key: cord-0029171-dqoho7zb
authors: Sanad, M.H.; Farag, A.B.; Bassem, Sabry A.; Marzook, F.A.
title: Radioiodination of zearalenone and determination of Lactobacillus plantarum effect of on zearalenone organ distribution: In silico study and preclinical evaluation
date: 2022-02-11
journal: Toxicol Rep
DOI: 10.1016/j.toxrep.2022.02.003
sha: 45611dab38981992d141eee19fceedbf7b17bbc9
doc_id: 29171
cord_uid: dqoho7zb

PURPOSE: Zearalenone (ZEN) which is one of the known fusarium species mycotoxin, produced primarily on many cereal crops. Consequently, the current study aims to estimate the possibility of labeling zearalenone and the pattern of accumulation of the produced labeled zearalenone [(125)I]-ZEN in different mice tissues, and the possible protective effect of Lactobacillus plantarum to reduce organ accumulation of Zearalenone. MATERIALS AND METHODS: the experiment was conducted on two groups of mice were used; the two groups received [(125)I] Zearalenone administered by tail vein injection, the first group receive nothing else while the second group received also L. plantarum (as a control agent) orally. The mice were kept under observation for 120 min to monitor zearalenone distribution. RESULTS: by monitoring the zearalenone distribution the maximum concentration was found to be mainly primarily in the intestine (45.8 %) followed by the liver (27.15 %) while in the ovary (the most susceptible organ was (3.22 %) after120 min, in the first group of mice. The same pattern was observed in the second group with concentrations of (46.1 %), (30.19 %) and (0.09 %) in the intestine, liver respectively. CONCLUSION: These results indicated the lactic acid bacteria played a role in decreasing labeled zearalenone in the ovaries which is the target organ. [(125)I]-labeled ZEN is a promising novel tracer for organ imaging and that a significant role that L. plantarum could play in decreasing the zearalenone bioavailability of in mice organs.

Zearalenone (ZEN) is considered one of the major mycotoxins produced by fusarium species, and is formed primarily on many cereal crops which are considered the main host plants primarily in the field, but several reports indicated its presence during poor grain storage conditions. Zearalenone (ZEN) belongs to resorcyclic acid lactone mycotoxins ( Fig. 1) The climatic conditions is considered one of the controlling factors of the natural occurrence of zearalenone [1] . reported the increase of the natural occurrence of ZEN as a result of climatic changes in relation to rain fall as, the increase of Rainfall accompanied by moderate temperatures throughout the blossoming and maturation seasons were found to increase cereals infestation (mostly Triticum and Zea mays) with Fusarium culmorum and accordingly Zearalenone infestation. The variation of concentrations of zearalenone in maize from one year to the other is mostly associated with rainfall. ZEN concentrations were remarkably elevated in maize collected in the period from 2014 to 2017 in Central Europe. Also in Southern European, while levels ZEN were relatively elevated in maize harvested in the same period opposite observations In East Asian maize, as the levels of ZEN were comparatively low in maize harvested at the same time these results shed light on the increasing importance of ZEN with the occurring climate changes nowadays.

ZEN is usually called (an estrogenic mycotoxin) which causes obvious estrogenic effects in both human and animals, which is a direct result to the structural similarity to the natural estrogens. The IARC has considered ZEN to be Group 3 carcinogen. As a result of its strong hazardous effects a lot of public health concerns arise. ZEN binds competitively to estrogenic receptors (ERα and ERβ) in many in vitro or in vivo systems in different species, causing serious malignant alterations and lesions in the female reproductive system [2] .

