Abstract
Deoxynivalenol (DON) is a kind of Fusarium toxin that can cause a variety of toxic effects. Oxidative stress and DNA damage play a critical role in the toxicity of DON. However, previous studies focused more on acute toxicity in vivo/vitro models and lacked subchronic toxicity study in vivo. The potentially harmful effect of DON given at doses comparable to the daily human consumption in target organs, especially the liver, which is the main detoxification organ of DON, is also still not fully understood. Otherwise, Heme Oxygenase-1 (HO-1) has also reduced cell damage under the DON condition according to our previous study. Therefore, we used a rodent model that mimicked daily human exposure to DON and further explored its mechanism of toxic effects on liver tissue and Hepa 1–6 cell line. We also used adeno-associated virus (AAV)-modified HO-1 expressing by tail vein injection and constructed lentivirus-Hepa 1–6 cell line for mimicking HO-1 protective ability under the DON condition. The main results showed that both 30 d and 90 d exposures of DON could cause low-grade inflammatory infiltration around hepatic centrilobular veins. The reactive oxygen species (ROS) and 8-hydroxy-2 deoxyguanosine (8-OHdG) increased during DON exposure, indicating oxidation stress and DNA damage. Significantly, AAV-mediated liver-specific overexpression of HO-1 reduced DON-induced liver damage and indirectly protected the abilities of antioxidant enzyme/DNA damage repair system, while AAV-mediated silence of HO-1 produced the opposite effect. In addition, we found that overexpression of HO-1 could enhance autophagy and combined it with an antioxidant enzyme/DNA damage repair system to inhibit DON-induced hepatocyte damage. Altogether, these data suggest that HO-1 reduces the oxidative stress and DNA damage caused by DON sub-chronic exposure through maintaining DNA repair, antioxidant activity, as well as autophagy.
Highlights
Deoxynivalenol (DON) is one of the most widely distributed trichothecenes and it has various toxic effects on humans and animals [1,2,3]
We used adeno-associated virus (AAV)-modified Heme Oxygenase-1 (HO-1) expressing by tail vein injection and constructed lentivirus-Hepa 1–6 cell line for mimicking HO-1 protective ability under the DON condition
In this work, we aim to evaluate the impact of subchronic intoxication in mice liver with DON given at doses below the non-observed-adverse effect level (NOAEL), i.e., 100 μg/kg bw [24]
Summary
Deoxynivalenol (DON) is one of the most widely distributed trichothecenes and it has various toxic effects on humans and animals [1,2,3]. Acute DON exposure can cause vomiting, diarrhea, and even shock-like death. Such clinical intoxications are rare in humans, who are most frequently, exposed to low DON doses without developing acute symptoms. Long-term low-dose DON exposure may cause anorexia, growth retardation, and immunotoxicity [4]. The adverse effects of long-term exposure to the human daily intake of DON cannot be completely ruled out. According to the 2011 World Health Organization report, the average daily intake of DON by humans is 0.2–14.5 μg/kg bw/day [5]. Long-term low-dose daily exposure to DON may have become a global threat to human health [7]
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