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24 May 2018

Aflatoxin B1 and M1: Biological Properties and Their Involvement in Cancer Development

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1
Unità di Farmacologia e Tossicologia—Dipartimento di Medicina Veterinaria e Produzioni Animali, Università degli Studi di Napoli “Federico II”, 80138 Napoli, Italy
2
Unità di Farmacologia Sperimentale, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, 80131 Napoli, Italy
*
Author to whom correspondence should be addressed.
Toxins2018, 10(6), 214;https://doi.org/10.3390/toxins10060214
This article belongs to the Special Issue Dietary Mycotoxin Exposure: Emerging Risks to Human Health
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Abstract

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.
Keywords:
aflatoxin; AFB1; AFM1; cancer
Key Contribution:
Aflatoxin B1 (AFB1) and M1 (AFM1) are classified as human carcinogens. Therefore, it is always necessary to identify the genes/proteins/miRNAs that can be used as markers of cellular damage due to AFB1 and AFM1 exposure and cancer initiation.

1. Introduction

Aflatoxins are secondary metabolites produced by different strains of fungi, like Aspergillus flavus and A. parasiticus, widely found as contaminants in a great variety of crops—cereals, oilseeds, tree nuts and spices. Although it is well known that a hot and humid climate promotes diffusion of aflatoxin-producing moulds, representing a greater hazard in tropical areas of the world, the contamination is commonly due to the combination of meteorological conditions, environmental factors and improper agricultural practices, like incorrect harvesting and storage of crops. Indirect exposure to aflatoxins is another point of concern to human and animal health since these compounds can be transferred to offspring during gestation or lactation, or to other species upon the assumption of contaminated products like milk, eggs and meat. Accordingly, for all these reasons aflatoxins still represent a great socio-economic and health issue for both developing and industrialized countries.
Interest in aflatoxins rose in 1960’s when this class of mycotoxins was identified for the first time after an outbreak of acute feed-related mycotoxicosis occurred in England [1]. Since then, different studies ascribed to these compounds some toxic, carcinogenic, mutagenic, teratogenic and immunosuppressive effects on animals and humans [2], defining the liver as the major target organ [3]. The International Agency for Research on Cancer (IARC) evaluated both epidemiological and laboratory studies and indicated aflatoxins as carcinogenic (Group 1) and potentially carcinogenic to human (Group 2B) [4]. The wide range of adverse effects caused by aflatoxin assumption is named aflatoxicosis and has been reported in two forms: (i) “acute intoxication” caused by short exposure to great amount of toxins and characterized by severe liver damage, jaundice, haemorrhage, oedema and eventually death; and (ii) “chronic sublethal exposure,” which leads to immunosuppression, nutritional dysfunctions and cancer.
Among these toxins, Aflatoxin B1 (AFB1) is considered the most recurrent and also the most harmful. Its carcinogenicity and immunosuppression capacity have been extensively reported in all kind of animals, including poultry [5], trout [6], cattle [7] and rats [8,9] with different incidence across species, gender and age. The toxicity in humans has been assessed in association with different outbreaks of acute intoxication, especially in developing countries [10]. Many epidemiological studies focused on the connection between aflatoxins assumption through contaminated food and health problems [11,12]. Several in vitro studies demonstrated that the carcinogenicity of AFB1 is prevalently exerted upon activation by Cytochromes P450 (CYP450) in the liver and elucidated the mechanism of its toxicity [13]. Immunoresponse modulation has been observed on murine macrophages after AFB1 exposure; in fact, some authors showed an anti-proliferative action not related to apoptotic pathways and a reduction in NO levels upon exposure to not cytotoxic concentrations [14].
Another toxin causing great concern is Aflatoxin M1 (AFM1), the principal hydroxylated metabolite of AFB1, found in milk (hence the designation M) of mammals fed upon contaminated feedstuff. Carry-over of AFB1 as AFM1 in the milk of dairy cows has been established to range from 0.3% to 6.2% [15]. However, AFM1 was also found in lactating mother’s milk [16]. Several studies reported carcinogenic [9] and immunosuppressive effects [17] similar to that of AFB1, on both humans and other animals, even if with a less potent effect. Neal et al., demonstrated toxic potential of AFM1 exerted even in absence of the metabolic activation typically needed to AFB1, thus pointing out that caution should be put when classifying AFM1 as essentially detoxification product of AFB1 metabolism [13]. However, AFM1 is the only mycotoxin for which maximum residue limits (MRLs) in milk were established.
Even if a great number of studies focused on aflatoxins in the past fifty years, a complete assessment of the risk for human health has not been completed. Still few in vitro studies can be found, in particular regarding AFM1, in contrast with the concern aroused. To better understand the effects on human health, with particular regard to children which results more sensitive to intoxications due to biological and exposure causes, more studies should be carried out.
Therefore, in this review, we decided: (i) to summarize the activation pathways of AFB1 and AFM1; (ii) to describe the data, already reported in literature, about their correlation with cancer development and progression; and (iii) to identify by a bioinformatic analysis 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.