Iodine-131 is one of the most used isotopes used therapeutically for hyperthyroidism and it is also considered as one of the first radiotracers used in nuclear medicine. The principal releases of iodine-131 decay are electrons, with a maximum energy of 606 keV (89 % abundance, others 248-807 keV) and 364 keV gamma radiation (81 % abundance). That's why, it's not recommended to be utilized in optimum conditions or bio distribution just in case of the presence of its high energy with beta emission. Therefore, we preferred to use Iodine-125 for the development of all our study due to the fact that it is characterized by its low energy (about 35 Kev). Iodine-125 is the isotope of choice for medical imaging with a half-life to 59.49 days and decays by electron capture to an excited state of tellurium-125 (not the metastable state). That decays immediately by gamma decay to give Iodine-125 with a maximum energy of 35 keV The toxicity of deoxynivalenol was evaluated via the administration of [ 125 I] -labeled deoxynivalenol in mice [3] .

One of the most promising technique in prevention of mycotoxin hazardous effects is via the use of lactic acid bacteria, Lactic acid bacteria (LAB) are a large species of gram-positive bacteria the majority of which are non-movable rods and cocci. LAB usually get its carbohydrates needs through fermentation forming lactic acid which is considered its end product [4] . LAB are extensively engaged in the fermentation processes of food and feed, which add extensively to its hygienic and safety characteristics, storage constancy and desirable physical properties [5] and [6] . One of the main benefits of these bacteria it the fact that LAB are of great importance in their usage in the bio-preservation of human food and animal feed, and that is essentially attributed to its ability to produce natural antimicrobial compounds. Lactobacillus plantarum usually found abundantly all over the environment with wide-ranging of uses L. plantarum safe utilization has a long history in a variety of food products especially with human gastrointestinal tract (GIT) being its normal host. Several studies investigated L. plantarum strains and results supported the fact that LAB possess substantial capability to inhibit many undesirable bacteria, including both Gram negative and Gram positive species, that may infect food causing diseases in humans. These strains preserve a significant ability to counteract numerous undesirable bacteria, including both Gram-negative and Gram-positive species that can infect food causing sicknesses in humans. The biosynthesis of many metabolites (organic acids, enzyme systems, and bioactive peptides ….etc) is a suggested mechanism for the antimicrobial, antioxidant, properties of probiotic bacteria which enables it to act as natural preservatives agents against pathogenic microorganisms that may affect food quality during food process from harvest to human. Which in turn decrease the need for chemical preservatives, increasing health and safety and decreasing the risks for the consumer.

A lot of researches revealed that various species of LAB have the ability to eliminate mycotoxins. The ability of LAB for the removal vary from small amounts up to complete elimination [7] [8] [9] [10] [11] [12] . The species that showed the best activities were Lactobacillus rhamnosus, L. acidophilus, L. plantarum, L. lactis, Streptococcus thermophilus, and Bifidobacterium bifidum. While the activity of the different spices differ according to the type of the mycotoxin yet L. rhamnosus, was found to have the ability to eliminate several mycotoxins at the same time [9, [13] [14] [15] [16] .

That is why, the aim of the current work was to clarify the distribution of [ 125 I]-labeled ZEN in mice organs, and the possible role of Lactobacillus plantarum as a protector against Zearalenone organ toxicity.

Zearalenone (ZEN), chloramines-T (Ch-T), ethanol and methanol were acquired from Sigma-Aldrich. Aluminum sheets thin layer chromatography (TLC) plates (20 × 25 cm) SG-60 F254 from Merck. All the chemical substances used in this study were of analytical or clinical grade & were directly used no more purification except else was stated. 

We used a fixed volume of the reaction mixture (approximately ~ 720 μL). 

The stability of [ 125 I] ZEN was determined using two different media, saline and serum: In rat serum, 0.1 mL of the radiotracer was mixed with 1.9 mL of serum [0. 

