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World Mycotoxin Journal, 2021

2021;online
## (##): 1-16 ARTICLE IN PRESS P u b l i s h e r s

An update on genotoxic and epigenetic studies of fumonisin B1

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I.B. Molina-Pintor1,2, A.E. Rojas-García1, I.M. Medina-Díaz1, B.S. Barrón-Vivanco1, Y.Y. Bernal-Hernández1,
L. Ortega-Cervantes1, A.J. Ramos3, J.F. Herrera-Moreno4 and C.A. González-Arias1*

1Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma

de Nayarit, Los fresnos s/n. Tepic, Nayarit C.P. 63155, México; 2Posgrado en Ciencias Biológico Agropecuarias, Unidad
Académica de Agricultura, Km. 9 Carretera Tepic-Compostela, Xalisco, Nayarit, Mexico; 3Food Technology Department,
Lleida University, UTPV-XaRTA, Agrotecnio Center, Av. Rovira Roure 191, Lleida, 25198, Spain; 4Laboratory of Precision
Environmental Health Sciences, Mailman School of Public Health, Columbia University, 630 west 168th Street, P&S Building
Room 16-416, New York, NY, USA; cyndia.gonzalez@uan.edu.mx

Received: 25 June 2021 / Accepted: 5 September 2021

© 2021 Wageningen Academic Publishers

REVIEW ARTICLE
Abstract

Fumonisins (FBs), a widespread group of mycotoxins produced by Fusarium spp., are natural contaminants in cereals
and foodstuffs. Fumonisin B1 (FB1) is the most toxic and prevalent mycotoxin of this group, and it has been reported
that FB1 accounts for 70-80% of FBs produced by the mycotoxigenic strains. The mode of action of FB1 depends
on the structural similarity with sphinganine/sphingosine N-acyltransferase. This fact causes an accumulation of
sphingoid bases and blocks the sphingolipid biosynthesis or the function of sphingolipids. Diverse toxic effects and
diseases such as hepatocarcinogenicity, hepatotoxicity, nephrotoxicity, and cytotoxicity have been reported, and
diseases like leukoencephalomalacia in horses and pulmonary oedema in horses and swine have been described. In
humans, FBs have been associated with oesophageal cancer, liver cancer, neural tube defects, and infantile growth
delay. However, despite the International Agency for Research on Cancer designated FB1 as a possibly carcinogenic to
humans, its genotoxicity and epigenetic properties have not been clearly elucidated. This review aims to summarise
the progress in research about the genotoxic and epigenetics effects of FB1.

Keywords: mycotoxin, apoptosis, cytotoxicity, genotoxicity, epigenetics

1. Introduction FBs are ubiquitous mycotoxins commonly found in maize

Fumonisins (FBs) are a group of mycotoxins mainly produced
by Fusarium verticillioides (formerly F. moniliforme)
and Fusarium proliferatum, but also produced by other
Fusarium species, such as Fusarium sacchari, Fusarium
subglutinans, Fusarium thapsinum, Fusarium anthophilum,
Fusarium globosum, Fusarium nygamai, Fusarium fujikuroi,
Fusarium dlamini, Fusarium napiforme, Fusarium
pseudonygamai, Fusarium andiyazi, Fusarium oxysporum
and Fusarium polyphialidicum (Munaut et al., 2011;
Rheeder et al., 2002). Structurally similar compounds have
been described to be produced by members of the fungal
genera Alternaria (AAL-toxins, produced by Alternaria
alternata f. sp. lycopersici).
and derivatives. Their presence in animal and human
food has been reported worldwide (Marschik et al., 2013;
Sydenham et al., 1991). Until now, 28 types of FBs have
been identified and grouped into four series: A, B, C
and P (Bartók et al., 2010; Rheeder et al., 2002). The FBs
family is characterised by a polyhydroxy alkyl carbon chain
containing 18-20 carbon atoms, which can be mono or
diesterified, mainly with propane-1,2,3-tricarboxylic acid
(tricarballylic acid, TCA) (Bartók et al., 2010; Munkvold et
al., 2019). Furthermore, the series of FBs differ in number
and location of the hydroxyl groups in the hydrocarbons
of the main chain of the molecule (Bartók et al., 2010).
The most crucial series due to its natural abundance is
the B series, and its toxicologically important analogues
are fumonisin B1, B2 and B3 (Marasas, 1996). The most
toxic and prevalent analogue of series B is fumonisin B1

ISSN 1875-0710 print, ISSN 1875-0796 online, DOI 10.3920/WMJ2021.27201

 I.B. Molina-Pintor et al.

(FB1), which represent about 70 to 80% of the FBs produced
(Bartók et al., 2010; Rheeder et al., 2002). This molecule has
an amino group and two TCAs at positions 14C and 15C
(Figure 1). Nowadays, there is no information regarding
the pKa of FB1 in the literature. However, based on the pKa
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the organic anion transporter of rat and humans (rOATs/
hOATs) and organic cation of human transporters (hOCTs),
and these may be the ingress pathway into the liver and
reuptake in the kidney of FB1, leading the induction
of adverse effects in these organs (Sekine et al., 2000;