2. Chemical Properties of AFB1 and AFM1

In general, the aflatoxins are a family of compounds generally classified as difuranocoumarins, highly substituted coumarin derivatives containing a fused dihydrofurofuran moiety. In particular, AFB1 is characterized by the fusion of a cyclopentenone ring to the lactone ring of the coumarin structure (Figure 1) and by strong fluorescence emission in the blue region (hence the designation B) when exposed to ultraviolet light. AFM1 is the principal hydroxylated metabolite of AFB1 and is produced upon the action of Cytochrome P450 1A2 (CYP1A2) [18,19]. It is strongly fluorescent, emitting blue-violet light.
Figure 1. Chemical structures of Aflatoxin B1 and Aflatoxin M1.
Both toxins have similar chemical properties: they are slightly soluble in water, insoluble in nonpolar solvents and freely soluble in polar organic solvents [20]. They have strong thermal stability, even at high temperature (>100 °C), that prevent them from being thermally degraded during food manufacturing. This represents a great obstacle in the reduction of aflatoxin food contamination, especially in milk and dairy products, since pasteurization and other thermal treatment alone showed to be poorly effective [21,22].
Other chemical properties like instability to UV light or extreme pH condition (<3 or >10) and the reactivity of lactone moiety in presence of ammonia or hypochlorite, led to the development of other methods of decontamination of feed and food. However, several physical treatments like microwaves, gamma-rays, X-rays and ultra-violet light have been investigated but controversial results discouraged the use of these methods, especially for heavily contaminated samples [23]. At present, ammoniation [24] and adsorption on clays or organic adsorbents [21] are commonly used to assure a good level of decontamination without disruption of the nutritional properties or safety of feed. Focusing on AFM1 in milk, recently some researchers are focusing on the AFM1-binding capacity of different strains of Lactobacilli [25,26].

