Journal of Hazardous Materials 389 (2020) 122087

Contents lists available at ScienceDirect

Journal of Hazardous Materials

journal homepage: www.elsevier.com/locate/jhazmat

Review

Effects of mycotoxin-contaminated feed on farm animals T

a a, b,
Changwon Yang , Gwonhwa Song *, Whasun Lim **
a
Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of
Korea
b
Department of Food and Nutrition, Kookmin University, Seoul, 02707, Republic of Korea

GRAPHICAL ABSTRACT

ARTICLE INFO ABSTRACT

Editor: R. Debora Mycotoxins are secondary products produced by fungi in cereals and are frequently found in the livestock industry
Keywords: as contaminants of farm animal feed. Studies analyzing feed mycotoxins have been conducted worldwide and have
Toxin confirmed the presence of mycotoxins with biological activity, including aflatoxin, ochratoxin A, fumonisin, zear-
Farm animal alenone, and deoxynivalenol, in a large proportion of feed samples. Exposure to mycotoxins can cause im-
Pig munotoxicity and impair reproductive function in farm animals. In addition, exposure of tissues, such as the kid-
Poultry neys, liver, and intestines, to mycotoxins can exert histopathological changes that can interfere with animal growth
Aflatoxin and survival. This review describes previous studies regarding the presence of major mycotoxins in the feed of farm
animals, especially pigs and poultry. Moreover, it describes the adverse effects of mycotoxins in farm animals
following exposure, as well as the biological activity of mycotoxins in animal-derived cells. Mycotoxins have been
shown to regulate signaling pathways, oxidative stress, endoplasmic reticulum stress, apoptosis, and proliferation in
porcine and bovine cells. A clear understanding of the effects of mycotoxins on farm animals will help reduce farm
household economic loss and address the health concerns of people who consume these meat and dairy products.

1. Introduction environment at all stages of the food chain. Mycotoxin-contaminated

cereal grains and animal feed are frequently found throughout the
Mycotoxins, which are produced by fungi, are secondary metabo- world (Placinta et al., 1999). Humans and animals are exposed to
lites found in the food, feed, and living organisms of an agricultural mycotoxins through the consumption of contaminated food (Hussein

⁎
Corresponding author.
⁎⁎
Corresponding author at: Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul, 02707, Republic of Korea.
E-mail addresses: ghsong@korea.ac.kr (G. Song), wlim@kookmin.ac.kr (W. Lim).