values at physiological pH between 6 and 9 for TCA (3.49,
4.56 and 5.83) and the amine group (pKa = 9), FB1 could
have amphoteric characters due to the transfer of a proton
from their carboxylate group towards their amino group
(National Toxicology Program, 2001; Pietri and Bertuzzi,
2012). Additionally, FB1 is a stable thermal molecule at
75 °C for 135 min or 125 °C for 5 min (National Toxicology
Program, 2001). Nonetheless, their stability depends on pH
conditions, because in alkaline environments FB1 could be
hydrolysed to forms without one or both TCA groups, and
the hydrolysis increases with pH, preferentially at pH 7.5
(Bryła et al., 2017).
Due to its structural similarity with sphinganine/sphingosine,
FB1 is a potent inhibitor of the enzyme ceramide synthase
(CerS), also known as sphingosine-N-acetyltransferase, what
causes an accumulation of sphingoid bases and blocks the
sphingolipids biosynthesis or the function of sphingolipids
(Wang et al., 1991). Relating to FB1 genotoxicity and
carcinogenicity, the International Agency for Research on
Cancer (IARC) has designated this compound as possibly
carcinogenic to humans (Group 2B) (IARC, 2002).
2. Toxicokinetic of fumonisin B1
Fumonisin B 1 is unsuccessfully absorbed after oral
administration (Shier, 2000). However, based on recent
information, it could alter the intestinal barrier throughout
Tachampa et al., 2008).
In biotransformation, there is no evidence that FB1 is
metabolised in the liver by cytochrome P450 or any
microsomal enzyme. Nevertheless, it was reported that
intestinal microbiota in primates (Shephard et al., 1994a),
ruminants (Rice and Ross, 1994) and pigs (Fodor et al., 2008)
hydrolytically remove the TCA groups and produce a partially
hydrolysed fumonisin (Fodor et al., 2008; Shephard et al.,
1994a). Currently, three FB1 metabolites have been identified,
two partially hydrolised, the aminopoliol 1 (PHFB1) and
aminopoliol 2 (PHFB2), and aminopentol (HFB1) the
complete hydrolysed metabolite (Caloni et al., 2002; Rice
and Ross, 1994; Shephard et al., 1994a,b) (Figure 2).
The main difference between FB1 and its metabolites is
the change in polarity and the ability to pass membranes,
because of the cleavage of TCA groups; for example, HFB1 is
more polar than FB1 and the partially hydrolysed products.
In vitro studies exhibited higher absorption by diffusion
across cell membranes (Caloni et al., 2002; De Angelis et
al., 2005; Schmelz et al., 1998). In vitro studies have shown
that HFB1 absorption occurs through P-glycoprotein and
proteins associated with multidrug resistance (De Angelis
et al., 2005; Xue et al., 2015).
Concerning in vivo studies, several models of mammal
species have been employed to evaluate the toxicokinetics

O
OH
O

OH
O
O OH
H3C
CH3
CH3 CH3 OH OH
O NH2
O
HO

O
HO
O
Figure 1. Structure of fumonisin B1 (FB1). The molecular formula of FB1 is C34H59NO15, the molecular weight is 721.83 g/mol, the
IUPAC name is (2R,2’R)-2,2’ [[(5R,6R,7S,9S,11R,16R,18S,19S)-19-amino-11,16,18-trihydroxy-5,9-dimethyl-6,7 icosanediyl]bis[oxy(2-
oxo-2,1-ethanediyl)]] disuccinic acid and its synonyms are 1,2,3-propanetricarboxylic acid, 1,1N-[1-(12-amino-4,9,11-trihydroxy-
2-methyltridecyl)-2-(1-methylpentyl)1,2 ethanediyl]ester and macrofusin (National Toxicology Program, 2001).

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  Genotoxic and epigenetic effects of fumonisin B1

OH OH

H3C
CH3
CH3 CH3 OH OH
O NH2
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O
HO

O
HO
O
Partially hydrolysed B1 (PHFB2)
O
OH
O

OH
O
O OH
H3C
CH3
CH3 CH3 OH OH
OH NH2
Partially hydrolysed B1 (PHFB1)

OH OH

H3C
CH3
CH3 CH3 OH OH
OH NH2
Hydrolysed fumonisin B1 (HFB1)

Figure 2. Fumonisin B1 (FB1) metabolites: aminopoliol 1 (PHFB1), aminopoliol 2 (PHFB2) and aminopentol (HFB1).

of FB1 and most of them have reported that FB1 has low
bioavailability and that its elimination occurs majorly
through faeces, minorly through urine, and it has its largest
accumulations in the liver and kidney (Dilkin et al., 2010;
Martinez-Larranaga et al., 1999; Prelusky et al., 1994, 1996;
Schertz et al., 2018; Shephard et al., 1992a,b, 1994c; Tardieu
et al., 2008, 2009; Vudathala et al., 1994). It should be taken
into account that several factors influence the toxicokinetics
of FB1, such as concentrations, dosing route and exposure
time, age, sex, physiological condition, nutritional status
and environment.
3. Mechanism of action of fumonisin B1
The principal mechanism of action described for FB1
is the inhibition of CerS (Wang et al., 1991), which is
based on its structural similarity with sphingoids bases
like sphingosine (So) and sphinganine (Sa) (Figure 3). FB1
appears to interact with binding sites for sphinganine and
fatty-acyl-coenzyme A (CoA), and this biological activity
is induced by its free amino group at C2 (Humpf et al.,
1998; Merrill et al., 1993). As a result of this inhibition, an
accumulation of Sa and So and an increase in the Sa:So
ratio occurred (Bolger et al., 2001; Voss et al., 2001). The
reduction of the concentration of ceramide subsequently
increases sphingosine 1-phosphate and reduces the
formation of sphingomyelin (Marasas et al., 2004; Riley et
al., 2001). In this sense, sphingolipids are essential for cell
regulatory processes, and Sa and So accumulation are highly
toxic for cells (Wen et al., 2016). According to Riley et al.
(2001), the mechanism of action follows three sequences of
events: (1) inhibition of ceramide biosynthesis by blocking
the enzyme CerS, (2) increase of free sphinganine and
sphinganine and (3) increase of intracellular concentration
of free sphingoid bases and their 1-phosphates. Processes
discussed earlier have been related with to apoptosis,
proliferation, differentiation, morphology, cytotoxicity
and carcinogenicity in vivo and in vitro studies (Bolger et
al., 2001; Feijó Corrêa et al., 2018; Marasas et al., 2004;
Voss et al., 2002).