3. Principal Activation Pathways of AFB1 and AFM1

To understand the mechanism through which aflatoxins exert their toxic effects, it is important to understand how they are metabolized. The aflatoxins have been reviewed already in 1994 by Eaton and Gallagher [27]. In Figure 2 we report a schematic representation of AFB1 and AFM1 metabolism.
Figure 2. Schematic representation of AFB1 and AFM1 metabolism.
In detail, AFB1 is mainly metabolized in the liver upon the action of the microsomal mixed function oxidase (MFO) enzymes belonging to the superfamily of CYP450. Upon action of these oxidases, AFB1 is converted in the reactive 8,9-epoxide, existing as two stereoisomers, exo and endo, with the former reported to be the toxic species responsible for AFB1 genotoxic properties [13]. The exo-8,9-epoxide has a high binding affinity toward the DNA, forming the 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-AFB1 (AFB1-N7-Gua) adduct, thus leading to DNA mutations [28]. This epoxide form is involved also in other pathways: (i) conjugation with glutathione (GSH) catalysed by Glutathione-S-Transferase (GST) with subsequent excretion as AFB-marcapturate; this pathway is vital for the detoxification of AFB1 as a carcinogen, even if a depletion of GHS could lead to high levels of reactive oxigene species (ROS) causing oxidative damage [29]; (ii) enzymatic and non-enzymatic conversion in AFB1-8,9-dihydroxydiol, that can be further converted in the dialdehyde form; aflatoxin dialdehyde can be excreted through urine as dialcohol upon action of aflatoxin aldehyde reductase (AFAR) or can bind proteins, like albumin [18]; (iii) binding to other macromolecules like proteins or RNA, causing dysregulation of normal cellular functions and inhibition of proteins, DNA and RNA synthesis [28]. Microsomal biotransformation of AFB1 includes also hydroxylation of the toxin, leading to the formation of more polar and less toxic metabolites, mainly AFM1 and Aflatoxin Q1 (AFQ1). Different studies tried to assess the role of CYP450 enzymes responsible for the formation of carcinogenic or detoxifying metabolites. CYP1A2 and CYP3A4 resulted to be the most active isoenzymes of this family and capable to activate AFB1 [30]. In detail, CYP3A4 is responsible for the formation of AFB1-exo-8,9-epoxide and of little amount of AFQ1, whereas CYP1A2 leads to both exo- and endo-8,9-epoxide and to the hydroxylated AFM1. The other two isoenzymes that resulted to have AFB1 as a substrate, even if in minor extent, are CYP3A7, expressed in human foetal liver and CYP3A5 [18].
It is well established that AFB1 epoxidation is the key step in the genotoxic process and thus in the carcinogenesis. The high affinity of the epoxide intermediate for purine bases of DNA leads to the formation of AFB1-N7-Gua adduct, that promotes mutations in nucleotide sequence. The charged adduct causes depurination and thus apurinic site formation [18]. The predominant mutation caused by AFB1-N7-Gua adduct has been identified to be the G→T transversion on the site of the original adduct [31]. Moreover, the mutation has been reported to affect specific base pair locations, showing selectivity towards guanine bases with a guanine or a cytosine as 5′ base and more specifically at the third base of codon 249 of the p53 tumour suppressor gene [32]. This mutation resulted really common in a great number of epidemiological studies on hepatocellular carcinoma (HCC) patients from regions of high aflatoxin exposure, strengthening the association between HCC incidence and aflatoxin exposure [33]. Another mutation has also been found in c-KRAS oncogene in AFB1-induced HCC in rats [34] and activation of human HRAS proto-oncogene was reported in vitro [35] suggesting an involvement of these genes in AFB1-related tumorigenesis.
Interestingly, aside from the principal biotransformation pathway involving CYP, other activation mechanisms have been reported. In fact, the epoxidation catalysed by Prostaglandin H (PGH) synthase has been described by Battista et al. [36], whereas Weng et al. hypothesized a novel mechanism in which lipid peroxidase (LPO) is the main responsible for AFB1 carcinogenesis, triggering the production of cyclic α-methyl-γ-hydroxy-1,N2-propano-dG (meth-OH-PdG) adduct and inhibiting DNA repair [37].
Another important role in DNA damage and thus carcinogenesis, is played by oxidative stress. In fact, a recent study showed that AFB1 induced ROS and oxidative stress and activated mitochondrial ROS-dependent signal pathways, which induced apoptosis through the mitochondrial signal pathway [38].
On the other hand, it is important to underline that AFM1 is primarily considered a detoxification product of AFB1 metabolism, showing only 10% of mutagenicity compared to its precursor [39]. The metabolic fate of AFM1 resulted to be similar to that of AFB1, with the difference that AFM1 represents a poorer substrate for epoxidation, thus explaining the differences in genotoxicity potencies. Moreover, it has been reported that CYP activation is not required to AFM1 to exert cytotoxic effects [13].

