Abstract
Chronic exposure to the mycotoxin deoxynivalenol (DON) from grain-based food and feed affects human and animal health. Known consequences include entereopathogenic and immunotoxic defects; however, the neurotoxic potential of DON has only come into focus more recently due to the observation of behavioural disorders in exposed farm animals. DON can cross the blood-brain barrier and interfere with the homeostasis/functioning of the nervous system, but the underlying mechanisms of action remain elusive. Here, we have investigated the impact of DON on mouse astrocyte and microglia cell lines, as well as on primary hippocampal cultures by analysing different toxicological endpoints. We found that DON has an impact on the viability of both glial cell types, as shown by a significant decrease of metabolic activity, and a notable cytotoxic effect, which was stronger in the microglia. In astrocytes, DON caused a G1 phase arrest in the cell cycle and a decrease of cyclic-adenosine monophosphate (cAMP) levels. The pro-inflammatory cytokine tumour necrosis factor (TNF)-α was secreted in the microglia in response to DON exposure. Furthermore, the intermediate filaments of the astrocytic cytoskeleton were disturbed in primary hippocampal cultures, and the dendrite lengths of neurons were shortened. The combined results indicated DON’s considerable potential to interfere with the brain cell physiology, which helps explain the observed in vivo neurotoxicological effects.
Highlights
Chronic exposure to the mycotoxin deoxynivalenol (DON) from grain-based food and feed affects human and animal health
The microglia were notably more sensitive in the cytotoxicity assay than the astrocytes, with significant differences to the untreated control at 3.1 μM
Considering the ribotoxic activity of DON, interference wi tion, activation of the mitogen-activated protein kinase (MAPK) pathway, and the subsequent disruption o tions that initiate the transition to the S phase could have caused the obs parable to our findings, G1 arrest by low-level DON exposure for 24 h with damaged or abnormal DNA, the cell cycle progression in mammalian cells is under ation of apoptosis has previously been described in human monoc strict control by numerous factors, including mediator, effector, and regulator proteins, e.g., mouse macrophages rat intestinal phosphokinases, transcription(J774A.1)
Summary
The mycotoxin deoxynivalenol (DON) (Figure 1) occurs with high a prevalence in grain-based products worldwide [1]. Several in vivo studies have shown that chronic lo entereopathogenic, immunotoxic, and neurotoxic effec gut health, immunological resilience, and behaviours [8 has come into focus only recently, triggered by observe aggressiveness, anxiety, and increased locomotor activ mealworm beetle larvae after chronic exposure to feedb ing from 0.1 to 25 mg/kg [10,11,12,13,14]. Pro-inflammatory cytokines (interleu factor (TNF)-α), and the transcription factor c-Fos were including the nucleus accumbens, paraventricular nucleu tecta after repeated exposure to low DON concentratio with >1.3 mg DON/kg feed for 60 days disrupted the creased lipid oxidation, and decreased the activities of thione peroxidase and superoxide dismutase [23]. We have, focussed on investigating DON-induced effects on murine astrocytes and microglial cell lines, as well as on primary brain cells from young mice, while studying relevant endpoints of toxicity in several cytotoxic and functional tests
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