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On the other hand, in vivo studies reported that FB1 induced
NTD during the critical gestational window for the closure
of the neural tube accompanied by the markedly disrupted
sphingolipid metabolism (Gelineau-van Waes et al., 2005;
Sadler et al., 2002; Voss et al., 2009). In addition, two in
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toxic than the parent compound (Gelderblom et al., 1993;
Hopmans et al., 1997; Voss et al., 1996). Moreover, further
in vivo and in vitro results exposed that HFB1 and FB1 were
metabolised by CerS to N-acylated metabolites (Figure 3)
(with fatty acids of various chain lengths C16-HFB1 and

vitro studies in the literature reported that FB1 reduced
the levels of sphingolipids accompanied by the inhibition
of 5-methyltetrahydrofolate uptake and the decrease in
total folate binding by the decrease in the folate receptor
expression (Abdel Nour et al., 2007; Stevens and Tang,
1997). Folate is a methyl group donor in the one-carbon
metabolism cycle, that describes a complex biochemical
network of intracellular one-carbon transfer reactions as
methyl groups for nucleotide synthesis and methylation
reactions (Nijhout et al., 2008), and its deficiency has been
linked to a vast array of pathologies including cancer (Liu
and Ward, 2010).’ Yamazoe et al. (2017) suggested based
on animal’s models, that loss of phosphatydylcholine in bile
could be a main etiological factor by FB1. Due to deficiency
of phosphatidylcholine supply, the excretory function of bile
is suppressed and such suppression would be considered
the initial event of FB1-mediated liver toxicity.
It seems that the toxicity of HFB1 is lower than that of FB1,
as different in vivo and in vitro studies have demonstrated
(Caloni et al., 2002; Fodor et al., 2008; Gu et al., 2019;
Hendrich et al., 1993; Howard et al., 2002; Van der
Westhuizen et al., 1998; Voss et al., 2009). Contrarily,
other in vitro studies have shown that HFB1 could be more
C24: 1-HFB1), and these products also inhibited the CerS
and were more cytotoxic in vivo than HFB1 and in vitro than
the FB1 in human’s cells (Abou-Karam et al., 2004; Harrer
et al., 2013; Humpf et al., 1998; Seiferlein et al., 2007).
These results suggest that the toxicity of FB 1 and its
metabolites, in addition to altering sphingolipid metabolism,
may be mediated through their effects on folate status and
methyl donor metabolism.
4. Cytotoxicity of fumonisin B1
Cytotoxicity caused by FB1 has been reported in in vitro
models, and it is related to the increase in sphingoid bases
that could be linked to increased oxidative stress and
alteration on the cell membrane and in the cell cycle. In
this sense, Gelderblom et al. (1993) evaluated the cytotoxic
effect of FBs and its metabolites in primary rat hepatocytes
exposed to 250 to 1000 µM of FBs. The results showed
that FB2 has the highest cytotoxic effect followed by FB3
and FB1 in all doses tested. In contrast, fumonisin A1 and
A2 (FA1 and FA2) had lower cytotoxicity to 1000 µM than
FB1, whereas alternatively the aminopolyols (AP1 and AP2)
exhibited higher cytotoxicity than FB1. Another similar

Serine
+ ↓ Sphingomyelin
Palmitoyl-CoA
Diacylglycerol
↓ Complex
Glycosphingolipids

3-ketosphinganine
Glycosylceramide
↓ PC

↑ Sphinganine Dihydroceramide Ceramide ↑ Sphingosine

CerS
CerS

FB1
HFB1
↑ Sphinganine-1-P CerS ↑ Sphingosine-1-P

N-acyl-FB1
N-acyl-HFB1

Figure 3. Sphingolipids metabolism and disruption by fumonisin B1 and its metabolites. The level of sphingolipids and PC are
indicated using arrows. CerS: ceramide synthase. PC: phosphatidylcholine.