https://doi.org/10.1016/j.jhazmat.2020.122087
Received 8 October 2019; Received in revised form 9 January 2020; Accepted 13 January 2020
Available online 20 January 2020
0304-3894/ © 2020 Elsevier B.V. All rights reserved.
C. Yang, et al.
and Brasel, 2001). The United States Food and Drug Administration
(FDA), the European Union (EU), and countries with advanced agri-
cultural industries set guidelines for limiting concentrations to prevent
mycotoxin contamination in food and animal feed (Anukul et al., 2013;
Lee and Ryu, 2017). Many types of mycotoxins are found in human
blood or breast milk samples (Breitholtz-Emanuelsson et al., 1993; Scott
et al., 1998). Mycotoxin levels are found to be higher in farm animal
feed than in humans who consume relatively well-refined and pro-
cessed foods (Rodrigues and Naehrer, 2012). Therefore, mycotoxins are
prone to unprotected exposure among many environmental pollutants
in farm animals. It is difficult to detect the presence of mycotoxins,
especially in farm regions with climates where the fungi that produce
mycotoxins thrive. Pigs and poultry are the most susceptible and sen-
sitive farm animals to the effects of mycotoxins. Therefore, the majority
of mycotoxin toxicity studies have been performed on these animals.
Since these species are also widely reared by humans for meat, eggs,
milk, and other processed foods, it is very important to measure the
residual mycotoxin levels in the animal feed, tissues, and body fluids.
Animals that consume a mycotoxin-contaminated diet are adversely
affected by neoplastic, estrogenic, and immunosuppressive effects.
These excessive or persistent properties can result in weight loss and the
increased development of diseases resulting from immunosuppression
and reproductive disorders (D’Mello et al., 1999; Lindemann et al.,
1993).
The health risks that mycotoxin exposure pose to livestock cause
economic loss, either by adverse effects on the animals themselves or by
the secondary cost to humans who eat contaminated animal-derived
foods. The agricultural environment affects the fungal habitat, and thus,
the number of mycotoxins produced. For example, in harvested grains,
the presence of fumonisins, a group of mycotoxins, is high when dry
weather is followed by wet weather (Kendra and Dyer, 2007). Some
studies have reported that mycotoxin contamination in feed samples
depends on seasonal temperature conditions (Abidin et al., 2017).
However, in Thailand, studies measuring the mycotoxin contamination
in pasteurized milk suggest that mycotoxin contamination in dairy
products are more affected by farm management factors than seasonal
effects (Suriyasathaporn and Nakprasert, 2012). Research has been
conducted to measure the concentration of mycotoxins in livestock feed
in numerous agricultural regions worldwide (Sarathchandra and
Muralimanohar, 2013; Monge et al., 2013; Shar et al., 2014; Sherazi
et al., 2015). Important indicators in mycotoxin toxicity studies include
the level of mycotoxin contamination in livestock feed and the number
of metabolites present in body tissues and fluids. Additionally, analyses
have been performed on residual mycotoxin levels in body fluids, such
as blood and urine, and tissues, such as intestines and kidneys (Vulic
et al., 2012; Danicke and Winkler, 2015; Danicke and Brezina, 2013).
Various biological, chemical, and physical methods have been ap-
plied to prevent mycotoxin contamination or to eliminate toxicity (Yu
et al., 2018; Zhai et al., 2018; Li et al., 2019; Elliott et al., 2019). As a
feed additive, mycotoxin adsorbents, including phyllosilicate minerals,
activated charcoal, and synthetic resins, have been applied to reduce
the risk of mycotoxin presence (Rosa et al., 2001; Raju and Devegowda,
2000; Galvano et al., 1996). The addition of natural zeolite to the diet
of farm animals allows the consumed feed to adsorb polar mycotoxins
and mitigate toxicity (Katsoulos et al., 2016). The addition of sodium
carbonate also helps to remove feed-contaminated mycotoxins (Polak
et al., 2009). Gamma-irradiation is a major method for reducing my-
cotoxins in food and feed processing, although there is some debate
about its effectiveness (Jalili et al., 2012; Herzallah et al., 2008;
Hooshmand and Klopfenstein, 1995; Di Stefano et al., 2014). UV ra-
diation has also been suggested as an option for removing mycotoxins
from poultry feed (Murata et al., 2008; Ameer Sumbal et al., 2016).
Moreover, organic acids, which are frequently used in food and feed
preservation, such as citric acid and lactic acid, also help reduce the
concentration of mycotoxins in feed samples (Humer et al., 2016). The
use of chemicals to block signaling pathways or oxidative stress can
2
Journal of Hazardous Materials 389 (2020) 122087
target the toxic mechanisms of mycotoxins and have a beneficial impact
on livestock health (Hou et al., 2018). Natural compounds extracted
from and fed to animals are potential candidates to mitigate mycotoxin
toxicity, minimizing side effects (Gan et al., 2018a; Qin et al., 2015).
Melatonin supplementation is an emerging method shown to relieve
mycotoxin toxicity effects while inhibiting oxidative stress (Meki et al.,
2001; Gesing et al., 2006; Cheng et al., 2019). In this review, we de-
scribe the effects of compounds that can prevent the contamination or
mitigate the toxicity of mycotoxins as feed additives.
Among the different types of mycotoxins, only a few are known to
cause toxicity via exposure to farm animals. These major mycotoxins
are the first to be identified when investigating mycotoxin contamina-
tion in animal feeds worldwide, and they cause significant economic
losses to livestock farms. Therefore, several studies examining the
toxicity of mycotoxins in farm animals have focused on the physiolo-
gical action mechanisms of some mycotoxins. This review examines the
types and features of major mycotoxins that can be contaminants in
farm animal feed, especially for pigs and poultry. It will also cover the
major studies on the types and concentrations of mycotoxins and their
metabolites, which are found in livestock tissues and body fluids. Next,
we will describe how mycotoxins can have adverse immunological,
endocrine, reproductive, genetic, and histopathological effects in farm
animals. Avian, porcine, and bovine cells treated with different doses of
mycotoxin are used to study apoptosis mechanisms mediated by oxi-
dative stress, autophagy, and inflammatory responses (Fig. 1). In ad-
dition, in vivo and in vitro studies will be presented to identify which
compounds are useful in mitigating the toxicity of mycotoxins.
2. Mycotoxins identified in animal feed
2.1. Occurrence of aflatoxins in feed
The most commonly found mycotoxins are aflatoxins, ochratoxin A
(OTA), trichothecenes, zearalenone (ZEA), and fumonisins. The con-
centration range of these mycotoxins in farm animal feeds and their
intracellular physiological action mechanisms have been reported.
Therefore, we focused on the concentration range of the five myco-
toxins in animal feed and the body, and their toxicity mechanisms.
Aflatoxin is produced by Aspergillus flavus or Aspergillus parasiticus and is
suggested to have carcinogenic and mutagenic effects in humans, in-
cluding growth problems in children (Gong et al., 2004; Peters and
Teel, 2003; Abnet, 2007). The FDA limits the aflatoxin levels to 20 ppb
in food and animal feeds and the EU limits the aflatoxin levels to 15
ppb, which is relatively concentration, although they vary by grain type
and country (Alshannaq and Yu, 2017; Sarma et al., 2017). In poultry,
aflatoxin in feed is metabolized into aflatoxin M and aflatoxicol and
accumulates in organs, such as the gizzard, breast, and liver and also in
eggs (Wolzak et al., 1985; Trucksess et al., 1983; Gregory and Manley,
1982). Aflatoxin M1 (AFM1) is the hydroxylated metabolite of aflatoxin
B1 (AFB1) and is found in dairy products derived from animals that have
been fed with contaminated feed (Nakajima et al., 2004). AFM1 is a less
toxic form that is frequently found in animal milk. The process by
which AFB1 is metabolized in the body of animals involves the activity
of the cytochrome p450 (CYP450) family in the liver, which differs with
species (Deng et al., 2018). CYP1A2 is the major enzyme that converts
AFB1 into AFM1. Another major pathway in which AFB1 is metabolized
is during the conversion to highly toxic exo-AFB1-8,9-epoxide (AFBO),
which is epoxidated by the CYP450 family members such as CYP1A1,
CYP1A2, and CYP2A6 (Dohnal et al., 2014). AFB1 is frequently found in
cattle and poultry feed, and the eggs and edible tissues. Measurements
conducted in Japan revealed that AFB1 was found in maize fed to dairy
cattle and was subsequently found to be contaminating the milk
(Sugiyama et al., 2008). Analysis of AFB1-contaminated poultry feed
samples conducted in Brazil showed concentrations ranging from 1.2 to
17.5 μg/kg, higher than fumonisins or ZEA (Oliveira et al., 2006). In a
case study conducted on farms in South Africa, AFB1 was found to
C. Yang, et al.
Fig. 1. Physiological properties regulated by major mycotoxins that exert toxicity in exposed cells derived from farm animals. Aflatoxin B1, ochratoxin A, fumonisin
B1, zearalenone, and deoxynivalenol are the most frequently found mycotoxins in the feed of farm animals. Cultured porcine and avian cells have been used to
characterize the cytotoxicity of major mycotoxins. Mycotoxins induce either increased apoptosis or decreased proliferation, or both in animal cells. There are various
physiological changes that underlie mycotoxin-induced cytotoxicity, including oxidative stress, autophagy, ER stress, and signaling pathways.
contaminate various feed materials and it was found in retail milk at
concentrations of 0.01–3.1 μg/L (Dutton et al., 2012). A survey of milk
samples from farm animals in Italy found that AFM1 levels below 5.0
ng/L were observed in 92 % of raw milk samples, while AFM1 was
found in approximately 42 % of various dairy products (Santini et al.,
2013).
Laying hens with AFB1-contaminated diets show high concentra-
tions of AFB1 residues in eggs and liver tissue (Trucksess et al., 1983).
Regional studies conducted in Japan showed that AFM1 was found in
domestic milk samples at a mean of 0.009 μg/kg (Nakajima et al.,
2004). Monitoring conducted in Argentina detected AFM1 in 63.8 % of
raw bulk milk samples from farm cooling tanks, suggesting that it could
pose a threat to milk consumers (Alonso et al., 2010). In Iran, AFM1
levels were found to be 66.7 %, 31.0 %, and 35.4 % in bovine, ovine,
and caprine bulk milk samples, respectively (Rahimi and Ameri, 2012).
Some non-toxic feed additives have a high affinity with AFM1 and are
used to prevent contamination in milk samples. Dietary administration
with clinoptilolite, a natural zeolite, significantly reduces the con-
centration of AFM1 in dairy cattle milk, suggesting that it mitigates the
toxicity caused by AFB1 and AFM1 in livestock (Katsoulos et al., 2016).
Hydrated sodium calcium aluminosilicate has also been reported to
reduce AFM1 levels in cattle milk (Harvey et al., 1991).
2.2. Occurrence of ochratoxin A in feed
Ochratoxin A (OTA) is a mycotoxin produced by several species of
the Aspergillus and Penicillium genera and is found in cereal grains and
dairy products. OTA is naturally produced and observed in animal feed
worldwide (Birzele et al., 2000; Scudamore and Patel, 2000; Hohler,
1998), but its frequent presence in pork products threatens food safety
(Rodriguez et al., 2012; Jorgensen and Petersen, 2002). The FDA has
not set a concentration limit for OTA in foods, but the EU has estab-
lished a maximum concentration limit of 5 ppb for cereal products and
10 ppb for dried vine fruits (Alshannaq and Yu, 2017; Malir et al.,
2016). OTA has carcinogenic properties when exposed to humans
(Pfohl-Leszkowicz and Manderville, 2007). It has also been shown to
cause immunosuppressive effects and problems with urinary tract de-
velopment in humans (Lea et al., 1989; Anon, 1991; Bozic et al., 1995).
