Evaluation of the Individual and Combined Toxicity of Fumonisin Mycotoxins in Human Gastric Epithelial Cells
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International Journal of Molecular Sciences Article Evaluation of the Individual and Combined Toxicity of Fumonisin Mycotoxins in Human Gastric Epithelial Cells Song Yu, Bingxuan Jia, Na Liu, Dianzhen Yu and Aibo Wu * SIBS-UGENT-SJTU Joint Laboratory of Mycotoxin Research, CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; [email protected] (S.Y.); [email protected] (B.J.); [email protected] (N.L.); [email protected] (D.Y.) * Correspondence: [email protected]; Tel.: +86-21-54920716 Received: 23 July 2020; Accepted: 14 August 2020; Published: 18 August 2020 Abstract: Fumonisin contaminates food and feed extensively throughout the world, causing chronic and acute toxicity in human and animals. Currently, studies on the toxicology of fumonisins mainly focus on fumonisin B1 (FB1). Considering that FB1, fumonisin B2 (FB2) and fumonisin B3 (FB3) could coexist in food and feed, a study regarding a single toxin, FB1, may not completely reflect the toxicity of fumonisin. The gastrointestinal tract is usually exposed to these dietary toxins. In our study, the human gastric epithelial cell line (GES-1) was used as in vitro model to evaluate the toxicity of fumonisin. Firstly, we found that they could cause a decrease in cell viability, and increase in membrane leakage, cell death and the induction of expression of markers for endoplasmic reticulum (ER) stress. Their toxicity potency rank is FB1 > FB2 >> FB3. The results also showed that the synergistic effect appeared in the combinations of FB1 + FB2 and FB1 + FB3. Nevertheless, the combinations of FB2 + FB3 and FB1 + FB2 + FB3 showed a synergistic effect at low concentration and an antagonistic effect at high concentration. We also found that myriocin (ISP-1) could alleviate the cytotoxicity induced by fumonisin in GES-1 cells. Finally, this study may help to determine or optimize the legal limits and risk assessment method of mycotoxins in food and feed and provide a potential method to block the fumonisin toxicity. Keywords: fumonisins; cytotoxicity; ER stress; risk prioritizing; combined toxicity 1. Introduction As akin natural contaminators produced by Fusarium, Fusarium mycotoxins are not necessary for fungal growth, while they can fertilize the process of crop infection and cause plant diseases [1–3]. According to the Food and Agriculture Organization of the United Nations (FAO), mycotoxin contamination is affecting the entire food chain and causes more than 25% cereal crops loss each year [4]. Fumonisin is a highly toxic low molecular weight fusarium mycotoxin, which is produced by a number of fusarium species, predominantly Fusarium verticillioides and Fusarium proliferatum [5,6]. The chemical structure of 28 kinds of fumonisins have been identified by now, which can be divided into A, B, C and P. Among them, fumonisin B1 (FB1), fumonisin B2 (FB2) and fumonisin B3 (FB3) are the main forms. Their structure is characterized by 20-carbon aminopolyhydroxy alkyl chain esterified with two molecules of tricarboxylic acid (-TCA), but they have different amounts of hydroxyl group (-OH) and the positions of the hydroxyl group (-OH) are different as well (Figure1)[ 7]. They have often been examined in food and feed all over the world, especially in corn and the products made of corn-flavored ingredients [8,9]. In 2001, a survey of mycotoxin contamination on 4327 grain samples Int. J. Mol. Sci. 2020, 21, 5917; doi:10.3390/ijms21165917 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5917 2 of 13 worldwideInt. J. Mol. Sci. showed2020, 21, x thatFOR PEER for major REVIEW fumonisin B (FBs) positive rates were approximately 27%,2 51%, of 13 58%, 56%, and 55%, respectively, in North America, Central Europe, Africa, South Asia, and Southeast Asia.Southeast The prevalenceAsia. The prevalence in South Americain South America was the highest,was the highest with a, positive with a positive rate of rate 76% of (average 76% (average level oflevel 1.50 of mg 1.50/kg) mg/kg) [10]. The[10]. content The content of FB of contaminators FB contaminators in compound in compound feed andfeedfeed and ingredientsfeed ingredients was 93.33%was 93.33% and 83.33%.and 83.33% Most. Most poultry poultry broiler broiler (early) (early) feeds feeds were were seriously seriously contaminated contaminated by FBs, by FBs, and and the highestthe high detectedest detected level level in one in one feed feed being being 12.82 12.82 mg /mg/kgkg in Korea in Korea in 2012 in 2012 [11]. [11] In. 2014, In 2014, the the incidence incidence of FB1,of FB1, FB2 FB2 and and FB3 FB3 in corn in corn products products (corn ( flakes,corn flakes, corn meal cornand meal grits) and in grits) Shandong in Shandong province province was 98.10%, was and98.10%, the highest and the levels highest were levels 5046, were 1350 and5046 712.10, 1350µ andg/kg, 712.10 respectively μg/kg, [ 12respectively]. Because of[12] the. Because characteristics of the ofcharacteristics this toxin such of asthis its toxin