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  Genotoxic and epigenetic effects of fumonisin B1
study conducted by Van der Westhuizen et al. (1998),
evaluated the cytotoxic effect of FB1 and compounds with
similar structures (AP1 and isomers of the AAL toxins,
designated TA1 and TB1) in primary rat hepatocytes. Their
results expressed that FB1 exhibited the highest cytotoxicity
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compared with other similar compounds at 75, 250 and 500
µM. AP1, TA1 and TB1 induced a greater increase in the
concentration of Sa than FB1, and the presence of an amino
group appears not to be a requisite for activity, because
FA1 increased the Sa:So ratio to the same extent as FB1.
Additionally, Yoo et al. (1992) exposed porcine kidney cells
(LLC-PKr cells) to 10, 35 and >35 µM of FB1 and fumonisin
B2 (FB2). After 24 h, the treatment between 10 and 35 µM
inhibited cell proliferation, whereas concentrations >35 µM
were cytotoxic with an increase in So and Sa levels in a dose-
dependent manner. Abel and Gelderblom (1998) reported
cytotoxicity with an increased level of lipid peroxidation
in primary rat hepatocytes treated with FB1 (75, 150, 250
and 500 µM) for 44 h. Ribeiro et al. (2010) reported the
cytotoxic effect of FB1 at concentrations of 50 µM after
4 h of treatment in rat primary hepatocytes. Besides,
Myburg et al. (2002) worked with human oesophageal
carcinoma cells (SNO) exposed to 2.165 to 34.64 μM of FB1,
and they observed that FB1-treated cells had 23% of cell
mortality with 34.64 μM FB1 after 48 h. According to the
results of several studies, the presence of the amino group
in the molecular structure of FB1 is essential but it does
not determine the inhibition of CerS and the subsequent
cytotoxic effect. It is essential to address the cytotoxic
properties of FB1 as inconsistent in the literature (Table 1).
Studies have reported the accumulation of free sphingolipid
bases and apoptosis by FB1 in different cell types, such as
kidney green monkey (CV-1) exposed to 1 and 5 µM of
FB1 (Wang et al., 1996) and human colonic epithelial cell
line (HT29 cells) exposed to 10 and 50 µM of FB1 (Schmelz
et al., 1998).
FB1 has been reported to induce apoptosis extrinsically
and intrinsically. The extrinsic pathway is activated after
a ligand binds to the tumour necrosis factor (TNF) family
receptor, triggering its intracellular portion to activate the
pro-caspase-8 initiator, which subsequently activates the
executing caspases (-3 and -7), responsible for the cleavage
of cytoskeleton proteins and nuclear proteins, which leads
to cell apoptosis (Ashkenazi and Dixit, 1998; García and
Vecino, 2003). Some studies have reported the activation
of TNF receptors by FB1. Ciacci-Zanella and Jones (1999)
co-transfected CV-1 cells, human primary lung fibroblasts
(IMR-90) and human neonatal kidney cells, and FB1-
induced apoptosis was inhibited by inhibitors of apoptosis
protein (IAP) in all cell types. As IAP prevents apoptosis
by interfering with the TNF or Fas pathway, the authors
hypothesised that FB1-induced apoptosis occurs via the
TNF pathway and activates specific caspases downstream
of the TNF receptor. Jones et al. (2001) indicated that IAP
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efficiently inhibited apoptosis by FB1, caspase 8 were
activated and cdk2 activity increased two- to three-old by
FB1 treatment in CV-1 cells; whereas in mouse embryo
fibroblasts (MEF) p53–/– or p53+/+, p53 was not to be
absolutely necessary for FB1-induced apoptosis, it appeared
to have an effect on the ability of Bcl-2 to inhibit apoptosis.
Additionally, some authors have reported that repeated
treatments in several strains of mice with FB1 increase gene
expression of TNF and caspase-8 (Bhandari and Sharma,
2002; Bhandari et al., 2002a,b; He et al., 2002; Sharma et
al., 2000, 2001).
Bhandari et al. (2002b) observed in adult male and female
BALB/c mice that FB1 treatment caused induction of
pro-apoptotic Bax and Bad expression in both sexes,
whereas anti-apoptotic Bcl-2 expression increased only
in females. Bcl-2 is an anti-apoptotic protein that is
located in the outer membrane of mitochondria and
functions by blocking the release of cytochrome C from
the mitochondria, while Bax proteins are pro-apoptotic
and are located in the mitochondrial membrane, inducing
the release of cytochrome C from mitochondria and the
apoptosis; and it has been hypothesised that Bax induces
the release of cytochrome C by inhibiting the function
of Bcl-2 or that the levels of Bcl-2 in the mitochondrial
membrane could decrease with increasing levels of Bax
(Pawlowski and Kraft, 2000). According to the authors, the
induction of Bcl-2 in females could have a protective effect
in response to the greater toxicity observed in females
than in males. However, BAX expression was lower in
females than in males, therefore it is possible that BAX
levels were not sufficient to decrease Bcl-2 expression.
However, the expression of caspase-3 increased after FB1
treatment in both males and females. Thus, an increase in
caspase-3 has been associated with apoptosis mediated by
FB1 in some cells. Galvano et al. (2002b) exposed human
fibroblasts to 50 and 100 µM of FB1, and the treatment
induced DNA damage and an enhancement of caspase-3-
activity. Other authors reported similar results in human
kidney epithelial-1 (IHKE-1) cells (Seefelder et al., 2003),
human U-118MG glioblastoma cells, mouse GT1-7
hypothalamic and rat C6 glioblastoma cells (Stockmann-
Juvala et al., 2006), splenocytes (Abbès et al., 2016), primary
rat hepatocytes (Kim et al., 2008; Riedel et al., 2016)
and porcine kidney LLC-PK1 cells (Gopee and Sharma,
2004). Indeed, Chuturgoon et al. (2015) exposed HepG2
cells to 200 µM of FB1. In this experimental condition,
activities of caspase-3/-7 were not affected but caspase-8/-9
activities increased at 50 µM of FB1. Contrarily, Khan et
al. (2018), treated SNO cells with lower treatment than
Chuturgoon et al. (2015), and observed an increase in
caspase-3/-7 activity in cells exposed to 1.25 and 10 µM.
In summary, the cytotoxic effect of FB1 can be caused by the
inhibition of CerS, and this inhibition causes various cellular
events that promote apoptosis. This review proposes that
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Table 1. Fumonisin B1 (FB1) cytotoxic and non-cytotoxic effects in different cell types.