3
Journal of Hazardous Materials 389 (2020) 122087
OTA is converted into various metabolites by the activity of the CYP450
enzyme in the liver. Metabolites such as 4-hydroxyochratoxin A (4'-OH-
OTA), 5'-OH-OTA, 7'-OH-OTA, 9'-OH-OTA, and ochratoxin B (OTB) are
observed in the liver microsomes and feces of farm animals such as pigs,
cattle, and chickens (Tao et al., 2018). Most metabolites of OTA are
reported to be less toxic, suggesting that the regulation of OTA meta-
bolism is important for mitigating toxicity in farm animals (Omar et al.,
1996). Analysis conducted on animal feed in Argentina showed that
OTA was found to be more contained in poultry feed at concentrations
of 25–30 ng/g than in the feed of other animals, including pigs and
rabbits (Dalcero et al., 2002). An analysis conducted in Italy found that
all feed samples from pig farms were contaminated with OTA, although
the contamination levels were lower than the limits recommended by
the European Commission (Pozzo et al., 2010). Monitoring conducted
in Pakistan found that the proportion and concentration of OTA con-
tamination in poultry complete feeds were 38 % and 75 μg/kg, re-
spectively (Sherazi et al., 2015).
Many countries have confirmed the presence of OTA in porcine
blood and edible tissues (Jorgensen, 1998; Morgan et al., 1986). OTA
was observed in the range of 0.05–13.4 ng/ml in 98 % of slaughtered
pig serum samples in Romania, whereas ZEA was found in only 17.3 %
of serum (Curtui et al., 2001). In addition, OTA levels were highest in
the kidney, followed by the liver and the muscles of slaughtered pigs.
Moreover, 1.0 % of porcine serum samples in Italy were positive for
OTA at a concentration of 0.03 to 0.8 ng/ml (Pozzo et al., 2010). In 82
% of swine plasma samples in Norway, the OTA concentrations were
above 0.1 ng/ml (Langseth et al., 1993). Serum samples from slaugh-
tered pigs in Serbia were found to have OTA concentrations up to 220.8
ng/ml, and up to 52.5 ng/g with the development of hemorrhages and
necrosis in the kidneys (Milicevic et al., 2008).
2.3. Occurrence of fumonisin in feed
Fusarium species are the most frequently found toxin-producing
fungi, which are widely distributed in the northern climates of the
Americas, Europe, and Asia. The most hazardous Fusarium mycotoxins
in farm animals are fumonisin, deoxynivalenol (DON), and ZEA. In
Korea, fumonisins, DON, and ZEA were found to be contaminated in
C. Yang, et al.
feeds at 93.33, 91.33, and 71.33 %, respectively (Kim et al., 2013).
Fumonisin is a mycotoxin produced by Fusarium moniliforme and Fu-
sarium proliferatum and is a naturally occurring feed contaminant. The
EU has set a maximum concentration limit of 4000 ppb for fumonisin in
raw corn, which is relatively higher than that for other mycotoxins,
although considerably lower limits have been set for processed foods
(Lee and Ryu, 2017; Alshannaq and Yu, 2017). Little is known about the
endogenous metabolism of fumonisin in farm animals (Fodor et al.,
2008). Veterinary drugs that are converted into low-toxic hydrolyzed
forms using enzymes involved in bacterial fumonisin catabolism are
used to remove fumonisin from pigs and poultry (Hartinger and Moll,
2011; Hahn et al., 2015). Fumonisin has three subtypes, B1 (FB1), B2
(FB2), and B3 (FB3), which vary in their chemical structure and also to
some extent in their degree of toxicity. Fumonisin is mainly found in the
feed of poultry. In Slovakia, FB1 and FB2 have been observed in poultry
feed at concentrations from 43 to 798 μg/kg and from 26 to 362 μg/kg,
respectively (Labuda et al., 2005). Studies confirming mycotoxin con-
centrations performed in whole corn in California have shown that
fumonisin is positive in the highest proportion of samples, with an
average concentration of 1698 μg/kg, higher than other types of my-
cotoxins such as aflatoxins, OTA, ZEA, and DON (Krout-Greenberg
et al., 2013). Research conducted on poultry feed from Nigerian farms
also shows that FB1 is the most frequently found mycotoxin, in 97 % of
samples, with a mean concentration of 1014 μg/kg (Akinmusire et al.,
2019). Little is known about whether fumonisin can accumulate in the
eggs and edible tissue of poultry. In addition, the metabolites of fu-
monisin in poultry are unclear, requiring further research into the
toxicokinetics of fumonisin.
2.4. Occurrence of zearalenone in feed
ZEA is an estrogenic mycotoxin produced by Fusarium species. ZEA
contains nonsteroidal resorcylic acid lactone, which mimics the activity
of estradiol-17β. The EU’s concentration limit for ZEA is 100 ppb in raw
maize and 20 ppb in cereal products (Lee and Ryu, 2017; Alshannaq
and Yu, 2017). Exposure of the uterus during pregnancy to ZEA causes
reproductive organ disorders in the offspring of rodents, suggesting
transgenerational effects (Nikaido et al., 2004). Plant and fungal me-
tabolites of ZEA, ZEA-14-O-β-glucoside, ZEA-16-O-β-glucoside, and
ZEA-14-sulfate are reported to be fully hydrolyzed in porcine gastro-
intestinal tracks (Binder et al., 2017). α-zearalenol (ZOL) and β-ZOL are
analogs of ZEA that are metabolized and produced in the liver and are
also found in pig and human excretory products. This metabolism is
similar to the reaction during the synthesis and inactivation of steroid
hormones since it is caused by the same dehydrogenase enzyme
(Malekinejad et al., 2006). Because α-ZOL has a higher binding capacity
to cytoplasmic estrogen receptors than β-ZOL, ZEA is more reactive in
species where conversion to α-ZOL is preferred (Katzenellenbogen
et al., 1979). In a study conducted in China, the maximum concentra-
tion of ZEA in pig feed was approximately 729 μg/kg (Ma et al., 2018).
A survey conducted in Vietnam revealed that the average concentration
of ZEA in complete feeds for pigs was 101.4 μg/kg (Thieu et al., 2008).
With oral administration of 10 mg/kg ZEA in pigs, the uptake rate is
80–85% (Biehl et al., 1993). In porcine follicular fluids, ZEA and its
metabolite, α-ZOL, are observed at concentrations up to 54.8 pg/ml and
26.4 pg/ml, respectively (Sambuu et al., 2011). Analytical studies
conducted on feeding supplies and urine from farm animals in Croatia
showed that ZEA and its metabolite, α-ZOL, peaked at concentrations of
577 ng/g and 241.1 ng/ml, respectively (Vulic et al., 2012).
2.5. Occurrence of deoxynivalenol in feed
DON, which also has an estrogenic function, is another mycotoxin
produced by a species of Fusarium (Diekman and Green, 1992). DON
belongs to the trichothecene group and is chemically stable, so it is not
easily removed during food or feed processing. The FDA’s maximum
4
Journal of Hazardous Materials 389 (2020) 122087
concentration limit of DON is 1000 ppb for processed foods, whereas
that of the EU is relatively lower, depending on the type of product (Lee
and Ryu, 2017; Alshannaq and Yu, 2017). DON is converted into a de-
epoxidized form, which is less toxic to the intestinal microflora of farm
animals (Danicke et al., 2010, 2004). When DON is administered to
DON, the amount of de-epoxy-DON relative to that of DON is higher in
the distal part of the intestine (Danicke and Brezina, 2013). However,
more than half of the ingested DON can be recovered from urine
(Danicke et al., 2004). In poultry, approximately 10 % of the total
concentration of DON and de-epoxy-DON in feces is observed as de-
epoxy-DON (Danicke and Brezina, 2013). Feed samples treated with
citric acid or lactic acid significantly reduced DON content (Humer
et al., 2016). In randomly harvested wheat samples from Germany,
DON was observed at 77–93% of samples, levels higher than other
mycotoxins including ZEA and nivalenol (NIV) (Muller et al., 2001). In
Pakistanian poultry feed, DON and aflatoxins were copresent at con-
centrations of 807 μg/kg and 18 μg/kg, respectively (Shar et al., 2014).
A survey of mycotoxins in pig feed in China revealed that the con-
centration of DON was up to 4000 μg/kg, the highest concentration
among mycotoxins (Ma et al., 2018).
3. Effects of mycotoxin exposure on farm animals
3.1. Effects of aflatoxins on farm animals
Studies on the toxicity of mycotoxins in farm animals are based on
the concentrations reported in feed surveys, confirming changes in
various physiological properties after consuming contaminated feed or
dose-dependent treatment of cells with mycotoxins. Reproductive
toxicity occurs in poultry or pigs that are contaminated with aflatoxins.
In addition, aflatoxins contribute to the damage of the immune system
of animals, making them vulnerable to disease (Oswald et al., 2005).
Diets contaminated with aflatoxins at concentrations of up to 400 μg/kg
cause functional problems depending on the concentration in the liver
of wild turkeys (Quist et al., 2000). Moreover, AFB1-contaminated diets
significantly inhibit the production of eggs in laying hens (Trucksess
et al., 1983). RNA sequencing analysis performed on turkey livers re-
vealed that AFB1 regulates transcripts involved in cancer, cell cycle
control, and lipid regulation (Monson et al., 2014). Analysis of tran-
scriptome changes in turkey spleens in response to AFB1 suggests that
AFB1 affects the poultry immune system (Monson et al., 2015). More-
over, AFB1 interferes with the maturation of porcine oocytes. In porcine
oocytes exposed to AFB1, DNA and histone methylation are affected in a
dose-dependent manner, suggesting epigenetic modifications (Liu et al.,
2015). In addition, AFB1 increases apoptosis of porcine oocytes, which
is mediated by increased oxidative stress and autophagy. Splenocytes
are the major target cells of AFB1 in pigs. AFB1 inhibits the production
of interleukin (IL)-2 when exposed to porcine splenocytes, leading to
immunotoxicity. The toxicity of AFB1 to porcine splenocytes occurred
in a dose-dependent manner. Moreover, AFB1 decreases the level of
reduced glutathione (GSH) and increases lipid peroxidation in porcine
splenocytes, which is accompanied by increased phosphorylation of
ERK1/2 (Hao et al., 2015). The effectiveness of some compounds has
been reported to reduce the toxicity of AFB1. They are generally not
toxic on their own and their targeting mechanisms are clear and
therefore have potential as feed supplements. In porcine splenocytes,
immunotoxicity by AFB1 is alleviated by selenium supplementation,
which improves the antioxidant capacity (Hao et al., 2016). The AFB1-
induced degradation of porcine oocytes is effectively prevented by the
inhibition of oxidative stress caused by melatonin application (Cheng
et al., 2019). Bush sophora root polysaccharide, a traditional herb, also
mitigates AFB1-induced toxicity in chicken liver cells by increasing
antioxidant activity (Gan et al., 2018a). Additionally, AFB1 induces
endoplasmic reticulum (ER) stress-mediated cell death in bovine
mammary epithelial cells, which is accompanied by DNA fragmentation
and mitochondrial dysfunction (Park et al., 2019). AFB2 increases
C. Yang, et al.
apoptosis and autophagy by inhibiting the activation of the PI3K/AKT/
mTOR signaling pathway in broiler hepatocytes (Chen et al., 2016).
AFB2 toxicity is dependent on the production of reactive oxygen species
(ROS) and the release of cytochrome c in hepatocytes. These studies
suggest that aflatoxins can exert toxicity by regulating various physio-
logical properties, such as oxidative stress, ER stress, and signaling
pathway regulation, in farm animals.
3.2. Effects of ochratoxin A on farm animals
OTA is generally more toxic than other ochratoxins because of its
late metabolism (Gautier et al., 2001). OTA-contaminated feed ad-
versely affects the growth of pigs (Malagutti et al., 2005; Lippold et al.,
1992) and has a physiological effect similar to aflatoxin B1 in animal
cells (Fig. 2). The cytotoxicity of OTA is mostly exerted in a dose-de-
pendent manner, altering various intracellular processes, including
oxidative stress, signaling pathways, and inflammatory responses. OTA
increases chromosomal aberrations and sister chromatid exchanges in
bovine lymphocytes, causing apoptotic cell death (Lioi et al., 2004).