Lactobacillus plantarum was obtained from the department of Dairy Science, National Research Centre. According to the method described by [18] as follow the strain was stored in De Man Rogosa Sharpe broth (MRS, Conda, Spain).Lactobacillus plantarum was sub-cultured twice in MRS broth before experimental use. Cells were removed by centrifugation at 10,000gfor 5 min, washed three times; freeze-dried. Each tube of prepared L. plantarum was frozen at-80 C for 8 h and then freeze-dried for 24 h. After the end of the freeze-drying cycle, the tubes were sealed under vacuum and stored at 20 • C. Frozen samples were re-suspended in sterile phosphate buffer saline(PBS, PH 7.0), and serial dilutions (101 to 109) were pre-pared in 0.1 % tryptone, placed on MRS agar medium and incubated at 37 • C for 24 h. The number of viable cells was determined as colony forming unit per milliliter (CFU/mL).

The total experiment was conducted on a total of 50 mice (Swiss Albino mice) weighted (30− 35 g) the mice were acclimatized for 1 week, then were divided into two groups (25mice/group). Group 1, treated intravenously with [ 125 I] ZEN 0.2 mL ([ 125 I] NaI, 7.5 MBq, and group 2, treated intravenously with [ 125 I] ZEN and orally with L. plantarum suspension (30 mL/kg b.w.) for two weeks. scarification of animals was conducted after certain times (5 min, 15 min, 30 min, 60 min and 2 h) after injection. Organs were collected in addition to (Fresh blood, bone, and muscle tissues) then measured against prepared standard solution of the labeled substrate . The mean percentage of the injected dose was calculated. The blood, bone, and muscles were anticipated to represent about 7, 10, and 40 % of the total body weight, respectively. Adjustments were done for background radiation and decay during the experiments. The data were analyzed statistically with one way Analysis of variance ANOVA test with P < 0.05.

All the animal experiments were carried out in compliance with the standards set out by the Animal Ethics Committee, Labeled Compounds Department-Egyptian Atomic Energy Authority (EAEA).

The x-ray crystallographic structure of estrogen receptor alpha (ERα) (PDB code: 5krc) bound to earalenone which was taken from Protein Data Bank RCSB website [www. rcsb. Org] (Research Collaboration for Structural Bioinformatics) was used to perform the docking studies. Chains B, C and D were deleted and chain A was prepared using the Structure Preparation application in Molecular Operating Environment (MOE), Then the protonate 3D application was used to add the missing hydrogens and assign the ionization states [24] [25] [26] .

The total yield of the radiotracer consists of free 

Effect of ZEN concentration: The quantity of substrate may influence the radiochemical yield as a function of ZEN concentration that was cleared in (Fig. 4a) . In which the radiochemical yield was increased to 98.0 ± 0.29 % by increasing the amount of ZEN up to 50 μg. The substrate beyond 50 μg not affecting on the radiochemical yield [24, 25] . It is important remembered that Chloramine-T have the ability to serve as an oxidizing agent, in both acidic and alkaline media, that also related with the nature of active oxidizing species according to the medium pH and the reaction conditions. Therefore, when chloramine-T was dissolved in water, then decomposed to ArSO2NCl, that is hydrolyzed in acidic medium giving HOCl. In addition, further hydrolysis of the hypohalous acid gave H2OCl+. But in alkaline solutions, Ch-T gave the following species HOCl and ClO. The HOCl or H2OCl + generated can (under acidic conditions) cause iodine oxidization leading to the formation of the oxidative state I+ (iodonium) and consequently reacts with any active sites within thiazole ring (in this case only on site present) that can undergo electrophilic substitution reaction. Effect of chloramine-T (Ch-T) concentration: is considered one of the most oxidizing agent used due to its capacity to oxidize the iodide (I-) leading to generate the extremely reactive, electrophilic species (H2OI + and HOI) that have vital part in the iodination reaction. Therefore, the quantity of chloramine-T used is of great importance in the iodination process. The yield of radioiodinated ZEN increases by increment of chloramine-T quantity from 25 to 100 μg (optimum concentration) leading to the formation of highest radiochemical outcome of 98.0 ± 0.29 as shown in (Fig. 4b) . Effect of reaction time: From the obtained results demonstrated in (Fig. 4c) . It was concluded that the radiochemical yield of radioiodinated ZEN at different times ranging from 5 to 60 min giving maximum radiochemical yield at 30 min of 98.0 ± 0.29. Effect of pH: The changing in pH was demonstrated graphically as illustrated in (Fig. 4d) . At pH 6, the yield was maximized (98.0 ± 0.29 %) as a result of the immense stability of radioiodinated ZEN structure at this pH value giving H+, which was easily replaced by the active iodonium ion I + . two different medium were used to study In-vitro stability of radioiodinated ZEN. results revealed that radioiodinated ZEN have high stability in saline up to 48 h. On the other hand different results were obtained in serum, as the stability was only up to 24 h giving 93.2 % (Fig. 5 ). Table 1 

