Mechanisms of Action and Toxicity of the Mycotoxin Alternariol: A Review

Abstract

The mycotoxin alternariol (AOH) is produced by Alternaria fungi. It occurs naturally in foodstuffs and is frequently found as contaminant in fruit and grain products. Most information regarding AOH toxicity and the potential mechanisms involved comes from in vitro studies, as only very limited in vivo studies have been performed. AOH forms reactive oxygen species (ROS) and interacts with DNA topoisomerase, thereby generating both single (SSB)-and double-strand DNA beaks (DSB). This triggers various DNA damage response pathways. AOH causes a marked reduction in proliferation in mammalian cells due to cell cycle arrest often in the G 2 /M-phase. After an additional inhibition of cytokinesis, cells with abnormal nuclei as well as polyploidy are reported. In macrophages, AOH may increase autophagic activity and induce senescence. Furthermore, AOH is found to change the morphology and phenotype of various human macrophage cell models. Studies so far indicate that the AOH-induced effects are primarily a result of DSB via its effects on topoisomerase activity. Thus, most probably there will be a threshold for the AOH-induced effects, typically seen in the 5-10 lM range. These in vitro mechanistic studies further support the in vivo studies suggesting low acute toxicity. However, a decreased immune response to infections and/or a disturbed balance of the adaptive immune system when exposed together with other mycotoxins cannot be excluded. This hypothesis needs to be further explored with proper in vivo studies.

Immunomodulatory effects of individual and combined mycotoxins in the THP-1 cell line

“…The most prevalent Alternaria toxin found in grain is alternariol (AOH). Several in vitro studies have reported that AOH induces DNAdamage (Pfeiffer et al, 2007;Solhaug et al, 2012), which is linked to its ability to act as a topoisomerase poison (Fehr et al, 2009;Solhaug et al, 2016). Cellular effects such as generation of ROS, cell cycle arrest, appearance of abnormal nuclei, autophagy, senescence (Solhaug et al, 2012(Solhaug et al, , 2013(Solhaug et al, , 2014, differentiation, secretion of cytokines and estrogenic potential (Frizzell et al, 2013) has also been reported.…”

Marine Fungi as Producers of Benzocoumarins, a New Class of Inhibitors of Glycogen-Synthase-Kinase 3β

“…Effects can be often observed in the 5–10 μM range suggesting low acute toxicity [19]. Alternariol-9-methyl ether ( 3 ) exhibited antibacterial activities with IC 50 values ranging from 59 nM to 141 nM.…”

Understanding the effect of postharvest tomato temperatures on two toxigenic Alternaria spp. strains: growth, mycotoxins and cell‐wall integrity‐related gene expression

“…Tenuazonic acid has been reported to be acutely toxic for several animals such as mice, chickens, and dogs, and has been associated with human hematological disorders like onyalai . Alternariol and AME are mutagenic and genotoxic in bacterial and mammalian cells in vitro . The presence in food of these two toxins has been associated with high levels of human oesophageal cancer in China .…”

“…[6][7][8][9] Alternariol and AME are mutagenic and genotoxic in bacterial and mammalian cells in vitro. 5,10 The presence in food of these two toxins has been associated with high levels of human oesophageal cancer in China. 8,11 Even though there are still no international regulations for any of the Alternaria mycotoxins in food and feed, the European Food Safety Authority (EFSA) recently highlighted that the major contribution of Alternaria spp.…”