OTA induces toxicity in piglet kidneys and livers by reducing anti-
oxidant parameters and causing oxidative stress, with histopathological
alterations (Zhang et al., 2016). OTA also induces the phosphorylation
of P38 and ERK1/2 in porcine splenocytes, leading to nephrotoxicity
and immunotoxicity, respectively (Gan et al., 2017a). Moreover, OTA
induces cytotoxicity by stimulating oxidative stress responses in porcine
kidney cells, as evidenced by the reduced toxicity seen with the pre-
treatment of N-acetyl-L-cysteine (NAC), a ROS scavenger (Klaric et al.,
2008). OTA also induces the phosphorylation of P38 and ERK1/2 in
5
Journal of Hazardous Materials 389 (2020) 122087
Fig. 2. Physiological functions of afla-
toxin B1, aflatoxin B2, and ochratoxin
A in animal cells. Aflatoxins and
ochratoxin A are mycotoxins produced
primarily by fungi of the Aspergillus
genera. In animal cells, these myco-
toxins share a similar mechanism of
action, including an increase in the
activity of MAP kinases such as ERK1/2
and P38, and they promote oxidative
stress. Transcriptomic analysis suggests
that these mycotoxins can modulate
various properties such as tumor-
igenicity, cell cycle control, and lipid
regulation. These mycotoxins also in-
hibit cell proliferation through mi-
tochondrial disruption, induction of ER
stress, and inhibition of PI3K/AKT sig-
naling pathways. N-acetyl-L-cysteine
and selenomethionine alleviate myco-
toxin-induced toxicity. The effects of
aflatoxin B1, aflatoxin B2, and ochra-
toxin A result in nephrotoxicity, hepa-
totoxicity, and reproductive disorders
in farm animals.
porcine alveolar macrophages (Xu et al., 2017), causing im-
munotoxicity through an increase in Toll-like receptor 4 (TLR4)-medi-
ated inflammatory signaling pathway proteins and elevated in-
tracellular ROS production. In vivo studies using feed containing OTA
also revealed that OTA activates the MAPK signaling pathway and in-
duces histopathological modifications by promoting ER stress and au-
tophagy in the kidneys and spleens of pigs (Gan et al., 2017b). OTA also
promotes mitochondrial ROS-mediated apoptosis in porcine intestinal
epithelial cells, which is confirmed by the presence of mitochondria
that target ROS (Wang et al., 2017). In addition, the toxicity of OTA in
porcine intestinal epithelial cells is mediated by increased intracellular
Ca2+ ion activity and myosin light chain kinase, suggesting the de-
struction of tight junctions (Wang et al., 2018). Recently, various
methods have been studied to mitigate the toxicity of OTA. Porcine
circovirus type 2 infection in pigs has an alleviating effect on OTA-
induced growth restriction and nephrotoxicity (Gan et al., 2018b).
Moreover, selenomethionine and NAC alleviate the toxicity of OTA and
AFB1 in porcine alveolar macrophages by regulating the activity of ERK
(Hou et al., 2018). In pigs, urinary alkalinization promotes the renal
excretion of OTA, thereby alleviating its toxicity (Blank and Wolffram,
2004). In this context, dietary sodium bicarbonate supplementation in
pigs reduces the systemic availability of OTA (Blank and Wolffram,
2005). The toxicity of OTA in chicken liver cells has been confirmed to
be mitigated by various compounds, such as ammonium glycyrrhizin, L-
arginine, silymarin, and glucurolactone (Yu et al., 2018). Identifying a
clear target mechanism for feed additives to mitigate the toxicity of
OTA will help prevent economic losses from OTA contamination in li-
vestock farms.
C. Yang, et al.
3.3. Effects of fumonisins on farm animals
In farm animals, fumonisin B1 (FB1) is reported to cause diseases
such as equine leukoencephalomalacia and porcine pulmonary edema
(Marasas, 1995). Moreover, when exposed to pigs, FB1 is associated
with the development of disorders such as pulmonary edema and liver
failure (Haschek et al., 2001). In vitro studies reported that FB1 ex-
posure to porcine intestinal epithelial cells inhibits cell proliferation
and barrier function (Bouhet et al., 2004). FB1 also reduces viability
and promotes lactate dehydrogenase release in porcine renal epithelial
cells, suggesting induction of nephrotoxicity (He et al., 2002). FB1 is
also reported to affect the porcine immune system by inhibiting lym-
phocyte proliferation and controlling the Th1/Th2 cytokine balance
(Harvey et al., 1995; Taranu et al., 2005). Another study reported de-
creased expression of IL-8 in the gut of pigs following the oral admin-
istration of 0.5 mg/kg FB1, although other cytokines were unaffected
(Bouhet et al., 2006). FB1 causes pig intestinal disorders by increasing
the level of free sphingolipid bases and reducing the number of glyco-
lipids in the plasma membrane (Loiseau et al., 2007). Moreover, FB1
causes a reduction in feed intake, egg production, and body weight in
poultry, while also causing disorders such as hepatic necrosis and
thymic cortical atrophy (Ledoux et al., 1992; Prathapkumar et al.,
1997). FB1-contaminated chicken feed, at a dose of 200 mg/kg, has
immunosuppressive effects and also causes mild hepatic necrosis (Li
et al., 1999; Ledoux et al., 2003). Moreover, when FB1 contaminates
broiler diets, it impairs immune parameters by modulating the ex-
pression of cytokines, including IL-1β and IL-2 in macrophages (Cheng
et al., 2006). It is reported that toxicity by sphingolipid metabolism,
which is altered by FB1 in duodenum and jejunum in turkeys and pigs,
is detoxified by carboxylesterase (Masching et al., 2016).
3.4. Effects of zearalenone on farm animals
ZEA is reported to cause diseases related to infertility in pigs. Pigs
exposed to ZEA have vaginal and rectal prolapses, abortions, and lower
pregnancy rates (Etienne and Dourmad, 1994). Diets containing ex-
cessive concentrations of ZEA cause hyperestrogenism symptoms in
pigs (Kuiper-Goodman et al., 1987). Moreover, the addition of α-ZOL or
β-ZOL to porcine granulosa cell cultures inhibits the synthesis of pro-
gesterone, which is promoted by FSH or forskolin (Tiemann et al.,
2003). ZEA induces caspase-3- and caspase-9-mediated cell death in
porcine granulosa cells (Zhu et al., 2012). In addition, ZEA reduces cell
proliferation by decreasing the mitochondrial membrane potential and
reducing ROS production in porcine granulosa cells. Exposure to ZEA
during the prepubertal period causes a deficiency of mature oocytes in
adulthood. ZEA contained in feeds at doses up to 1 mg/kg decreases
follicle integrity and increases estrogen receptor expression when ex-
posed to lactating pigs (Schoevers et al., 2012). The increased oxidative
stress caused by ZEA in porcine granulosa cells is alleviated by cur-
cumin, an Asian traditional herb derived from Curcuma longa (Qin et al.,
2015). ZEA also induces the formation of abnormal chromosomes and
reduces the mitotic index in bovine lymphocytes (Lioi et al., 2004).
Bovine oocytes exposed to ZEA are arrested in metaphase 1 and im-
mature but fertilization is not affected (Takagi et al., 2008). Little is
known about the detailed physiological mechanisms of ZEA toxicity in
farm animals. Therefore, further research on the toxicokinetics and
regulatory mechanisms of ZEA is needed to develop effective methods
to alleviate the toxicity of ZEA.
3.5. Effects of deoxynivalenol on farm animals
Reports indicate that DON-contaminated pig feed causes feed re-
jection and vomiting (Diekman and Green, 1992). Feeds containing
DON at 600 μg/kg lead to an increase in immunoglobulin A (IgA) levels
in the serum of piglets (Drochner et al., 2004). Evidence suggests that
DON causes immaturity of porcine oocytes by interference with
6
Journal of Hazardous Materials 389 (2020) 122087
microtubule dynamics. When pig cumulus-oocyte complexes are ex-
posed to DON there is inhibition of cumulus expansion and spindle
malformations (Schoevers et al., 2010). DON also inhibits barrier
function in the porcine intestinal epithelium by regulating the expres-
sion of tight junction proteins (Pinton et al., 2010). DON-mediated in-
testinal barrier destruction is prevented with TLR2 ligand pre-treatment
by mediating activation of the PI3K/AKT signaling pathway (Gu et al.,
2016). Broilers that consume DON-contaminated feed lose body weight
and liver weight (Lucke et al., 2017). DON-contaminated feed at a
concentration of 10 mg/kg reduces feed intake and feed efficiency in
broilers (Ghareeb et al., 2012). DON also interferes with biochemical
indicators, suggesting impaired protein and lipid metabolism in
chickens, along with altered immune responses, such as changes in the
number of lymphocytes and antibodies (Yunus et al., 2012a). Small
intestinal morphology that is associated with macronutrient retention is
also altered in broilers (Yunus et al., 2012b). Diets containing DON
cause a significant reduction in the length of duodenal and jejunal villi
of the chick, and this is accompanied by lipid peroxidation (Awad et al.,
2006, 2014). Dietary DON decreases TNF-α levels in the plasma and IL-
1β, TGFBR1, and IFN-γ mRNA levels in the jejunum of broiler chicks,
suggesting the immunomodulatory function of DON in poultry
(Ghareeb et al., 2013). DON-contaminated diets alter the humoral im-
mune response to viral vaccines in broiler chicks, a finding that was
validated by serum antibody levels (Ghareeb et al., 2016). Moreover,
DON alters lipid profiles, such as increasing serum cholesterol and tri-
glycerides in broilers. Feeds contaminated with up to 10 mg/kg of DON
interfere with mineral homeostasis in the bones of chickens (Keci et al.,
2019). The adverse effects of DON in chicken are largely mitigated by
microbial feed additives (Ghareeb et al., 2012, 2013), which are also
able to mitigate DNA damage in lymphocytes induced by DON in
broilers (Awad et al., 2014).
3.6. Interaction effect of mycotoxins on farm animals
Farm animals are generally exposed to two or more types of my-
cotoxins simultaneously, rather than a single mycotoxin (Klaric et al.,
2009). Therefore, studies of the toxicity of mycotoxins in animals re-
quire an understanding of the effects of multiple mycotoxins. Different
combinations of mycotoxins have a synergistic effect on environmental
toxicity, while some combinations cause antagonistic effects. Several
review papers have described the interaction effects caused by different
types of mycotoxins (Alassane-Kpembi et al., 2017; Feijo Correa et al.,
2018). Exposure to more than one mycotoxin has been demonstrated to
have an interaction effect on hepatotoxicity, gastrointestinal toxicity,
and reproductive toxicity in human and rodent cells (Sun et al., 2014;
Alassane-Kpembi et al., 2013; Li et al., 2014). Studies also revealed that
combinations of mycotoxins have synergistic or antagonistic effects on
cells derived from farm animals. The combination of AFB1, FB1, ZEA,
and DON in porcine kidney 15 cells (PK-15) causes either synergistic or
antagonistic effects on ROS production and apoptosis (Lei et al., 2013).
The combined treatment of OTA, FB1, and beauvericin also exerts sy-
nergistic effects on the apoptotic index in PK-15 cells (Klaric et al.,
2008). The combination of OTA and FB1 has a synergistic effect on
reducing cell viability in porcine lymphocytes (Mwanza et al., 2009).
ZEA and DON are observed together in cereal grains and animal feed
supplies. Therefore, the physiological effects of their combined pre-
sence have been studied in animal cells (Fig. 3). Diets contaminated
with ZEA and DON inhibit the proliferative capacity of splenocytes and
cause histopathological modifications associated with spleen hemosi-
derosis in gilts (Tiemann et al., 2006a). Feed contaminated with ZEA
and DON increase the percentage of degenerated meiotic chromatin in
oocytes recovered from the ovaries of gilts and interfere with normal
oocyte maturation (Alm et al., 2006). Pregnant sows fed a diet con-
taining 15 % ZEA and DON suffer from splenic disorders, such as he-
mosiderosis (Tiemann et al., 2008). Diets contaminated with ZEA and
DON also cause histopathological disorders in the porcine liver without
C. Yang, et al. Journal of Hazardous Materials 389 (2020) 122087