Cell type1 FB1 concentration Treatment time Effects Reference

MDCK cells 2.5 μg/ml 4 days Cytotoxic Shier et al. (1991)

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Primary rat hepatocytes 250, 500 and1000 µM 48 hours Gelderblom et al. (1993)
H4TG cells 4.2 and 18 µM 48 hours Abbas et al. (1993)
MDCK cells 54.1 and 36.2 µM
Primary human keratinocytes 10 µM 5 days Tolleson et al. (1996)
HET-IA 100 µM
Primary rat hepatocytes 75, 250 and 500 µM 40 hours Van der Westhuizen et al. (1998)
LLC-PKr 10 to 35 and >35 µM 5 to 8 days Yoo et al. (1992)
Primary rat hepatocytes 75,150, 250 and 500 µM 44 hours Abel and Gelderblom (1998)
SNO 34.64 μM 48 hours Myburg et al. (2002)
C6 glioma cells 3-30 μM 24 hours Mobio et al. (2003)
Primary astrocytes BV-2 cell 20 and 50 μM 8 days and 4 days Osuchowski and Sharma (2005)
Vero cells 0.01-10 μg/ml 24 hours Yahia and Kamata (2017)
PK-15 cells 16 and 32 µM 24 hours Li et al. (2021)
Rat astrocytes 10, 50 and 100 µM 48 hours Not cytotoxic Galvano et al. (2002a)
Human fibroblasts 10, 50 and 100 µM 48 and 72 hours Galvano et al. (2002b)
IPEC-J2 5, 10, 20 and 40 µM 24 hours Wan et al. (2013)
HepG2 50 and 100 µM 24 hours Chuturgoon et al. (2015)
Caco-2 0.001-100 µM 24 hours Fernández-Blanco et al. (2016)
HepG2 0.5-45 µM 24 hours Wentzel et al. (2017)
HepG2 0.625-20 µM 72 hours Sobral et al. (2018)
HepG2 0.28-11.2 µM 48 hours Meneely et al. (2018)
PK-15 cells 1-8 µM 24 hours Li et al. (2021)

1 MDCK = Madin-Darby Canine Kidney; H4TG = rat hepatoma cell; HET-IA = SV-40 large T-antigen immortalised human oesophageal epithelial
cells; C6 glioma = rat brain glioma cell line C6; BV-2 = murine microglial cell line; Vero = monkey kidney cells; PK-15 = porcine kidney epithelial cell
line; IPEC-J2 = intestinal porcine enterocyte cell line; Caco-2 = cell line of human colorectal adenocarcinoma cells; HepG2 = human hepatocellular
carcinoma.

the exposure to FB1 and subsequent accumulation of
sphingosine, have a significant impact on the extrinsic
and intrinsic pathways of apoptosis, respectively, as shown
in Figure 4.
5. Genotoxicity and mutagenicity of fumonisin B1
Genotoxicity refers to processes that alter the structure,
information content, or segregation of DNA (Pellevoisin et
al., 2018). Table 2 showed studies related to mutagenicity
and genotoxicity of FB1. Several studies have contributed to
designate FB1 as possibly carcinogenic to humans (Group
2B) (IARC, 1993, 2002).
Gelderblom et al. (1988a,b; 1991) isolated F. moniliforme
from field samples for feeding male BD IX rats that exhibits
cancer promoting activity and developed benign and
malignant tumours in the liver. Later, Gelderblom and
Snyman (1991) evaluated the mutagenicity from isolated
F. moniliforme using tester strains TA97a, TA98, TA100
and TA102 of Salmonella typhimurium treated with 0.2,
0.5, 1.5 and 10 µg/plate of FB1, and negative results for
mutagenic activities were obtained. Similar results were
reported by Park et al. (1992), where FB1 (high pure 90%)
was non-mutagenic in tester strain TA100 of Salmonella
treated with 100 µg/plate of FB1. Additionally, Norred et al.
(1992) and Gelderblom et al. (1992) exposed rat hepatocytes
to 80 µM of FB1 and did not observe an unscheduled DNA
synthesis. Contrary to the results obtained from AMES test
(S. typhimurium reverse mutation assay), Sun and Stahr
(1993) reported a positive result for genotoxicity treated
with 5-20 µg/ml of FB1 using bioluminescence bacterial
genotoxicity test.
However, Knasmüller et al. (1997) evaluated mutagenicity
using S. typhimurium strains TA98 and TA100 in SOS
chrome tests with Escherichia coli strain PQ37 in the
presence and absence of metabolic activation, and their
results suggested that FB1 was not mutagenic in higher
concentrations (2000 µg/plate), whereas chromosomal
aberrations and cytokinesis block micronucleus assay
(CBMN) were used for genotoxicity in primary hepatocytes

