolites; illustrates the systemic toxicity and probable mechanisms of action leading to the risk associated with ZEA.

Summary: Macrophages are among the most sensitive immune cells because of their phagocytic activity and are prone to become dysfunctional or not able to perform properly if nanoparticle load increases. We have previously reported that zinc oxide nanoparticles (ZNPs) induce inflammatory responses in macrophages that contribute to their death. Recognition of ZNPs by pattern recognition receptors such as toll‐like receptors (TLRs) might be a factor in the initiation of these responses in macrophages. Therefore, in this study we explored the role played by TLR6 and mitogen‐activated protein kinase (MAPKs) pathways in the inflammatory responses of macrophages during ZNPs exposure. ZNPs‐activated macrophages showed enhanced expression of activation and maturation markers (CD1d, MHC‐II, CD86 and CD71). Among various TLRs screened, TLR6 emerged as the most potent activator for ZNPs‐induced inflammatory responses. Downstream signalling proteins myeloid differentiation 88, interleukin‐1 receptor associated kinase and tumour necrosis factor receptor‐associated factor were also enhanced. On inhibiting MAPKs pathways individually, the inflammatory responses such as interleukin‐1β, interleukin‐6, tumour necrosis factor‐α, cyclooxygenase‐2 and inducible nitric oxide synthase were suppressed. TLR6 silencing significantly inhibited the pro‐inflammatory cytokine levels, reactive nitrogen species generation and inducible nitric oxide synthase expression. Also, inhibition of MAPKs in the absence of TLR6 signalling validated the link between TLR6 and MAPKs in ZNPs‐induced inflammatory responses. TLR6 was found to be co‐localized with autophagosomes. Macrophages lacking TLR6 inhibited the autophagosome marker protein‐microtubule‐associated protein1 light chain 3‐isoform II formation and phagocytosis. These results demonstrate that inflammatory responses caused by ZNPs‐activated macrophages strongly depend on TLR6‐mediated MAPK signalling.