Fig. 3. Physiological functions of zearalenone and deoxynivalenol in animal cells. Zearalenone and deoxynivalenol are mycotoxins produced by the Fusarium species.
Zearalenone is metabolized in the liver to form zearalenol, which promotes ROS generation and induces mitochondria-dependent cell death. Deoxynivalenol aug-
ments the effects of zearalenol by inhibiting the PI3K/AKT signaling pathway. In intestinal cells, deoxynivalenol induces epithelial barrier destruction by inhibiting
tight junction proteins. Curcumin and TLR2 ligands alleviate the toxicity of zearalenone and deoxynivalenol, respectively. Exposure to both zearalenone and
deoxynivalenol causes ovarian, splenic, liver, and intestinal dysfunction in farm animals.

causing clinical symptoms (Tiemann et al., 2006b). In porcine granu- Declaration of Competing Interest
losa cells, DON alone promotes the production of P4 and E2, whereas
ZEA alone has not been shown to affect the production of steroid hor- The authors declare that they have no known competing financial
mones (Kolesarova et al., 2017). RNA sequencing was performed on interests or personal relationships that could have appeared to influ-
liver samples from piglets fed with ZEA and DON-contaminated feed, ence the work reported in this paper.
indicating an effect on the expression and network of immune-related
transcripts (Reddy et al., 2018). Acknowledgements

This article was supported by two funding sources as below: 1)

4. Conclusions
Mycotoxin contamination of farm animal feed causes significant
economic loss. Mycotoxins cause fertility disorders and histopatholo-
gical changes in the kidneys and liver of pigs and poultry. Furthermore,
in vitro studies have shown that mycotoxins may regulate signaling
pathways in animal cells, promoting oxidative stress and mitochondria-
dependent cell death. Aflatoxin, ochratoxin A, fumonisin, ZEA, and
DON, which are thought to be the most threatening to farm animals, are
naturally occurring in farm animal feed and frequently identified
during monitoring. Moreover, mycotoxins, which accumulate in animal
tissues and are present in the blood and milk of livestock, can be a
threat to people who consume meat or dairy products. Recently, various
chemical and biological methods for mitigating mycotoxin toxicity have
been proposed, and through continued research, we hope to reduce the
economic loss incurred by farmers and also resolve the risks to human
health.
Korea Health Technology R&D Project through the Korea Health
Industry Development Institute funded by the Ministry of Health &
Welfare (grant number: HI17C0929), Republic of Korea; and 2)
National Research Foundation of Korea (NRF) grant funded by the
Ministry of Science and ICT (MSIT) (No. 2018R1C1B6009048),
Republic of Korea.
References
Abidin, Z., Khatoon, A., Arooj, N., Hussain, S., Ali, S., Manzoor, A.W., Saleemi, M.K.,
2017. Estimation of ochratoxin A in poultry feed and its ingredients with special
reference to temperature conditions. Br. Poult. Sci. 58, 251–255.
Abnet, C.C., 2007. Carcinogenic food contaminants. Cancer Invest. 25, 189–196.
Akinmusire, O.O., El-Yuguda, A.D., Musa, J.A., Oyedele, O.A., Sulyok, M., Somorin, Y.M.,
Ezekiel, C.N., Krska, R., 2019. Mycotoxins in poultry feed and feed ingredients in
Nigeria. Mycotoxin Res. 35, 149–155.
Alassane-Kpembi, I., Kolf-Clauw, M., Gauthier, T., Abrami, R., Abiola, F.A., Oswald, I.P.,
Puel, O., 2013. New insights into mycotoxin mixtures: the toxicity of low doses of
Type B trichothecenes on intestinal epithelial cells is synergistic. Toxicol. Appl.
Pharmacol. 272, 191–198.