Nowadays human health suffer from exposure to several types of pollutants that vary in its nature as well as its effects, some of these pollutants are due to industrialization, and unfortunately others are naturally produced and mostly unavoidable such as mycotoxins. Zearalenone is a mycotoxin that could be categorized as environmental pollutant that infest grain crops worldwide. It is extensively repo1rted in food and feed having hazardous effects on health of animals and human beings [29] [30] [31] . Investigation confirmed that ZEN and ZEN metabolites generally react on oestrogen target organs causing reproductive syndromes in animals and grave oestrogen disorder in humans [29] . Nevertheless, most of the previous records focused on its estrogenic effects only giving lesser concern to the fact that other organs could be also affected by Zearalenone through its bio-distribution. The present study, showed clearly the bio-distribution of labeled ZEN in different organs and fluids of mice following the pattern; Blood-> liver > intestine > muscle > kidney > ovary > lung. Labeled ZEN initially declined at a fast rate during the 1 st 120 min in all tissues except for kidney, intestine, and liver. The highest radiochemical yield was determined using different ZEN concentrations which revealed that the maximum radiochemical transformation to [ 125 I]-iodo ZEN was 98.0 % at 50 Micrro gram l g of the substrate. These findings differ from those reported by previous studies [32, 39] who reported that the after 24 h purity declined to 89.0 %. The study of the biodistribution of [ 125 I]-iodo ZEN revealed that [ 125 I]-iodo ZEN rapidly accumulate in the blood, liver, intestine, and kidney. Such results follow the same pattern as the results of previous reports [39] and [40] who reported that the accumulation of 125 I-labeled deoxynivalenol in the liver and kidney was observed following intravenous administration in mice. Another report by [41] revealed the presence ZEN in the rats, ZEN was found in kidneys, liver, and lung after intravenous administration. According to the International Agency for Research on Cancer (IARC), zearalenone belongs to group No. 3, which includes mycotoxins that are not classified as carcinogenic to humans [42] . The toxicity of ZEN in vivo was studied by many research mostly reported the hazardous effect of Zearalenone on the reproductive systems either in male or female [42] , also there was a specific concern about the lipid peroxidation of membranes which is included in the means by which ZEN exert its toxic action on human [413, another concern was the findings of [44] who demonstrated the ability of Zearalenone to disrupt liver functions and affect the liver thoroughly to the degree of suppression of cytochrome P450 in the liver results of our work gave clear data about the distribution of Zearalenone in different body organs which in turn could reveal the most susceptible organs that could suffer from Zearalenone/derivatives toxicity . By examining the beneficial effect of L. plantarum on the organ exposure to Zearalenone/derivatives, results revealed that although the administration of L. plantarum did not significantly alter the accumulation of [ 125 I]-iodo-ZEN in different mice organs and there were observed similarity in the pattern of Zearalenone distribution through different organs yet there was marked reduction in the Zearalenone concentration in the ovary and that was observed from the 1st 5 min of administration, and since the ovaries are considered the most sensitive (target) organ of Zearalenone toxicity that could provide additional benefit for the use of LAB as it was reported to demonstrate anti-inflammatory, anti-genotoxic and improve ovarian fertility [45] , the decline in the accumulation of [ 125 I]iodo ZEN in mice organs may be attributed to the lactic acid bacterial capability to bind and/or alter ZEN to other compound [9] . Which in turn could result in the decrement of the ZEN in the ovaries leading to the reduction in their related estrogenic influence [46] . Established the ability of some lactic acid bacterial strains to remove ZEN and its derivatives from contaminated from liquid media.