thermal such stability as its thermal and corrosion stability resistance,and corrosion they resistance, are difficult they to eliminateare difficult [13 to]. Onceeliminate they are[13] absorbed. Once they by humansare absorbed and animals by human throughs and the animals food chain, through they the will food threaten chain, human they andwill animalthreaten health human and and cause animal serious health economic and cause losses serious [14]. economic losses [14]. Figure 1. The chemical structure of major fumonisin B: (A) fumonisin B1; (B) fumonisin B2; and (C) Figure 1. The chemical structure of major fumonisin B: (A) fumonisin B1; (B) fumonisin B2; and (C) fumonisin B3. fumonisin B3. Fumonisin B1 (FB1) is the most prevalent member of fumonisin and causes diverse toxic effects in Fumonisin B1 (FB1) is the most prevalent member of fumonisin and causes diverse toxic effects humans and domestic animals, including neurotoxicity, hepatotoxicity and carcinogenesis, resulting in humans and domestic animals, including neurotoxicity, hepatotoxicity and carcinogenesis, from oxidative stress, apoptosis, necrosis and alterations in cell proliferation and differentiation [15–19]. resulting from oxidative stress, apoptosis, necrosis and alterations in cell proliferation and Ceramide synthase catalyzes the formation of ceramide from sphinganine and acyl-CoA as substrates. differentiation [15–19]. Ceramide synthase catalyzes the formation of ceramide from sphinganine and Several lines of evidence indicate that the toxicity of FB1 caused by the aminopentol backbone competes acyl-CoA as substrates. Several lines of evidence indicate that the toxicity of FB1 caused by the against the binding of the sphingoid base substrate, whereas the tricarballylic acids interfere with the aminopentol backbone competes against the binding of the sphingoid base substrate, whereas the binding of the fatty acyl-CoA, the accumulation of free sphingoid bases via the inhibition of ceramide tricarballylic acids interfere with the binding of the fatty acyl-CoA, the accumulation of free synthase leads to the disruption of the sphingolipid metabolism. FB1 can be converted to N-acylation sphingoid bases via the inhibition of ceramide synthase leads to the disruption of the sphingolipid FB1 by ceramide synthase [20–23]. However, there are limited studies on the toxicity of FB2 and FB3, metabolism. FB1 can be converted to N-acylation FB1 by ceramide synthase [20–23]. However, there and no studies have assessed the toxicity of fumonisin B (FBs) mixtures. It is worth mentioning that are limited studies on the toxicity of FB2 and FB3, and no studies have assessed the toxicity of the current safety limit standards and regulatory formulations of mycotoxins mainly use the toxicology fumonisin B (FBs) mixtures. It is worth mentioning that the current safety limit standards and data as references. With the development of toxicology technology, only the consideration of toxicity regulatory formulations of mycotoxins mainly use the toxicology data as references. With the from one single mycotoxin but not the combined effects (synergistic, additive, and antagonistic) of development of toxicology technology, only the consideration of toxicity from one single mycotoxin the mycotoxin mixtures did not obviously reflect the real toxicity of mycotoxins [24–26]. However, but not the combined effects (synergistic, additive, and antagonistic) of the mycotoxin mixtures did the data focused on the combination toxicity of mycotoxin are limited. Many investigative studies have not obviously reflect the real toxicity of mycotoxins [24–26]. However, the data focused on the shown that the presence of fumonisin family mycotoxins in food and feed is always spatiotemporally combination toxicity of mycotoxin are limited. Many investigative studies have shown that the synchronized [27–29]. Therefore, the evaluation of the toxicological effects of mycotoxin interactions is presence of fumonisin family mycotoxins in food and feed is always spatiotemporally synchronized important for accurately calculating the health risks of such mycotoxin contaminations and formulating [27–29]. Therefore, the evaluation of the toxicological effects of mycotoxin interactions is important relevant safety regulations. for accurately calculating the health risks of such mycotoxin contaminations and formulating relevant The gastrointestinal tract is often an important target for first exposure to these dietary toxins [30,31]. safety regulations. It is reported that FB1 can affect the health of the gastrointestinal tract (GIT) in animals [32,33]. The gastrointestinal tract is often an important target for first exposure to these dietary toxins Nevertheless, the effect of fumonisin on the human gastrointestinal tract was poorly understood. [30,31]. It is reported that FB1 can affect the health of the gastrointestinal tract (GIT) in animals [32,33]. In order to obey the rules of 3R, the human gastric epithelial cell line (GES-1) was used in this study as Nevertheless, the effect of fumonisin on the human gastrointestinal tract was poorly understood.