7
C. Yang, et al.
Alassane-Kpembi, I., Schatzmayr, G., Taranu, I., Marin, D., Puel, O., Oswald, I.P., 2017.
Mycotoxins co-contamination: methodological aspects and biological relevance of
combined toxicity studies. Crit. Rev. Food Sci. Nutr. 57, 3489–3507.
Alm, H., Brussow, K.P., Torner, H., Vanselow, J., Tomek, W., Danicke, S., Tiemann, U.,
2006. Influence of Fusarium-toxin contaminated feed on initial quality and meiotic
competence of gilt oocytes. Reprod. Toxicol. 22, 44–50.
Alonso, V.A., Monge, M.P., Larriestra, A., Dalcero, A.M., Cavaglieri, L.R., Chiacchiera,
S.M., 2010. Naturally occurring aflatoxin M1 in raw bulk milk from farm cooling
tanks in Argentina. Food Addit. Contam. A 27, 373–379.
Alshannaq, A., Yu, J.H., 2017. Occurrence, toxicity, and analysis of major mycotoxins in
food. Int. J. Environ. Res. Public Health 14.
Ameer Sumbal, G., Hussain Shar, Z., Hussain Sherazi, S.T., Sirajuddin, Nizamani, S.M.,
Mahesar, S.A., 2016. Decontamination of poultry feed from ochratoxin A by UV and
sunlight radiations. J. Sci. Food Agric. 96, 2668–2673.
Anon, 1991. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumours. IARC Sci
Publ, pp. 1–336.
Anukul, N., Vangnai, K., Mahakarnchanakul, W., 2013. Significance of regulation limits in
mycotoxin contamination in Asia and risk management programs at the national
level. J. Food Drug Anal. 21, 227–241.
Awad, W.A., Bohm, J., Razzazi-Fazeli, E., Ghareeb, K., Zentek, J., 2006. Effect of addition
of a probiotic microorganism to broiler diets contaminated with deoxynivalenol on
performance and histological alterations of intestinal villi of broiler chickens. Poultry
Sci 85, 974–979.
Awad, W.A., Ghareeb, K., Dadak, A., Hess, M., Bohm, J., 2014. Single and combined
effects of deoxynivalenol mycotoxin and a microbial feed additive on lymphocyte
DNA damage and oxidative stress in broiler chickens. PLoS One 9, e88028.
Biehl, M.L., Prelusky, D.B., Koritz, G.D., Hartin, K.E., Buck, W.B., Trenholm, H.L., 1993.
Biliary excretion and enterohepatic cycling of zearalenone in immature pigs. Toxicol.
Appl. Pharmacol. 121, 152–159.
Binder, S.B., Schwartz-Zimmermann, H.E., Varga, E., Bichl, G., Michlmayr, H., Adam, G.,
Berthiller, F., 2017. Metabolism of Zearalenone and its major modified forms in pigs.
Toxins (Basel) 9.
Birzele, B., Prange, A., Kramer, J., 2000. Deoxynivalenol and ochratoxin A in German
wheat and changes of level in relation to storage parameters. Food Addit. Contam.
17, 1027–1035.
Blank, R., Wolffram, S., 2004. Alkalinization of urinary pH accelerates renal excretion of
ochratoxin A in pigs. J. Nutr. 134, 2355–2358.
Blank, R., Wolffram, S., 2005. Effect of dietary sodium bicarbonate supplementation on
the toxicokinetics of ochratoxin A in pigs. Mycotoxin Res. 21, 147–149.
Bouhet, S., Hourcade, E., Loiseau, N., Fikry, A., Martinez, S., Roselli, M., Galtier, P.,
Mengheri, E., Oswald, I.P., 2004. The mycotoxin fumonisin B1 alters the proliferation
and the barrier function of porcine intestinal epithelial cells. Toxicol. Sci. 77,
165–171.
Bouhet, S., Le Dorze, E., Peres, S., Fairbrother, J.M., Oswald, I.P., 2006. Mycotoxin fu-
monisin B1 selectively down-regulates the basal IL-8 expression in pig intestine: in
vivo and in vitro studies. Food Chem. Toxicol. 44, 1768–1773.
Bozic, Z., Duancic, V., Belicza, M., Kraus, O., Skljarov, I., 1995. Balkan endemic ne-
phropathy: still a mysterious disease. Eur. J. Epidemiol. 11, 235–238.
Breitholtz-Emanuelsson, A., Olsen, M., Oskarsson, A., Palminger, I., Hult, K., 1993.
Ochratoxin A in cow’s milk and in human milk with corresponding human blood
samples. J. AOAC Int. 76, 842–846.
Chen, B., Li, D., Li, M., Li, S., Peng, K., Shi, X., Zhou, L., Zhang, P., Xu, Z., Yin, H., Wang,
Y., Zhao, X., Zhu, Q., 2016. Induction of mitochondria-mediated apoptosis and PI3K/
Akt/ mTOR-mediated autophagy by aflatoxin B2 in hepatocytes of broilers.
Oncotarget 7, 84989–84998.
Cheng, Y.H., Ding, S.T., Chang, M.H., 2006. Effect of fumonisins on macrophage immune
functions and gene expression of cytokines in broilers. Arch. Anim. Nutr. 60,
267–276.
Cheng, L., Qin, Y., Hu, X., Ren, L., Zhang, C., Wang, X., Wang, W., Zhang, Z., Hao, J., Guo,
M., Wu, Z., Tian, J., An, L., 2019. Melatonin protects in vitro matured porcine oocytes
from toxicity of Aflatoxin B1. J. Pineal Res. 66, e12543.
Curtui, V.G., Gareis, M., Usleber, E., Martlbauer, E., 2001. Survey of Romanian slaugh-
tered pigs for the occurrence of mycotoxins ochratoxins A and B, and zearalenone.
Food Addit. Contam. 18, 730–738.
D’Mello, J.P.F., Placinta, C.M., Macdonald, A.M.C., 1999. Fusarium mycotoxins: a review
of global implications for animal health, welfare and productivity. Anim. Feed Sci.
Technol. 80, 183–205.
Dalcero, A., Magnoli, C., Hallak, C., Chiacchiera, S.M., Palacio, G., Rosa, C.A., 2002.
Detection of ochratoxin A in animal feeds and capacity to produce this mycotoxin by
Aspergillus section Nigri in Argentina. Food Addit. Contam. 19, 1065–1072.
Danicke, S., Brezina, U., 2013. Kinetics and metabolism of the Fusarium toxin deox-
ynivalenol in farm animals: consequences for diagnosis of exposure and intoxication
and carry over. Food Chem. Toxicol. 60, 58–75.
Danicke, S., Winkler, J., 2015. Invited review: diagnosis of zearalenone (ZEN) exposure of
farm animals and transfer of its residues into edible tissues (carry over). Food Chem.
Toxicol. 84, 225–249.
Danicke, S., Valenta, H., Doll, S., 2004. On the toxicokinetics and the metabolism of
deoxynivalenol (DON) in the pig. Arch. Anim. Nutr. 58, 169–180.
Danicke, S., Hegewald, A.K., Kahlert, S., Kluess, J., Rothkotter, H.J., Breves, G., Doll, S.,
2010. Studies on the toxicity of deoxynivalenol (DON), sodium metabisulfite, DON-
sulfonate (DONS) and de-epoxy-DON for porcine peripheral blood mononuclear cells
and the Intestinal Porcine Epithelial Cell lines IPEC-1 and IPEC-J2, and on effects of
DON and DONS on piglets. Food Chem. Toxicol. 48, 2154–2162.
Deng, J., Zhao, L., Zhang, N.Y., Karrow, N.A., Krumm, C.S., Qi, D.S., Sun, L.H., 2018.
Aflatoxin B1 metabolism: regulation by phase I and II metabolizing enzymes and
chemoprotective agents. Mutat. Res. 778, 79–89.
8
Journal of Hazardous Materials 389 (2020) 122087
Di Stefano, V., Pitonzo, R., Cicero, N., D’Oca, M.C., 2014. Mycotoxin contamination of
animal feedingstuff: detoxification by gamma-irradiation and reduction of aflatoxins
and ochratoxin A concentrations. Food Addit. Contam. Part A Chem. Anal. Control
Expo. Risk Assess. 31, 2034–2039.
Diekman, M.A., Green, M.L., 1992. Mycotoxins and reproduction in domestic livestock. J.
Anim. Sci. 70, 1615–1627.
Dohnal, V., Wu, Q., Kuca, K., 2014. Metabolism of aflatoxins: key enzymes and inter-
individual as well as interspecies differences. Arch. Toxicol. 88, 1635–1644.
Drochner, W., Schollenberger, M., Piepho, H.P., Gotz, S., Lauber, U., Tafaj, M., Klobasa,
F., Weiler, U., Claus, R., Steffl, M., 2004. Serum IgA-promoting effects induced by
feed loads containing isolated deoxynivalenol (DON) in growing piglets. J. Toxicol.
Environ. Health A 67, 1051–1067.
Dutton, M.F., Mwanza, M., de Kock, S., Khilosia, L.D., 2012. Mycotoxins in South African
foods: a case study on aflatoxin M1 in milk. Mycotoxin Res. 28, 17–23.
Elliott, C.T., Connolly, L., Kolawole, O., 2019. Potential adverse effects on animal health
and performance caused by the addition of mineral adsorbents to feeds to reduce
mycotoxin exposure. Mycotoxin Res.
Etienne, M., Dourmad, J.Y., 1994. Effects of zearalenone or glucosinolates in the diet on
reproduction in sows – a review. Livest Prod Sci 40, 99–113.
Feijo Correa, J.A., Orso, P.B., Bordin, K., Hara, R.V., Luciano, F.B., 2018. Toxicological
effects of fumonisin B1 in combination with other Fusarium toxins. Food Chem.
Toxicol. 121, 483–494.
Fodor, J., Balogh, K., Weber, M., Mezes, M., Kametler, L., Posa, R., Mamet, R., Bauer, J.,
Horn, P., Kovacs, F., Kovacs, M., 2008. Absorption, distribution and elimination of
fumonisin B(1) metabolites in weaned piglets. Food Addit. Contam. A 25, 88–96.
Galvano, F., Pietri, A., Bertuzzi, T., Fusconi, G., Galvano, M., Piva, A., Piva, G., 1996.
Reduction of carryover of aflatoxin from cow feed to milk by addition of activated
carbons. J. Food Prot. 59, 551–554.
Gan, F., Zhou, Y.J., Hou, L.L., Qian, G., Chen, X.X., Huang, K.H., 2017a. Ochratoxin A
induces nephrotoxicity and immunotoxicity through different MAPK signaling
pathways in PK15 cells and porcine primary splenocytes. Chemosphere 182,
630–637.
Gan, F., Hou, L., Zhou, Y., Liu, Y., Huang, D., Chen, X., Huang, K., 2017b. Effects of
ochratoxin A on ER stress, MAPK signaling pathway and autophagy of kidney and
spleen in pigs. Environ. Toxicol. 32, 2277–2286.
Gan, F., Yang, Y., Chen, Y., Che, C., Pan, C., Huang, K., 2018a. Bush sophora root poly-
saccharide could help prevent aflatoxin B1-induced hepatotoxicity in the primary
chicken hepatocytes. Toxicon 150, 180–187.
Gan, F., Zhou, Y., Qian, G., Huang, D., Hou, L., Liu, D., Chen, X., Wang, T., Jiang, P., Lei,
X., Huang, K., 2018b. PCV2 infection aggravates ochratoxin A-induced ne-
phrotoxicity via autophagy involving p38 signaling pathway in vivo and in vitro.
Environ. Pollut. 238, 656–662.
Gautier, J., Richoz, J., Welti, D.H., Markovic, J., Gremaud, E., Guengerich, F.P., Turesky,
R.J., 2001. Metabolism of ochratoxin A: absence of formation of genotoxic deriva-
tives by human and rat enzymes. Chem. Res. Toxicol. 14, 34–45.
Gesing, A., Jagiela, J., Lewinski, A., 2006. Effects of melatonin on the process of apoptosis
in rat thyroid follicular cells. Neuro Endocrinol. Lett. 27, 81–84.
Ghareeb, K., Awad, W.A., Bohm, J., 2012. Ameliorative effect of a microbial feed additive
on infectious bronchitis virus antibody titer and stress index in broiler chicks fed
deoxynivalenol. Poult. Sci. 91, 800–807.
Ghareeb, K., Awad, W.A., Soodoi, C., Sasgary, S., Strasser, A., Bohm, J., 2013. Effects of
feed contaminant deoxynivalenol on plasma cytokines and mRNA expression of im-
mune genes in the intestine of broiler chickens. PLoS One 8, e71492.
Ghareeb, K., Awad, W.A., Zebeli, Q., Bohm, J., 2016. Deoxynivalenol in chicken feed
alters the vaccinal immune response and clinical biochemical serum parameters but
not the intestinal and carcass characteristics. J. Anim. Physiol. Anim. Nutr. (Berl)
100, 53–60.
Gong, Y., Hounsa, A., Egal, S., Turner, P.C., Sutcliffe, A.E., Hall, A.J., Cardwell, K., Wild,
C.P., 2004. Postweaning exposure to aflatoxin results in impaired child growth: a
longitudinal study in Benin, West Africa. Environ. Health Perspect. 112, 1334–1338.
Gregory, J.F., Manley, D.B., 1982. High-performance liquid-chromatographic quantita-
tion of aflatoxin metabolites in animal-tissues. J. Assoc. 65, 869–875.
Gu, M.J., Song, S.K., Lee, I.K., Ko, S., Han, S.E., Bae, S., Ji, S.Y., Park, B.C., Song, K.D., Lee,
H.K., Han, S.H., Yun, C.H., 2016. Barrier protection via Toll-like receptor 2 signaling
in porcine intestinal epithelial cells damaged by deoxynivalnol. Vet. Res. 47, 25.
Hahn, I., Nagl, V., Schwartz-Zimmermann, H.E., Varga, E., Schwarz, C., Slavik, V.,
Reisinger, N., Malachova, A., Cirlini, M., Generotti, S., Dall’Asta, C., Krska, R., Moll,
W.D., Berthiller, F., 2015. Effects of orally administered fumonisin B-1 (FB1), par-
tially hydrolysed FB1, hydrolysed FB1 and N-(1-deoxy-D-fructos-1-yl) FB1 on the
sphingolipid metabolism in rats. Food Chem. Toxicol. 76, 11–18.
Hao, S., Pan, S., Hu, J., Qian, G., Gan, F., Huang, K., 2015. Aflatoxin B1 suppressed T-cell
response to Anti-pig-CD3 monoclonal antibody stimulation in primary porcine sple-
nocytes: a role for the extracellular regulated protein kinase (ERK1/2) MAPK sig-
naling pathway. J. Agric. Food Chem. 63, 6094–6101.
Hao, S., Hu, J., Song, S., Huang, D., Xu, H., Qian, G., Gan, F., Huang, K., 2016. Selenium