5. Analysis of Genes/Proteins Modulated by AFB1/AFM1 by Systems Biology Approach

On the basis of the data reported above, there are some proteins modulated by AFM1/AFB1 like CYP1A2, CYP1A5, CYP3A4, TP53, GSMT1, MDM2, CAT, OGG1, IRS1, IRS2, SRC, AKT1, MAPK1, MAPK3 and PDK1. These proteins are involved in important metabolic pathways such as FoxO signalling pathway, PI3K-Akt signalling pathway, AMPK signalling pathway, MAPK signalling pathway and VEGF signalling pathway (Table 1).
Table 1. Pathways in which the proteins modulated by AFB1/AFM1 are involved.
Considering that it is important to understand the molecular mechanisms through which these aflatoxins can modulate contemporaneously many proteins, we mapped them on the entire human interactome (INTACT) and constructed the relative interaction network by Cytoscape in order to know if and how these proteins are correlated between them using the same protocol that our group has recently developed [91]. The obtained network resulted to be composed of 71 nodes (proteins) and 121 edges (interactions). In particular, thirteen proteins modulated by AFM1/AFB1 (CYP3A4, TP53, GSMT1, MDM2, CAT, OGG1, IRS1, IRS2, SRC, AKT1, MAPK1, MAPK3 and PDK1) were present. In detail, we can underline that: (i) AKT1 shows a direct interaction with SRC and MDM2 nodes; (ii) TP53 displays a direct interaction with MAPK1 and MDM2 nodes; and (iii) MAPK1 is directly linked to MAPK3. On the other hand, the other proteins (CYP3A4, GSMT1, CAT, OGG1, IRS1, IRS2, SRC and PDK1) are correlated between them by other nodes present in the network (Figure 3). Among these nodes, we found NR1I2 (encoding a transcriptional regulator of CYP3A4) and GNMT (encoding an enzyme that catalyses the conversion of S-adenosyl-l-methionine to S-adenosyl-l-homocysteine and sarcosine) that are known to be modulated by AFM1 even if in non-specific cancer studies. In fact, AFM1 is able to increase the activity of NR1I2 protein [92], whereas GNMT induces the increased secretion of AFM1 [93]. However, in general, GNMT is known to have a role in the methionine metabolism and in the gluconeogenesis and to act as tumour gene. In fact, studies have demonstrated decreasing levels of GNMT in both HCC cell lines and tumour tissues [94] and higher cytoplasmic levels correlated to growing promotion and progression of prostate cancer [95]. On the other hand, NR1I2 has higher expression levels in prostate cancer and breast cancer progression [96] and has also a role in endometrial tumours and their progression [97] and in hematologic cancers such as B cell lymphoma [98]. It is resulted also to be involved in ovarian cancer and colorectal cancer initiation; in fact, its activation induces both tumour progression and chemotherapy resistance in both these tumours [97,99,100].
Figure 3. Interaction network of proteins modulated by AFM1 where these proteins are depicted in light-blue whereas the linking nodes in blue.
In summary, the correlation between these nodes indicates that they are strictly correlated between them at functional level and, thus, we can suggest evaluating their levels to predict the effects of AFB1 and AFM1 exposure on cancer initiation and progression.
Considering the important role of miRNAs in cancer initiation and progression, we have analysed what miRNAs can target fifteen selected genes and created the related miRNA-gene interaction network using the same protocol reported in [91]. In detail, firstly, the list of miRNAs able to target the selected genes was extracted by MirNet tool; and secondly, an interaction network between selected miRNAs and genes was constructed by the Cytoscape package. Our analysis has identified 2053 miRNAs able to target fifteen genes (CYP1A2, CYP3A4, NR1I2, GNMT, NR1I2, TP53, MDM2, CAT, OGG1, IRS1, IRS2, SRC, AKT1, MAPK1, MAPK3 and PDK1). Starting from the list of all the identified miRNAs we constructed an interaction network composed by 2068 nodes and 19218 interactions. Focusing on the miRNAs able to target different genes at the same time, we evidenced that the genes are targeted by twelve following miRNAs: hsa-miR24-3p, hsa-miR-6778-5p, hsa-miR-6514-3p, hsa-miR-5010-5p, hsa-miR-23a-5p, hsa-miR-25-5p, hsa-miR-6792-5p, hsa-miR-6866-5p, hsa-miR-4728-5p, hsa-miR-6825-5p, hsa-miR-6803-3p, hsa-miR-6794-5p (Table 2 and Figure 4).
Table 2. List of twelve miRNAs linking and targeting genes modulated by AFB1/AFM1.
Figure 4. Sub-network of genes modulated by AFB1/AFM1 and twelve miRNAs linking these genes. In detail, miRNAs are shown in orange and genes in blue.
Some of these twelve miRNAs are already reported as involved in cancer in literature. In fact, it is important to underline that hsa-miR-24-3p is up-regulated in gastric cancer and breast cancer and promotes cell growth, apoptosis and invasion mechanisms [101,102]. Hsa-miR-23a-5p promotes the cell growth in gastric cancer [103], regulates colon cancer metastasis and induces invasion and progression [104], is capable to induce higher vascular and endothelial permeability in lung cancer [105] and contributes to metastasis and autophagic process in melanoma cancer [106]. In regard to hsa-miR-25-5p, it is involved in proliferation and invasion mechanisms in lung cancer [107], is associated with a poor survival in gastric cancer patients [108], regulates apoptosis in ovarian cancer [109], promotes cell proliferation in triple negative breast cancer [110] and reduces the cell invasion in prostate cancer [111]. Hsa-miR-4728-5p is a negative regulator of MAPK correlated with a negative overall survival in breast cancer [112] and was found as a tumour suppressor in the ulcerative colitis associated with colon cancer [113]. Hsa-miR-6803 results a potential diagnostic and prognostic biomarker in colorectal cancer and its increased levels are associated with a poor overall survival and prognosis [114]. No information about the involvement of hsa-miR-6778-5p, hsa-miR-6514-3p, hsa-miR-5010-5p, hsa-miR-6792-5p, hsa-miR-6866-5p, hsa-miR-6825-5p, hsa-miR-6794-5p in cancer can be found in literature, suggesting the necessity of further studies to elucidate their role in cancer initiation, also due to AFM1 and AFB1 exposure.