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  Genotoxic and epigenetic effects of fumonisin B1
Extrinsic pathway
FB1
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TRADD Sphingosine
FADD
Pro Active
Caspase 8 Caspase 8
Caspase
3/7
Apoptosis
Figure 4. Possible mechanism by which fumonisin B1 (FB1) causes apoptosis in cells based on its mechanism of action. TRADD
= TNFR1-associated death domain protein. FADD = Fas-associating protein with a death domain. C = cytochrome C. Created
with BioRender.com
exposed up to 100 µg/ml of FB1, where an increase in the
frequency of each parameter was observed. Using the
Comet assay, Mobio et al. (2000a) reported that FB1 caused
a significant migration of DNA in C6 glioma cells exposed
to 9 and 18 µM. On the other hand, a dose-dependent
comet formation was reported by Galvano et al. (2002b)
in human fibroblasts exposed to 10, 50 and 100 µM and by
Ehrlich et al. (2002) in HepG2 cells exposed to ≥25 µg/ml of
FB1. Additionally, Ehrlich et al. (2002) in HepG2 observed
induction of micronucleus (MN), like Aranda et al. (2000) in
mouse bone marrow exposed to 25 mg/kg and 100 mg/kg.
Although no consistent results were obtained through all
genotoxic assays, the results presented in the literature
suggest that FB1 is not mutagenic in bacterial strains but
causes DNA damage evidenced through comet assay and
MN test data. Few studies had explored the genotoxic effect
of FB1 in co-exposure with other mycotoxins. The results of
the co-exposure of FB1 with ochratoxin A (OTA) in adult
male Wistar rats (kidney cells) showed oxidative lesions,
DNA strand breaks, major tail length, tail intensity and olive
tail moment in all treated animals. The authors suggest
World Mycotoxin Journal ## (##)
Intrinsic pathway
BCL-2
Active
Caspase 8 BAX
BAD
C C
Pro
Caspase 9
C
C
Caspase 9
P53
DNA damage
that oxidative stress is likely to be responsible for DNA
damage, and a synergistic effect was suggested between
OTA and FB1 in kidney cells (Domijan et al., 2006). Klarić
et al. (2008) reported the impact of FB1, beauvericin (BEA)
and OTA in PK15 cells (24 and 48 h), both single and in
co-exposure. Their results suggest induction of MN in
a dose-dependent manner, and the combined treatment
increased MN frequency in an additive manner, with an
increase in MN frequency in combinations of BEA+OTA
and FB1+BEA+OTA. Additionally, Pinhão et al. (2020)
observed an increase in oxidative DNA damage in HepG2
treated with OTA and FB1 (individually). However, the
combination did not induce a notable increase in DNA
damage nor in oxidative DNA damage.
In summary, FB1 in previous studies showed not to have
mutagenic properties, but to indeed have genotoxic activity
via oxidative stress, and DNA damage at low and high
concentrations in different cell types. However, further
research is needed to elucidate to elucidate the genotoxic
mechanisms and properties of FB1.
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 I.B. Molina-Pintor et al.

Table 2. Studies of evaluation of genotoxic and mutagenic effects of fumonisin B1 (FB1).1

Assay Model FB1 concentration Treatment time Result Reference

Reverse mutation AMES Salmonella typhimurium in vitro; 0.2, 0.5, 1,5 and 10 48 hours non-mutagenic2 Gelderblom and
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test TA97a, TA98, TA100 mg/plate Snyman (1991)

and TA102
Salmonella typhimurium in vitro; 100 µg/plate 48 hours non-mutagenic3 Park et al. (1992)
TA100
Salmonella typhimurium in vitro; 0.7, 2.1, 6.2, 19, 55, 48 hours non-mutagenic2 Knasmüller et al. (1997)
TA98 and TA100 167 and 500 µg/plate
Salmonella typhimurium in vitro; 10, 20 and 50 µg/plate 48 hours non-mutagenic2 Aranda et al. (2000)
TA100, TA102 and TA98
Salmonella typhimurium in vitro; 25, 50, 100 and 200 48 hours non-mutagenic3 Ehrlich et al. (2002)
TA98, TA100, TA102, µg/plate
TA1535 and TA1537
Unscheduled DNA Primary rat hepatocytes in vitro; 0.5, 2.5, 5.0, 25, 50 and 18 hours non-genotoxic Norred et al. (1992)
synthesis 250 µM
Primary rat hepatocytes in vitro; 80 µM/plate 18 hours non-genotoxic Gelderblom et al. (1992)
Bioluminescent bacterial Vibrio fischeri M169 in vitro; 5-20 µg/ml 24 hours genotoxic Sun and Stahr, (1993)
genotoxicity test
SOS chromotests E. coli strain PQ37 in vitro; 5, 16, 50, 166 and 500 ND non-genotoxic2 Knasmüller et al. (1997)
µg/ml
Chromosomal Primary rat hepatocytes in vitro; 0.010, 0.100, 1, 10 and 3 hours genotoxic Knasmüller et al. (1997)
aberrations 100 µg/ml
Human lymphocytes in vitro; 10 µg/g 24 hours genotoxic Lerda et al. (2005)
Sister chromatid Human lymphocytes in vitro; 5 and 10 µg/g 24 hours genotoxic Lerda et al. (2005)
exchange Bovine lymphocytes in vitro; 100 µM ND genotoxic Lorenzi et al. (2005)
Cytokinesis block Primary rat hepatocytes in vitro; 0.010, 0.100 and 1 µg/ml 3 hours non-genotoxic Knasmüller et al. (1997)
micronucleus assay Mouse bone marrow poly­ in vivo; i.p 25 and 100 mg/kg 30 hours/i.p genotoxic Aranda et al. (2000)
chromatic erythro­cytes
HepG2 in vitro; 25, 50 and 200 µg/ml 24 hours genotoxic Ehrlich et al. (2002)
RK13 in vitro; 100, 200 and 500 nM 24 and 48 hours genotoxic Rumora et al. (2002)
Human lymphocytes in vitro; 5 and 10 µg/g 24 hours genotoxic Lerda et al. (2005)
Bovine lymphocytes in vitro; 50 and 100 µM 24 hours genotoxic Lorenzi et al. (2005)
PK15 cells in vitro; 0.05, 0.5 and 5 µg/ml 24 and 48 hours genotoxic4 Klarić et al. (2008)
BALB/c mice bone marrow in vivo; 0.1, 1.0 and 10 mg/kg 24 and 48 hours non-genotoxic Karuna and Rao (2013)
Comet assay C6 glioma cells in vitro; 9 and 18 µM 24 hours genotoxic Mobio et al. (2000a)
HepG2 in vitro; 25, 50 and 200 µg/ml 24 hours genotoxic Ehrlich et al. (2002)
Human fibroblasts in vitro; 50 and 100 µM 48 and 72 hours genotoxic Galvano et al.(2002b)
Rat kidney cells in vivo; 200 ng/kg b.w., 0.05 5 days genotoxic4 Domijan et al. (2006)
and 0.5 mg/kg b.w.
Human lymphocytes in vitro; 20 µg/ml 1 hours genotoxic Domijan et al. (2007)
HepG2 in vitro; 200 µM 24 hours genotoxic Chuturgoon et al.
(2014a)
Human lymphocytes in vitro; 20 µg/ml 24 hours genotoxic Domijan et al. (2015)
HK-2 in vitro; 225, 550 and 1100 µM 24 and 48 hours genotoxic4 Pinhão et al. (2020)
HepG2 in vitro; 40, 80 and 160 µM