alleviates aflatoxin B(1)-induced immune toxicity through improving glutathione
peroxidase 1 and selenoprotein S expression in primary porcine splenocytes. J. Agric.
Food Chem. 64, 1385–1393.
Hartinger, D., Moll, W.D., 2011. Fumonisin elimination and prospects for detoxification
by enzymatic transformation. World Mycotoxin J. 4, 271–283.
Harvey, R.B., Kubena, L.F., Phillips, T.D., Corrier, D.E., Elissalde, M.H., Huff, W.E., 1991.
Diminution of aflatoxin toxicity to growing lambs by dietary supplementation with
hydrated sodium calcium aluminosilicate. Am. J. Vet. Res. 52, 152–156.
Harvey, R.B., Edrington, T.S., Kubena, L.F., Elissalde, M.H., Rottinghaus, G.E., 1995.
Influence of aflatoxin and fumonisin B1-containing culture material on growing
barrows. Am. J. Vet. Res. 56, 1668–1672.
C. Yang, et al.
Haschek, W.M., Gumprecht, L.A., Smith, G., Tumbleson, M.E., Constable, P.D., 2001.
Fumonisin toxicosis in swine: an overview of porcine pulmonary edema and current
perspectives. Environ. Health Perspect. 109 (Suppl. 2), 251–257.
He, Q., Riley, R.T., Sharma, R.P., 2002. Pharmacological antagonism of fumonisin B1
cytotoxicity in porcine renal epithelial cells (LLC-PK1): a model for reducing fumo-
nisin-induced nephrotoxicity in vivo. Pharmacol. Toxicol. 90, 268–277.
Herzallah, S., Alshawabkeh, K., Al Fataftah, A., 2008. Aflatoxin decontamination of ar-
tificially contaminated feeds by sunlight, gamma-radiation, and microwave heating.
J. Appl. Poultry Res. 17, 515–521.
Hohler, D., 1998. Ochratoxin A in food and feed: occurrence, legislation and mode of
action. Z. Ernahrungswiss 37, 2–12.
Hooshmand, H., Klopfenstein, C.F., 1995. Effects of gamma-irradiation on mycotoxin
disappearance and amino-acid contents of corn, wheat, and soybeans with different
moisture contents. Plant Foods Hum. Nutr. 47, 227–238.
Hou, L., Zhou, X., Gan, F., Liu, Z., Zhou, Y., Qian, G., Huang, K., 2018. Combination of
selenomethionine and N-acetylcysteine alleviates the joint toxicities of aflatoxin B1
and ochratoxin a by ERK MAPK signal pathway in porcine alveolar macrophages. J.
Agric. Food Chem. 66, 5913–5923.
Humer, E., Lucke, A., Harder, H., Metzler-Zebeli, B.U., Bohm, J., Zebeli, Q., 2016. Effects
of citric and lactic acid on the reduction of deoxynivalenol and its derivatives in
feeds. Toxins (Basel) 8.
Hussein, H.S., Brasel, J.M., 2001. Toxicity, metabolism, and impact of mycotoxins on
humans and animals. Toxicology 167, 101–134.
Jalili, M., Jinap, S., Noranizan, M.A., 2012. Aflatoxins and ochratoxin a reduction in black
and white pepper by gamma radiation. Radiat. Phys. Chem. 81, 1786–1788.
Jorgensen, K., 1998. Survey of pork, poultry, coffee, beer and pulses for ochratoxin A.
Food Addit. Contam. 15, 550–554.
Jorgensen, K., Petersen, A., 2002. Content of ochratoxin A in paired kidney and meat
samples from healthy Danish slaughter pigs. Food Addit. Contam. 19, 562–567.
Katsoulos, P.D., Karatzia, M.A., Boscos, C., Wolf, P., Karatzias, H., 2016. In-field eva-
luation of clinoptilolite feeding efficacy on the reduction of milk aflatoxin M1 con-
centration in dairy cattle. J. Anim. Sci. Technol. 58, 24.
Katzenellenbogen, B.S., Katzenellenbogen, J.A., Mordecai, D., 1979. Zearalenones:
characterization of the estrogenic potencies and receptor interactions of a series of
fungal beta-resorcylic acid lactones. Endocrinology 105, 33–40.
Keci, M., Lucke, A., Paulsen, P., Zebeli, Q., Bohm, J., Metzler-Zebeli, B.U., 2019.
Deoxynivalenol in the diet impairs bone mineralization in broiler chickens. Toxins
(Basel) 11.
Kendra, D.F., Dyer, R.B., 2007. Opportunities for biotechnology and policy regarding
mycotoxin issues in international trade. Int. J. Food Microbiol. 119, 147–151.
Kim, D.H., Lee, I.H., Do, W.H., Nam, W.S., Li, H., Jang, H.S., Lee, C., 2013. Incidence and
levels of deoxynivalenol, fumonisins and zearalenone contaminants in animal feeds
used in Korea in 2012. Toxins (Basel) 6, 20–32.
Klaric, M.S., Rumora, L., Ljubanovic, D., Pepeljnjak, S., 2008. Cytotoxicity and apoptosis
induced by fumonisin B(1), beauvericin and ochratoxin A in porcine kidney PK15
cells: effects of individual and combined treatment. Arch. Toxicol. 82, 247–255.
Klaric, M.S., Cvetnic, Z., Pepeljnjak, S., Kosalec, I., 2009. Co-occurrence of aflatoxins,
ochratoxin A, fumonisins, and zearalenone in cereals and feed, determined by com-
petitive direct enzyme-linked immunosorbent assay and thin-layer chromatography.
Arh. Hig. Rada Toksikol. 60, 427–434.
Kolesarova, A., Medvedova, M., Halenar, M., Sirotkin, A.V., Bulla, J., 2017. The influence
of deoxynivalenol and zearalenone on steroid hormone production by porcine
ovarian granulosa cells in vitro. J. Environ. Sci. Health B 52, 823–832.
Krout-Greenberg, N.D., Puschner, B., Davidson, M.G., DePeters, E.J., 2013. Preliminary
study to assess mycotoxin concentrations in whole corn in the California feed supply.
J. Dairy Sci. 96, 2705–2712.
Kuiper-Goodman, T., Scott, P.M., Watanabe, H., 1987. Risk assessment of the mycotoxin
zearalenone. Regul. Toxicol. Pharmacol. 7, 253–306.
Labuda, R., Parich, A., Vekiru, E., Tancinova, D., 2005. Incidence of fumonisins, mon-
iliformin and Fusarium species in poultry feed mixtures from Slovakia. Ann. Agric.
Environ. Med. 12, 81–86.
Langseth, W., Nymoen, U., Bergsjo, B., 1993. Ochratoxin A in plasma of Norwegian swine
determined by an HPLC column-switching method. Nat. Toxins 1, 216–221.
Lea, T., Steien, K., Stormer, F.C., 1989. Mechanism of ochratoxin A-induced im-
munosuppression. Mycopathologia 107, 153–159.
Ledoux, D.R., Brown, T.P., Weibking, T.S., Rottinghaus, G.E., 1992. Fumonisin toxicity in
broiler chicks. J. Vet. Diagn. Invest. 4, 330–333.
Ledoux, D.R., Broomhead, J.N., Bermudez, A.J., Rottinghaus, G.E., 2003. Individual and
combined effects of the Fusarium mycotoxins fumonisin B1 and moniliformin in
broiler chicks. Avian Dis. 47, 1368–1375.
Lee, H.J., Ryu, D., 2017. Worldwide occurrence of mycotoxins in cereals and cereal-de-
rived food products: public health perspectives of their co-occurrence. J. Agric. Food
Chem. 65, 7034–7051.
Lei, M., Zhang, N., Qi, D., 2013. In vitro investigation of individual and combined cy-
totoxic effects of aflatoxin B1 and other selected mycotoxins on the cell line porcine
kidney 15. Exp. Toxicol. Pathol. 65, 1149–1157.
Li, Y.C., Ledoux, D.R., Bermudez, A.J., Fritsche, K.L., Rottinghaus, G.E., 1999. Effects of
fumonisin B1 on selected immune responses in broiler chicks. Poult. Sci. 78,
1275–1282.
Li, Y., Zhang, B., He, X., Cheng, W.H., Xu, W., Luo, Y., Liang, R., Luo, H., Huang, K., 2014.
Analysis of individual and combined effects of ochratoxin A and zearalenone on
HepG2 and KK-1 cells with mathematical models. Toxins (Basel) 6, 1177–1192.
Li, H., Malyar, R.M., Zhai, N., Wang, H., Liu, K., Liu, D., Pan, C., Gan, F., Huang, K., Miao,
J., Chen, X., 2019. Zinc supplementation alleviates OTA-induced oxidative stress and
apoptosis in MDCK cells by up-regulating metallothioneins. Life Sci. 234, 116735.
Lindemann, M.D., Blodgett, D.J., Kornegay, E.T., Schurig, G.G., 1993. Potential
9
Journal of Hazardous Materials 389 (2020) 122087
ameliorators of aflatoxicosis in weanling growing swine. J. Anim. Sci. 71, 171–178.
Lioi, M.B., Santoro, A., Barbieri, R., Salzano, S., Ursini, M.V., 2004. Ochratoxin A and
zearalenone: a comparative study on genotoxic effects and cell death induced in
bovine lymphocytes. Mutat. Res. 557, 19–27.
Lippold, C.C., Stothers, S.C., Frohlich, A.A., Boila, R.J., Marquardt, R.R., 1992. Effects of
periodic feeding of diets containing Ochratoxin-a on the performance and clinical-
chemistry of pigs from 15 to 50 kg body-weight. Can. J. Anim. Sci. 72, 135–146.
Liu, J., Wang, Q.C., Han, J., Xiong, B., Sun, S.C., 2015. Aflatoxin B1 is toxic to porcine
oocyte maturation. Mutagenesis 30, 527–535.
Loiseau, N., Debrauwer, L., Sambou, T., Bouhet, S., Miller, J.D., Martin, P.G., Viadere,
J.L., Pinton, P., Puel, O., Pineau, T., Tulliez, J., Galtier, P., Oswald, I.P., 2007.
Fumonisin B1 exposure and its selective effect on porcine jejunal segment: sphin-
golipids, glycolipids and trans-epithelial passage disturbance. Biochem. Pharmacol.
74, 144–152.
Lucke, A., Doupovec, B., Paulsen, P., Zebeli, Q., Bohm, J., 2017. Effects of low to mod-
erate levels of deoxynivalenol on feed and water intake, weight gain, and slaugh-
tering traits of broiler chickens. Mycotoxin Res. 33, 261–271.
Ma, R., Zhang, L., Liu, M., Su, Y.T., Xie, W.M., Zhang, N.Y., Dai, J.F., Wang, Y., Rajput,
S.A., Qi, D.S., Karrow, N.A., Sun, L.H., 2018. Individual and combined occurrence of
mycotoxins in feed ingredients and complete feeds in China. Toxins (Basel) 10.
Malagutti, L., Zannotti, M., Scampini, A., Sciaraffia, F., 2005. Effects of Ochratoxin A on
heavy pig production. Anim. Res. 54, 179–184.
Malekinejad, H., Maas-Bakker, R., Fink-Gremmels, J., 2006. Species differences in the
hepatic biotransformation of zearalenone. Vet. J. 172, 96–102.
Malir, F., Ostry, V., Pfohl-Leszkowicz, A., Malir, J., Toman, J., 2016. Ochratoxin A: 50
years of research. Toxins 8.
Marasas, W.F.O., 1995. Fumonisins – History, Worldwide Occurrence and Impact. Abstr.
Pap. Am. Chem. S 209 56-Agfd.
Masching, S., Naehrer, K., Schwartz-Zimmermann, H.E., Sarandan, M., Schaumberger, S.,
Dohnal, I., Nagl, V., Schatzmayr, D., 2016. Gastrointestinal degradation of fumonisin
B(1) by carboxylesterase FumD prevents fumonisin induced alteration of sphingolipid
metabolism in Turkey and swine. Toxins (Basel) 8.
Meki, A.R., Abdel-Ghaffar, S.K., El-Gibaly, I., 2001. Aflatoxin B1 induces apoptosis in rat
liver: protective effect of melatonin. Neuro Endocrinol. Lett. 22, 417–426.
Milicevic, D., Juric, V., Stefanovic, S., Jovanovic, M., Jankovic, S., 2008. Survey of
slaughtered pigs for occurrence of ochratoxin A and porcine nephropathy in Serbia.
Int. J. Mol. Sci. 9, 2169–2183.
Monge, M.P., Dalcero, A.M., Magnoli, C.E., Chiacchiera, S.M., 2013. Natural co-occur-
rence of fungi and mycotoxins in poultry feeds from Entre Rios, Argentina. Food
Addit. Contam. B 6, 168–174.
Monson, M.S., Settlage, R.E., McMahon, K.W., Mendoza, K.M., Rawal, S., El-Nezami, H.S.,
Coulombe, R.A., Reed, K.M., 2014. Response of the hepatic transcriptome to aflatoxin
B1 in domestic turkey (Meleagris gallopavo). PLoS One 9, e100930.
Monson, M.S., Settlage, R.E., Mendoza, K.M., Rawal, S., El-Nezami, H.S., Coulombe, R.A.,
Reed, K.M., 2015. Modulation of the spleen transcriptome in domestic turkey
(Meleagris gallopavo) in response to aflatoxin B1 and probiotics. Immunogenetics 67,
163–178.
Morgan, M.R.A., Mcnerney, R., Chan, H.W.S., Anderson, P.H., 1986. Ochratoxin-a in Pig-
Kidney determined by enzyme-linked-immunosorbent-assay (Elisa). J. Sci. Food
Agric. 37, 475–480.
Muller, H.M., Reimann, J., Schumacher, U., Schwadorf, K., 2001. Further survey of the
occurrence of Fusarium toxins in wheat grown in southwest Germany. Arch. Anim.
Nutr. 54, 173–182.
Murata, H., Mitsumatsu, M., Shimada, N., 2008. Reduction of feed-contaminating my-
cotoxins by ultraviolet irradiation: an in vitro study. Food Addit. Contam. Part A
Chem. Anal. Control Expo. Risk Assess. 25, 1107–1110.
Mwanza, M., Kametler, L., Bonai, A., Rajli, V., Kovacs, M., Dutton, M.F., 2009. The cy-
totoxic effect of fumonisin B1 and ochratoxin A on human and pig lymphocytes using
the Methyl Thiazol Tetrazolium (MTT) assay. Mycotoxin Res. 25, 233–238.
Nakajima, M., Tabata, S., Akiyama, H., Itoh, Y., Tanaka, T., Sunagawa, H., Tyonan, T.,
Yoshizawa, T., Kumagai, S., 2004. Occurrence of aflatoxin M1 in domestic milk in
Japan during the winter season. Food Addit. Contam. 21, 472–478.
Nikaido, Y., Yoshizawa, K., Danbara, N., Tsujita-Kyutoku, M., Yuri, T., Uehara, N.,