6. Conclusions

In this review, we summarize the chemical properties of AFB1 and AFM1, their activation pathways and the data, already reported in literature, about their correlation with cancer development and progression. In the context, the published data evidenced that AFB1 and AFM1 exposure were already associated mainly with liver, lung and colon cancer initiation and progression. Still few data are known about other cancers, and, hence, further studies will be necessary.
Moreover, considering that few data suggest what genes/proteins/miRNAs can be used as damage markers due to AFB1 and AFM1 exposure, we performed an interaction network analysis and miRNA predictions able to target genes modulated by these two toxins. The network analysis suggests that thirteen proteins modulated by AFM1/AFB1 (CYP3A4, TP53, GSMT1, MDM2, CAT, OGG1, IRS1, IRS2, SRC, AKT1, MAPK1, MAPK3 and PDK1) are correlated between them both directly and through other nodes, such as NR1I2 and GNMT. On the other hand, the analysis of miRNA prediction has evidenced that there are twelve miRNAs able to target the genes known to be modulated by AFM1.
In conclusion, we suggest that it would be very interesting to focus further experimental studies on the evaluation of the expression changes of these genes/proteins/miRNAs to verify if they can be used as damage markers due to AFB1 and AFM1 exposure and, hence, as indexes of cancer initiation or progression.

Author Contributions

S.M., S.C. and L.S. conceived this manuscript; A.P. and S.C. performed the bioinformatics analysis; S.M., A.P., A.A. and S.V. contributed to write the paper; S.C. and L.S. revised the manuscript.

Acknowledgments

S.C. was supported by Italian Ministry of Health to IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Napoli (Italia) (progetto 5x1000 2016–2017). A.P. was supported by Progetto di Ricerca Corrente "Analisi integrata del profilo citochinomico e metabolomico mediante un approccio di systems biology" at IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Napoli (Italia). S.M. was supported by fellowship (Cod. 19-2018) at Dipartimento di Medicina Veterinaria e Produzioni Animali, Università degli Studi Di Napoli “Federico II”

Conflicts of Interest

The authors declare no conflict of interest.

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