1 PK15 = Porcinekidney 15 cells; HK-2 = human kidney cells; ND = no data found. The concentrations reported are those at which the effect was observed.
2 With and without added rat liver microsomal fraction.
3 With added rat liver microsomal fraction.
4 Experimental study conducted in co-exposure with another(s) mycotoxin.

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  Genotoxic and epigenetic effects of fumonisin B1
6. Epigenetic properties of fumonisin B1
Epigenetics is defined as heritable changes in gene
expression that are not accompanied by changes in DNA
sequence and is essential in physiological processes such
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as differentiation, silencing of chromosomal domains, stem
cell plasticity, ageing and genomic imprinting (Chuang
and Jones, 2017; Jones and Baylin, 2007). Epigenetic
changes are processed by non-genotoxic carcinogenic
compounds, and epigenetic non-genotoxic carcinogens
are catalogued as agents that induce tumour formation by
mechanisms excluding direct modification or damage to
DNA through cell growth modulation and cell death, and
the relationships between exposure and tumour formation
(Klaunig et al., 2000). Additionally, epigenetic regulations
are generally classified into DNA methylation and histone
modifications (acetylation and phosphorylation of histones).
Both modes of regulation work together to control gene
expression through the control of chromatin architecture
shaping, which forbids or authorise gene accessibility to
regulatory proteins (Malumbres, 2013; Pellanda et al.,
2012). An essential part of epigenetic events are microRNAs
(miRNAs), which are small non-coding RNAs regulating
gene expression involved in various biological processes
such as cell proliferation and apoptosis (Moutinho and
Esteller, 2017).
Currently, epigenetic studies related to FB1 are scarce
(Table 3). One of the first studies was conducted by
Mobio et al. (2000b), in rat C6 glioma cells exposed to
3 to 54 µM of FB1, and results showed cell cycle arrest
in phase G2/M (3 µM), inhibition of DNA synthesis and
protein (6 µM), reduction of the percentage of cells in S
phase (6 to 18 µM) and hypermethylation of the DNA
(9 to 18 µM of FB1). Also, Kouadio et al. (2007) reported
hypermethylation, lipid peroxidation, oxidative stress, DNA
damage, DNA fragmentation and cytotoxicity in Caco-2
cells exposed to 10 µM of FB1. Contrarily, Chuturgoon et
al. (2014a) reported hypomethylation of DNA and histone
demethylation by downregulating DNA methyltransferases
(DNMTs) and upregulating the major demethylase (MBD2),
and increased DNA migration in HepG2 exposed to 200
µM. The authors concluded that FB1 causes chromatin
instability and may lead to liver tumorigenesis, due to
FB1 global DNA hypomethylation induction and histone
demethylation. Alternatively, Demirel et al. (2015) did
not observe methylation alteration in promoter regions
of e-cadherin, VHL, p16 and p15 and c-Myc in Clone 9
and NRK-52E cells treated with 1 to 50 µM of FB1. The
promoter region of e-cadherin was methylated in both
cells, and the promoter region of p16 was methylated in
only NRK-52E cells. Contrary to the above findings, p16
was unmethylated in its CpG promoter regions in Clone
9 cells, while the CpG promoter of c-Myc oncogene was
methylated in Clone 9 cells and unmethylated in NRK-52E.
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Pellanda et al. (2012) worked with rat liver foetuses derived
from dams exposed to methyl-deficient diet (MDD) and
FB1 (PMTDI = 2 µg/kg/day). The authors observed that
methyl depletion the histone H4 lysine 20 trimethylation
(H4K20 me3) and combined MDD/FB1 decreased in H4K20
me3 and increase the histone H3 lysine 9 trimethylation
(H3K9 me3).
Gardner et al. (2016) observed that treatment with 40 µM
of FB1 in MEF resulted in significant accumulation of
sphinganine-1-phosphate (Sa1P) and corresponded
to decreased histone deacetylase (HDAC) activity and
increased histone acetylation at histone H2B arginine 12
(H2BK12), histone H3 lysine 9 (H3K9), histone H3 lysine
18 (H3K18) and histone H3 lysine 23(H3K23). The authors
suggest that epigenetic modifications may contribute to
the failure of the neural tube closure observed in LM/Bc
embryos exposed to FB1.
Furthermore, Sancak and Ozden (2015) investigated the
effects of FB1 in global histone modifications such as histone
H3 lysine 9 di-,trimethylation (H3K9 me2/me3), histone H3
lysine 4 trimethylation (H3K4 me3), histone H4 lysine 20
trimethylation (H4K20 me3), histone H3 lysine 9 acetylation
(H3K9ac) in NRK-52E cells exposed to 25, 50 and 100 µM
of FB1, and observed increased levels of global H3K9 me2/
me3, while the global levels of H4K20 me3 and H3K9ac
decreased.
It has been reported that HepG2 cells treated with 200
µM of FB1 had a negative association between expression
levels of miR-27b and cytochrome CYP1B1. CYP1B1 is
post-transcriptionally regulated by miR-27b, catalyses the
activation of several procarcinogens, and pro-mutagens
were highly expressed in some cancers (Chuturgoon et
al., 2014b). The authors concluded that FB1-induced
modulation of miR-27b in hepatic cells might be a mode
of hepatic neoplastic transformation. FB 1 (200 µM)
downregulated tumour suppressor phosphatase and
tensin homologue (PTEN) in HepG2 cells via miR-30c, and
PTEN inhibits the DNA damage checkpoint regulation via
phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)
(PI3K/AKT) signalling cascade and blocks the inhibitory
phosphorylation of checkpoint kinase 1 (CHK1), which
prevents and repairs DNA damage (Arumugam et al., 2020).
Likewise, FB1 (5, 50, 100, 200 µM) altered the methylation
pattern of m6A RNA. An increase was observed in levels of
N6-methyladenosine (m6A), accompanied by an increase in
the m6A writing (methyltransferase type 3 (METTL3) and
methyltransferase type 14 (METTL14) and readers (proteins
of the family of homology domains YT521-B 1, 2 and 3
(YTHDF1, YTHDF2, YTHDF3) to regulate the expression
and function of specific mRNA and proteins. The erasers
m6A decreased (homologue 5 of ALKB (ALKBH5) and
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 I.B. Molina-Pintor et al.

