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Aflatoxins are fungal metabolites found in feeds and foods. When the ruminants eat feedstuffs containing Aflatoxin B1 (AFB1), this toxin is metabolized and Aflatoxin M1 (AFM1) is excreted in milk. International Agency for Research on Cancer (IARC) classified AFB1 and AFM1 as human carcinogens belonging to Group 1 and Group 2B, respectively, with the formation of DNA adducts. In the last years, some epidemiological studies were conducted on cancer patients aimed to evaluate the effects of AFB1 and AFM1 exposure on cancer cells in order to verify the correlation between toxin exposure and cancer cell proliferation and invasion. In this review, we summarize the activation pathways of AFB1 and AFM1 and the data already reported in literature about their correlation with cancer development and progression. Moreover, considering that few data are still reported about what genes/proteins/miRNAs can be used as damage markers due to AFB1 and AFM1 exposure, we performed a bioinformatic analysis based on interaction network and miRNA predictions to identify a panel of genes/proteins/miRNAs that can be used as targets in further studies for evaluating the effects of the damages induced by AFB1 and AFM1 and their capacity to induce cancer initiation.

Human exposure to aflatoxin is through the diet, and probiotics are able to bind aflatoxin and prevent its absorption in the small intestine. This study aimed to determine the effectiveness of a fermented milk drink containing Lactobacillus casei Shirota (LcS) (probiotic drink) to prevent aflatoxin absorption and reduce serum aflatoxin B1-lysine adduct (AFB1-lys) and urinary aflatoxin M1 concentrations. The present study was a randomised, double-blind, cross-over, placebo-controlled study with two 4-week intervention phases. In all, seventy-one subjects recruited from the screening stage were divided into two groups – the Yellow group and the Blue group. In the 1st phase, one group received probiotic drinks twice a day and the other group received placebo drinks. Blood and urine samples were collected at baseline, 2nd and 4th week of the intervention. After a 2-week wash-out period, the treatments were switched between the groups, and blood and urine samples were collected at the 6th, 8th and 10th week (2nd phase) of the intervention. No significant differences in aflatoxin biomarker concentrations were observed during the intervention. A within-group analysis was further carried out. Aflatoxin biomarker concentrations were not significantly different in the Yellow group. Nevertheless, ANOVA for repeated measurements indicated that AFB1-lys concentrations were significantly different (P=0·035) with the probiotic intervention in the Blue group. The 2nd week AFB1-lys concentrations (5·14 (sd 2·15) pg/mg albumin (ALB)) were significantly reduced (P=0·048) compared with the baseline (6·24 (sd 3·42) pg/mg ALB). Besides, the 4th week AFB1-lys concentrations were significantly lower (P<0·05) with probiotic supplementation than with the placebo. Based on these findings, a longer intervention study is warranted to investigate the effects of continuous LcS consumption to prevent dietary aflatoxin exposure.

Aflatoxins are mycotoxins produced by Aspergillus flavus and several other related organisms and are common contaminants of numerous grains and nuts, especially maize (corn) and peanuts. Although, undoubtedly, aflatoxins have been present in the food of humans for millennia, their toxic effects were not discovered until 1960, first becoming evident as a non-infectious outbreak of poisoning of turkeys (Turkey X disease) arising from contaminated groundnut meal. The elucidation of specific chemical structures in 1963 led to the rapid characterization of aflatoxins as among the most potent chemical carcinogens of natural origin ever discovered. As a frontispiece to the Special Issue “65 Years on from Aflatoxin Discovery—A Themed Issue in Honor of Professor John D. Groopman”, we highlight many of Professor Groopman’s important contributions utilizing urinary (aflatoxin–N7–guanine) and, especially, serum (aflatoxin–albumin adducts) biomarkers; this work focused on over 40+ years of the development of analytical methods to measure biomarkers of aflatoxin exposure and their application in experimental and clinical studies. Collectively, this work serves as a template for using chemical-specific biomarkers as key tools to probe ‘exposure–disease relationships’—in this instance, dietary aflatoxins and liver cancer. New approaches to measuring carcinogen biomarkers will build upon this ‘aflatoxin paradigm’ to inform the public health implications of diverse exposures around the world.