The structural analysis for the Zearalenone ligand co-crystallized along with estrogen receptor alpha (ERα) (PDB code: 5krc) substratebinding pocket revealed S-score of − 14.8831 kcal/mol and hydrogen bond network comprising L387 and E353 [47] in-silico molecular modeling for the predicted iodindated zearalenone showed that all of them bind to the main pocket as zearalenone [co-crystallized ligand], as shown in (Fig. 6a, b) .

The results of the docking study were as follow: Monoiodo-zearalenone suggested structure (2a) has S-score of − 13.5369 kcal/mol and had two hydrogen bonds with 2 different amino acids: one with E353 of distance (1.35 Aº), one with L346 of distance (1.34 Aº), as shown in (Fig. 7) .

Diiodo-zearalenone suggested structure (2b) has S-score of − 12.5866 kcal/mol and had one hydrogen bond with H524 of distance (2.44 Aº), as shown in (Fig. 7) .

Monoiodo-zearalenone suggested structure (2c) has S-score of − 12.2297 kcal/mol and had two hydrogen bonds with 2 different amino acids: one with E353 of distance (1.91 Aº), one with H524 of distance (2.45 Aº), as shown in (Fig. 7) .

Conclusively, the presence of heavy iodine atom didn't disturb the binding ability of zearalenone to its target (5krc).

An optimized protocol for the synthesis of the radiotracer [125I]iodo ZEA in high radiochemical yield of ≥ 98 % has been developed by electrophilic substitution mediated by Ch-T. About 98 % radiolabeling purity was observed to be stable in normal saline and rat serum. The biodistribution studies in two groups of normal and infected mice indicated that the radiotracer [125I]-iodo ZEA has the same distribution except in ovaries. It was also observed that [125I]-iodo ZEA accumulation declined in the ovaries at the group of mice taking L. plantarum, infected group from 3.22 % to 0.09 at 2 h p.i. Therefore, this current 298 work proposes a possible attempt to diminish the GIT absorption of ZEA and/or other mycotoxins from the human diet.

For ZEN which is a widespread mycotoxin contaminating cereal crops, a lot of worries concerning the hazards effects resulting from acute ingestion or chronic ingestion of insanitary food as a result of mycotoxin contamination. This current work proposes a possible attempt to diminish the GIT absorption of ZEN and/or other mycotoxins from the human diet.

All persons who have made substantial contributions to the work but do not meet the criteria for authorship are listed in Acknowledgments section (technical help, writing assistance, general support, financial and material support).

None declared.

The authors declare no conflict of interest.

Data will be made available on request.

The authors report no declarations of interest. 

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Impact of graphene oxide nanoparticles and carbon black on the gamma radiation sensitization of acrylonitrile-butadiene rubber seal materials

Fabrication of sponge nitrile butadiene rubber (NBR) by subsequent sulphur and electron beam irradiation

Characterization of blend hydrogels based on plasticized starch/ cellulose acetate/carboxymethyl cellulose synthesized by electron beam irradiation

Gamma irradiation of polyethylene nanocomposites for food packaging applicationsagainst stored-product insect pests

Abo-State, Application of polyurethane /gamma-irradiated carbon nanotubes composites as antifouling coat

Irradiated rubber composite with nano and microfillers for mining rock application

Characterization of LDPE and LDPE/EVA blends crosslinked by electron beam irradiation and foamed with chemical foaming agent

Mechanical and physical properties of nanosilica/nitrile butadienerubber composites cured by gamma irradiation

Effect of ionizing radiation on the properties of some synthesized polyurethanes

Surface characteristics of cotton/ polyester fabric coated with poly-urethane elastomers cured thermally or by using gamma irradiation