Tsubura, A., 2004. Effects of maternal xenoestrogen exposure on development of the
reproductive tract and mammary gland in female CD-1 mouse offspring. Reprod.
Toxicol. 18, 803–811.
Oliveira, G.R., Ribeiro, J.M., Fraga, M.E., Cavaglieri, L.R., Direito, G.M., Keller, K.M.,
Dalcero, A.M., Rosa, C.A., 2006. Mycobiota in poultry feeds and natural occurrence of
aflatoxins, fumonisins and zearalenone in the Rio de Janeiro State, Brazil.
Mycopathologia 162, 355–362.
Omar, R.F., Gelboin, H.V., Rahimtula, A.D., 1996. Effect of cytochrome P450 induction
on the metabolism and toxicity of ochratoxin A. Biochem. Pharmacol. 51, 207–216.
Oswald, I.P., Marin, D.E., Bouhet, S., Pinton, P., Taranu, I., Accensi, F., 2005.
Immunotoxicological risk of mycotoxins for domestic animals. Food Addit. Contam.
22, 354–360.
Park, W., Park, M.Y., Song, G., Lim, W., 2019. Exposure to aflatoxin B1 attenuates cell
viability and induces endoplasmic reticulum-mediated cell death in a bovine mam-
mary epithelial cell line (MAC-T). Toxicol. In Vitro 61, 104591.
Peters, L.P., Teel, R.W., 2003. Effect of high sucrose diet on liver enzyme content and
activity and aflatoxin B1-induced mutagenesis. In Vivo 17, 205–210.
Pfohl-Leszkowicz, A., Manderville, R.A., 2007. Ochratoxin A: an overview on toxicity and
carcinogenicity in animals and humans. Mol. Nutr. Food Res. 51, 61–99.
Pinton, P., Braicu, C., Nougayrede, J.P., Laffitte, J., Taranu, I., Oswald, I.P., 2010.
Deoxynivalenol impairs porcine intestinal barrier function and decreases the protein
expression of Claudin-4 through a mitogen-acitivated protein kinase-dependent me-
chanism. J. Nutr. 140, 1956–1962.
C. Yang, et al.
Placinta, C.M., D’Mello, J.P.F., Macdonald, A.M.C., 1999. A review of worldwide con-
tamination of cereal grains and animal feed with Fusarium mycotoxins. Anim. Feed
Sci. Technol. 78, 21–37.
Polak, M., Gajecki, M., Kulik, T., Luczynski, M.K., Obremski, K., Gora, M., Gajecka, M.,
Jakimiuk, E., Zielonka, L., 2009. The evaluation of the efficacy of sodium carbonate
as zearalenone destructor in feeding stuffs. Pol. J. Vet. Sci. 12, 103–111.
Pozzo, L., Cavallarin, L., Nucera, D., Antoniazzi, S., Schiavone, A., 2010. A survey of
ochratoxin A contamination in feeds and sera from organic and standard swine farms
in northwest Italy. J. Sci. Food Agric. 90, 1467–1472.
Prathapkumar, S.H., Rao, V.S., Paramkishan, R.J., Bhat, R.V., 1997. Disease outbreak in
laying hens arising from the consumption of fumonisin-contaminated food. Br. Poult.
Sci. 38, 475–479.
Qin, X., Cao, M., Lai, F., Yang, F., Ge, W., Zhang, X., Cheng, S., Sun, X., Qin, G., Shen, W.,
Li, L., 2015. Oxidative stress induced by zearalenone in porcine granulosa cells and
its rescue by curcumin in vitro. PLoS One 10, e0127551.
Quist, C.F., Bounous, D.I., Kilburn, J.V., Nettles, V.F., Wyatt, R.D., 2000. The effect of
dietary aflatoxin on wild turkey poults. J. Wildl. Dis. 36, 436–444.
Rahimi, E., Ameri, M., 2012. A survey of aflatoxin M1 contamination in bulk milk samples
from dairy bovine, ovine, and caprine herds in Iran. Bull. Environ. Contam. Toxicol.
89, 158–160.
Raju, M.V., Devegowda, G., 2000. Influence of esterified-glucomannan on performance
and organ morphology, serum biochemistry and haematology in broilers exposed to
individual and combined mycotoxicosis (aflatoxin, ochratoxin and T-2 toxin). Br.
Poult. Sci. 41, 640–650.
Reddy, K.E., Jeong, J.Y., Lee, Y., Lee, H.J., Kim, M.S., Kim, D.W., Jung, H.J., Choe, C., Oh,
Y.K., Lee, S.D., 2018. Deoxynivalenol- and zearalenone-contaminated feeds alter gene
expression profiles in the livers of piglets. Asian-Aust. J. Anim. Sci. 31, 595–606.
Rodrigues, I., Naehrer, K., 2012. A three-year survey on the worldwide occurrence of
mycotoxins in feedstuffs and feed. Toxins (Basel) 4, 663–675.
Rodriguez, A., Rodriguez, M., Martin, A., Delgado, J., Cordoba, J.J., 2012. Presence of
ochratoxin A on the surface of dry-cured Iberian ham after initial fungal growth in the
drying stage. Meat Sci. 92, 728–734.
Rosa, C.A., Miazzo, R., Magnoli, C., Salvano, M., Chiacchiera, S.M., Ferrero, S., Saenz, M.,
Carvalho, E.C., Dalcero, A., 2001. Evaluation of the efficacy of bentonite from the
south of Argentina to ameliorate the toxic effects of aflatoxin in broilers. Poult. Sci.
80, 139–144.
Sambuu, R., Takagi, M., Shiga, S., Uno, S., Kokushi, E., Namula, Z., Otoi, T., Miyamoto,
A., Deguchi, E., Fink-Gremmels, J., 2011. Detection of zearalenone and its metabo-
lites in naturally contaminated porcine follicular fluid by using liquid chromato-
graphy-tandem mass spectrometry. J. Reprod. Dev. 57, 303–306.
Santini, A., Raiola, A., Ferrantelli, V., Giangrosso, G., Macaluso, A., Bognanno, M.,
Galvano, F., Ritieni, A., 2013. Aflatoxin M-1 in raw, UHT milk and dairy products in
Sicily (Italy). Food Addit. Contam. B 6, 181–186.
Sarathchandra, G., Muralimanohar, B., 2013. Occurrence of mycotoxins in livestock feeds
and feed stuffs of Tamil Nadu. J. Environ. Biol. 34, 825–830.
Sarma, U.P., Bhetaria, P.J., Devi, P., Varma, A., 2017. Aflatoxins: implications on Health.
Indian J. Clin. Biochem. 32, 124–133.
Schoevers, E.J., Fink-Gremmels, J., Colenbrander, B., Roelen, B.A.J., 2010. Porcine oo-
cytes are most vulnerable to the mycotoxin deoxynivalenol during formation of the
meiotic spindle. Theriogenology 74, 968–978.
Schoevers, E.J., Santos, R.R., Colenbrander, B., Fink-Gremmels, J., Roelen, B.A., 2012.
Transgenerational toxicity of Zearalenone in pigs. Reprod. Toxicol. 34, 110–119.
Scott, P.M., Kanhere, S.R., Lau, B.P., Lewis, D.A., Hayward, S., Ryan, J.J., Kuiper-
Goodman, T., 1998. Survey of Canadian human blood plasma for ochratoxin A. Food
Addit. Contam. 15, 555–562.
Scudamore, K.A., Patel, S., 2000. Survey for aflatoxins, ochratoxin A, zearalenone and
fumonisins in maize imported into the United Kingdom. Food Addit. Contam. 17,
407–416.
Shar, Z.H., Sumbal, G.A., Sherazi, S.T., Bhanger, M.I., Nizamani, S.M., 2014. Natural co-
occurrence of aflatoxins and deoxynivalenol in poultry feed in Pakistan. Food Addit.
Contam. Part B Surveill. 7, 162–167.
Sherazi, S.T., Shar, Z.H., Sumbal, G.A., Tan, E.T., Bhanger, M.I., Kara, H., Nizamani, S.M.,
2015. Occurrence of ochratoxin A in poultry feeds and feed ingredients from
Pakistan. Mycotoxin Res. 31, 1–7.
Sugiyama, K., Hiraoka, H., Sugita-Konishi, Y., 2008. Aflatoxin M1 contamination in raw
bulk milk and the presence of aflatoxin B1 in corn supplied to dairy cattle in Japan.
Shokuhin Eiseigaku Zasshi 49, 352–355.
Sun, L.H., Lei, M.Y., Zhang, N.Y., Zhao, L., Krumm, C.S., Qi, D.S., 2014. Hepatotoxic
effects of mycotoxin combinations in mice. Food Chem. Toxicol. 74, 289–293.
Suriyasathaporn, W., Nakprasert, W., 2012. Seasonal patterns of aflatoxin M1
10
Journal of Hazardous Materials 389 (2020) 122087
contamination in commercial pasteurised milk from different areas in Thailand. Food
Addit. Contam. Part B Surveill. 5, 145–149.
Takagi, M., Mukai, S., Kuriyagawa, T., Takagaki, K., Uno, S., Kokushi, E., Otoi, T.,
Budiyanto, A., Shirasuna, K., Miyamoto, A., Kawamura, O., Okamoto, K., Deguchi, E.,
2008. Detection of zearalenone and its metabolites in naturally contaminated folli-
cular fluids by using LC/MS/MS and in vitro effects of zearalenone on oocyte ma-
turation in cattle. Reprod. Toxicol. 26, 164–169.
Tao, Y., Xie, S., Xu, F., Liu, A., Wang, Y., Chen, D., Pan, Y., Huang, L., Peng, D., Wang, X.,
Yuan, Z., 2018. Ochratoxin A: toxicity, oxidative stress and metabolism. Food Chem.
Toxicol. 112, 320–331.
Taranu, I., Marin, D.E., Bouhet, S., Pascale, F., Bailly, J.D., Miller, J.D., Pinton, P.,
Oswald, I.P., 2005. Mycotoxin fumonisin B1 alters the cytokine profile and decreases
the vaccinal antibody titer in pigs. Toxicol. Sci. 84, 301–307.
Thieu, N.Q., Ogle, B., Pettersson, H., 2008. Screening of Aflatoxins and Zearalenone in
feedstuffs and complete feeds for pigs in Southern Vietnam. Trop. Anim. Health Prod.
40, 77–83.
Tiemann, U., Tomek, W., Schneider, F., Vanselow, J., 2003. Effects of the mycotoxins
alpha- and beta-zearalenol on regulation of progesterone synthesis in cultured
granulosa cells from porcine ovaries. Reprod. Toxicol. 17, 673–681.
Tiemann, U., Brussow, K.P., Jonas, L., Pohland, R., Schneider, F., Danicke, S., 2006a.
Effects of diets with cereal grains contaminated by graded levels of two Fusarium
toxins on selected immunological and histological measurements in the spleen of
gilts. J. Anim. Sci. 84, 236–245.
Tiemann, U., Brussow, K.P., Kuchenmeister, U., Jonas, L., Kohlschein, P., Pohland, R.,
Danicke, S., 2006b. Influence of diets with cereal grains contaminated by graded
levels of two Fusarium toxins on selected enzymatic and histological parameters of
liver in gilts. Food Chem. Toxicol. 44, 1228–1235.
Tiemann, U., Brussow, K.P., Dannenberger, D., Jonas, L., Pohland, R., Jager, K., Danicke,
S., Hagemann, E., 2008. The effect of feeding a diet naturally contaminated with
deoxynivalenol (DON) and zearalenone (ZON) on the spleen and liver of sow and
fetus from day 35 to 70 of gestation. Toxicol. Lett. 179, 113–117.
Trucksess, M.W., Stoloff, L., Young, K., Wyatt, R.D., Miller, B.L., 1983. Aflatoxicol and
Aflatoxin-B1 and Aflatoxin-M1 in eggs and tissues of laying hens consuming afla-
toxin-contaminated feed. Poultry Sci. 62, 2176–2182.
Vulic, A., Pleadin, J., Persi, N., Mitak, M., 2012. Analysis of naturally occurring zear-
alenone in feeding stuffs and urine of farm animals in Croatia. J. Immunoassay
Immunochem. 33, 369–376.
Wang, H., Chen, Y., Zhai, N., Chen, X., Gan, F., Li, H., Huang, K., 2017. Ochratoxin A-
induced apoptosis of IPEC-J2 cells through ROS-mediated mitochondrial perme-
ability transition pore opening pathway. J. Agric. Food Chem. 65, 10630–10637.
Wang, H., Zhai, N., Chen, Y., Fu, C., Huang, K., 2018. OTA induces intestinal epithelial
barrier dysfunction and tight junction disruption in IPEC-J2 cells through ROS/Ca
(2+)-mediated MLCK activation. Environ. Pollut. 242, 106–112.
Wolzak, A., Pearson, A.M., Coleman, T.H., Pestka, J.J., Gray, J.I., 1985. Aflatoxin de-
position and clearance in the eggs of laying hens. Food Chem. Toxicol. 23,
1057–1061.
Xu, H., Hao, S., Gan, F., Wang, H., Xu, J., Liu, D., Huang, K., 2017. In vitro immune
toxicity of ochratoxin A in porcine alveolar macrophages: a role for the ROS-relative
TLR4/MyD88 signaling pathway. Chem. Biol. Interact. 272, 107–116.
Yu, Z., Wu, F., Tian, J., Guo, X., An, R., 2018. Protective effects of compound ammonium
glycyrrhizin, Larginine, silymarin and glucurolactone against liver damage induced
by ochratoxin A in primary chicken hepatocytes. Mol. Med. Rep. 18, 2551–2560.
Yunus, A.W., Ghareeb, K., Twaruzek, M., Grajewski, J., Bohm, J., 2012a. Deoxynivalenol
as a contaminant of broiler feed: effects on bird performance and response to
common vaccines. Poultry Sci. 91, 844–851.
Yunus, A.W., Blajet-Kosicka, A., Kosicki, R., Khan, M.Z., Rehman, H., Bohm, J., 2012b.
Deoxynivalenol as a contaminant of broiler feed: intestinal development, absorptive
functionality, and metabolism of the mycotoxin. Poultry Sci. 91, 852–861.
Zhai, N., Wang, H., Chen, Y., Li, H., Viktor, K., Huang, K., Chen, X., 2018. Taurine at-
tenuates OTA-promoted PCV2 replication through blocking ROS-dependent autop-
hagy via inhibiting AMPK/mTOR signaling pathway. Chem. Biol. Interact. 296,
220–228.
Zhang, Z., Gan, F., Xue, H., Liu, Y., Huang, D., Khan, A.Z., Chen, X., Huang, K., 2016.
Nephropathy and hepatopathy in weaned piglets provoked by natural ochratoxin A
and involved mechanisms. Exp. Toxicol. Pathol. 68, 205–213.
Zhu, L., Yuan, H., Guo, C., Lu, Y., Deng, S., Yang, Y., Wei, Q., Wen, L., He, Z., 2012.
Zearalenone induces apoptosis and necrosis in porcine granulosa cells via a caspase-
3- and caspase-9-dependent mitochondrial signaling pathway. J. Cell. Physiol. 227,
1814–1820.