The Qidong Liver Cancer Institute (QDLCI) and the Qidong Cancer Registry were established in 1972 with input from doctors, other medical practitioners, and non-medical investigators arriving from urban centers such as Shanghai and Nanjing. Medical teams were established to quantify the extent of primary liver cancer in Qidong, a corn-growing peninsula on the north side of the Yangtze River. High rates of liver cancer were documented and linked to several etiologic agents, including aflatoxins. Local corn, the primary dietary staple, was found to be consistently contaminated with high levels of aflatoxins, and bioassays using this corn established its carcinogenicity in ducks and rats. Observational studies noted a positive association between levels of aflatoxin in corn and incidence of liver cancer across townships. Biomarker studies measuring aflatoxin B1 and its metabolite aflatoxin M1 in biofluids reflected the exposures. Approaches to decontamination of corn from aflatoxins were also studied. In 1993, investigators from Johns Hopkins University were invited to visit the QDLCI to discuss chemoprevention studies in some townships. A series of placebo-controlled clinical trials were conducted using oltipraz (a repurposed drug), chlorophyllin (an over-the-counter drug), and beverages prepared from 3-day-old broccoli sprouts (rich in the precursor phytochemical for sulforaphane). Modulation of biomarkers of aflatoxin DNA and albumin adducts established proof of principle for the efficacy of these agents in enhancing aflatoxin detoxication. Serendipitously, by 2012, aflatoxin exposures quantified using biomarker measurements documented a many hundred-fold reduction. In turn, the Cancer Registry documents that the age-standardized incidence rate of liver cancer is now 75% lower than that seen in the 1970s. This reduction is seen in Qidongese who have never received the hepatitis B vaccination. Aflatoxin mitigation driven by economic changes switched the dietary staple of contaminated corn to rice coupled with subsequent dietary diversity leading to lower aflatoxin exposures. This 50-year effort to understand the etiology of liver cancer in Qidong provides the strongest evidence for aflatoxin mitigation as a public health strategy for reducing liver cancer burden in exposed, high-risk populations. Also highlighted are the challenges and successes of international team science to solve pressing public health issues.

Aflatoxins (AFs) frequently contaminate food and animal feeds, especially in (sub) tropical countries. If animals consume contaminated feeds, AFs (mainly aflatoxin B1 (AFB1), B2 (AFB2), G1 (AFG1), G2 (AFG2) and their major metabolites aflatoxin M1 (AFM1) and M2 (AFM2)) can be transferred to edible tissues and products, such as eggs, liver and muscle tissue and milk, which ultimately can reach the human food chain. Currently, the European Union has established a maximum level for AFM1 in milk (0.05 µg kg−1). Dietary adsorbents, such as bentonite clay, have been used to reduce AFs exposure in animal husbandry and carry over to edible tissues and products. To investigate the efficacy of adding bentonite clay to animal diets in reducing the concentration of AFB1, AFB2, AFG1, AFG2, and the metabolites AFM1 and AFM2 in animal-derived foods (chicken muscle and liver, eggs, and cattle milk), chicken and cattle plasma and cattle ruminal fluid, a sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been developed. High-throughput sample preparation procedures were optimized, allowing the analysis of 96 samples per analytical batch and consisted of a liquid extraction using 1% formic acid in acetonitrile, followed by a further clean-up using QuEChERS (muscle tissue), QuEChERS in combination with Oasis® Ostro (liver tissue), Oasis® Ostro (egg, plasma), and Oasis® PRiME HLB (milk, ruminal fluid). The different procedures were validated in accordance with European guidelines. As a proof-of-concept, the final methods were used to successfully determine AFs concentrations in chicken and cattle samples collected during feeding trials for efficacy and safety evaluation of mycotoxin detoxifiers to protect against AFs as well as their carry-over to animal products.

The conversion of aflatoxin B1 in feed consumed by cows into aflatoxin M1 in their milk poses a challenge to food safety, with milk being a popular staple food and because of the harmful effects of these compounds. This study aimed at reviewing scientific information about the extent of carry-over of AFB1 from feed to milk. A range of studies reported about correlations of carry-over with different factors, particularly with milk yield and AFB1 intake. The extent of carry-over considerably varies, being 1–2% on average, which may be as high as 6% in the case of increased milk production. Specific factors influencing transfer rates, including milk yield, somatic cell counts, aflatoxin B1 intake, source of contamination, seasonal effects, particle size of feed, and the effects of certain interventions, namely vaccination and the use of adsorbents, are identified as the most important and are discussed in this review. The different mathematical formulas describing carry-over and instances of their application are reviewed as well. These carry-over equations may lead to largely different results, and no single carry-over equation can be suggested as the best one. While the exact quantification of carry-over is difficult as the process depends on many factors, including individual variabilities between animals, the intake of aflatoxin B1 and milk yield seem to be the most important factors influencing the excreted amount of aflatoxin M1 and the rate of carry-over.