Table 3. Studies of the evaluation of epigenetic properties of fumonisin B1 (FB1).

Assay FB1 concentration Treatment time Result Reference

DNA methylation
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C6 glioma cells in vitro; 9 to 18 µM 24 hours hypermethylation of the DNA Mobio et al. (2000b)
Caco-2 cells in vitro; 10 µM 24 hours hypermethylation of the DNA Kouadio et al. (2007)
HepG2 cells in vitro; 200 µM 24 hours hypomethylation of DNA and histone Chuturgoon et al. (2014a)
demethylation by downregulating DNMTs and
upregulating the MBD2
Clone 9 cells in vitro; 10, 25 and 50 µM 24 hours methylation of e-cadherin, p16 promoter region Demirel et al. (2015)
NRK-52E cells and c-Myc

Histone modifications

Liver from rat in vivo; 2 µg/kg/day One month decreased of H4K20me3 and increased Pellanda et al. (2012)
foetuses H3K9me3
Mouse embryo in vitro; 40 µM 24 hours increase in nuclear Sa1P, decrease in HDAC Gardner et al. (2016)
fibroblasts activity and increased histone acetylation of
H2BK12, H3K9, H3K18 and H3K23
NRK-52E cells in vitro; 25, 50 and 100 µM 24 hours increase levels of global H3K9 me2/me3 and Sancak and Ozden (2015)
decreased of H4K20 me3 and H3K9ac

microRNAs

HepG2 cells in vitro; 200 µM 24 hours modulation of miR-27b Chuturgoon et al. (2014b)
HepG2 cells in vitro; 200 µM 24 hours upregulation of miR-30cand decreased KDM5B Arumugam et al. (2020)
transcript levels and downregulation PTEN
HepG2 cells in vitro; 5, 50, 100, 200 µM 24 hours increase level of m6A, METTL3, METTL14, Arumugam et al. (2021)
YTHDF1, YTHDF2, YTHDF3, ALKBH5
and FTO; hypermethylation of Keap1 and
hypomethylation of promoters NF-E2 and Nrf2

1 NRK-52E = rat kidney epithelial cells. The concentrations reported are those at which the effect was observed.

protein associated with fat mass and obesity (FTO). 7. Conclusions

Additionally, hypermethylation and hypomethylation were
observed in Kelch-like ECH-associated protein 1 (Keap1)
and nuclear factor erythroid 2 (NF-E2)-related factor 2
(Nrf2) promoters, whereas miR-27b decreased (Arumugam
et al., 2021).
The studies reviewed introduce a novel insight into the
potential mechanism of FB1 carcinogenesis due to the
evidence that FB1 disrupts epigenetic events by altering
DNA methylation, global histone modifications, and
miRNAs. Therefore, its relationship with cancer in
laboratory animals and in different human populations,
as well as NTDs, could be explained.
Since FB1 was discovered, researchers have studied its
toxicological properties, which led to the proposal of the
paradox of FB1 by questioning how it can induce damage
and disease in animals and humans if it is not absorbed
successfully. Although its passage through the membrane
remains to be elucidated, it was reported that FB1 could
alter the integrity of the intestinal barrier by suppressing the
expression level of the tight junction protein, which could
facilitate its absorption. Additionally, it has been accepted
that its mechanism of action is based on the accumulation
of sphingolipids and a decrease in sphingomyelin, which
could have effects, such as the activation of extrinsic and
intrinsic pathways of apoptosis and induction of DNA
damage, cell cycle arrest, induction of oxidative stress and
modifications in epigenetic patterns. The above effects
together may affect cancer initiation. It is vital to acquire

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  Genotoxic and epigenetic effects of fumonisin B1
a deeper understanding of the molecular mechanisms by
which this mycotoxin exerts adverse effects. Presently, we
are still far from understanding the regulatory networks
and signalling pathways involved in the toxicity of FB1.
Future studies should focus on the genotoxic and epigenetic
https://www.wageningenacademic.com/doi/pdf/10.3920/WMJ2021.2720 - Wednesday, November 10, 2021 2:14:18 AM - Universitat de Lleida IP Address:193.144.12.133
mechanism by which FB1, its metabolites, and co-exposure
with other xenobiotics influence its toxicity.
Acknowledgements
The authors thank the Consejo Nacional de Ciencia
y Te c nolo g í a (C ONAC Y T ) under Grant co de
SALUD-2017-2-289726.
Conflict of interest
The authors declared no conflict of interest.
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