Laccases (LCs) are multicopper oxidases that find application as versatile biocatalysts for the green bioremediation of environmental pollutants and xenobiotics. In this study we elucidate the degrading activity of Lac2 pure enzyme form Pleurotus pulmonarius towards aflatoxin B1 (AFB1) and M1 (AFM1). LC enzyme was purified using three chromatographic steps and identified as Lac2 through zymogram and LC-MS/MS. The degradation assays were performed in vitro at 25 °C for 72 h in buffer solution. AFB1 degradation by Lac2 direct oxidation was 23%. Toxin degradation was also investigated in the presence of three redox mediators, (2,2′-azino-bis-[3-ethylbenzothiazoline-6-sulfonic acid]) (ABTS) and two naturally-occurring phenols, acetosyringone (AS) and syringaldehyde (SA). The direct effect of the enzyme and the mediated action of Lac2 with redox mediators univocally proved the correlation between Lac2 activity and aflatoxins degradation. The degradation of AFB1 was enhanced by the addition of all mediators at 10 mM, with AS being the most effective (90% of degradation). AFM1 was completely degraded by Lac2 with all mediators at 10 mM. The novelty of this study relies on the identification of a pure enzyme as capable of degrading AFB1 and, for the first time, AFM1, and on the evidence that the mechanism of an effective degradation occurs via the mediation of natural phenolic compounds. These results opened new perspective for Lac2 application in the food and feed supply chains as a biotransforming agent of AFB1 and AFM1.

The efficacy of a UV-A light emitting diode system (LED) to reduce the concentrations of aflatoxin B , aflatoxin M (AFB , AFM ) in pure water was studied. This work investigates and reveals the kinetics and main mechanism(s) responsible for the destruction of aflatoxins in pure water and assesses the cytotoxicity in liver hepatocellular cells. Irradiation experiments were conducted using an LED system operating at 365 nm (monochromatic wave-length). Known concentrations of aflatoxins were spiked in water and irradiated at UV-A doses ranging from 0 to 1,200 mJ/cm . The concentration of AFB and AFM was determined by HPLC with fluorescence detection. LC-MS/MS product ion scans were used to identify and semi-quantify degraded products of AFB and AFM . It was observed that UV-A irradiation significantly reduced aflatoxins in pure water. In comparison to control, at dose of 1,200 mJ/cm UV-A irradiation reduced AFB and AFM concentrations by 70 ± 0.27 and 84 ± 1.95%, respectively. We hypothesize that the formation of reactive species initiated by UV-A light may have caused photolysis of AFB and AFM molecules in water. In cell culture studies, our results demonstrated that the increase of UV-A dosage decreased the aflatoxins-induced cytotoxicity in HepG2 cells, and no significant aflatoxin-induced cytotoxicity was observed at UV-A dose of 1,200 mJ/cm . Further results from this study will be used to compare aflatoxins detoxification kinetics and mechanisms involved in liquid foods such as milk and vegetable oils.

Aflatoxin M1 (AFM1) is a hydroxylated metabolite of aflatoxin B1 (AFB1) that can be excreted in milk of cows after consuming contaminated feed. The aim of this study consisted of a field monitoring to assess the contamination levels of AFB1 in 60 feed samples from two feeding systems for high-yielding dairy cows and of AFM1 in the corresponding raw milk samples. The aflatoxins were analyzed by in-house validated methods based on high-performance liquid chromatography (HPLC) with fluorescence detection. AFB1 was detected in 55% of feed samples (mean 0.61 μg/kg, with 2 samples exceeding the European Union (EU) maximum level set at 5 μg/kg), with greater incidence and concentration in compound feed than in unifeed rations (p < 0.05). AFM1 was detected in 38.3% milk samples (mean 12.6 ng/kg, with 5 samples exceeding the EU maximum level set at 50 ng/kg), with a higher occurrence in milk of cows fed compound feed, as well as in spring milk compared to that produced in winter. The overall transfer ratio of aflatoxins from feed to milk was 3.22%, being higher in cows fed with compound feed and in spring milkings. In a selection of positive matched samples (n = 22), the ratio AFM1/AFB1 exceeded the European Food Safety Authority (EFSA) estimated 6% threshold for high-yielding dairy cows.

Aflatoxins, particularly Aflatoxin B 1 (AFB 1 ), produced by Aspergillus flavus and other species, pose significant health risks due to their carcinogenic properties. This study investigates the inhibitory effects of Protocatechuic Acid (PCA) on mycotoxigenic fungi and AFB 1 production. PCA demonstrated significant dose-dependent antifungal activity against various Aspergillus species, with A. flavus showing inhibition zones ranging from 5.3 mm to 16.7 mm at concentrations of 50 µg/ml to 250 µg/ml, while A. ochraceus exhibited the highest sensitivity, with zones up to 23.6 mm. Additionally, PCA effectively reduced AFB 1 production in liquid media, achieving up to 80.21% inhibition at 250 µg/ml, and decreased the mycelial weight of A. flavus by 60.8%. Gene expression analysis revealed that PCA significantly downregulated the expression of the AFB 1 biosynthetic genes nor -1 (95% reduction) and omt-A (74% reduction), suggesting that PCA disrupts multiple stages of aflatoxin synthesis. Furthermore, PCA demonstrated efficacy in controlling AFB 1 contamination in postharvest corn grains, with inhibition percentages of 44.8%, 55.7%, and 64.6% at 150, 200, and 250 µg/ml, respectively. These findings indicate PCA’s potential as a natural antifungal agent, offering promising applications in food safety and postharvest management.