Fumonisins - The underrated mycotoxins in poultry, livestock and humans

FUMONISINS THE UNDERRATED MYCOTOXINS in poultry, livestock and humans

Deepthi B V and M Y Sreenivasa Department of Studies in Microbiology, University of Mysore, India.

Email: sreenivasamy@gmail.com; mys@microbiology.uni-mysore.ac.in

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Fumonisins are mycotoxins majorly produced by

Fusarium verticillioides and Fusarium proliferatum species and are predominantly associated with maize and maize-based poultry and animal feeds (Dass et al., 2008; Sreenivasa et al., 2011; Deepa et al., 2016).

Cereal grains and their by-products,

CONTAMINATION WITH FUMONISIN-PRODUCING FUSARIUM SPECIES

being major ingredients of feeds,

64.28%

represent an excellent substrate for

poultry feed

the growth and reproduction of fungi and have serious consequences on the safety of foods and feeds.

In a mycological study carried

45.37% feed mixtures from Karnataka

25% animal feed

out by our laboratory, 45.37% of feed mixtures collected all over Karnataka (India) showed contamination with fumonisin-producing Fusarium species (Figure 1).

Furthermore, the study revealed a frequency of 25% and 64.28% of Fusarium contamination in animal and poultry feeds, respectively.

Figure 1. Fusarium and other mycotoxigenic fungal species isolated from animal and poultry feed mixtures.

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Per cent frecuency

On the other hand, other fungal genera such as Aspergillus flavus,

A. columnaris, A. candidus, A. niger, A. parasiticus, Penicillium,

Poultry feeds

Cladosporium, Rhizopus, Helminthosporium, Mucor, sterile hyphae, etc. showed a frequency of 50% and 82.1%

Animal feeds

in animal and poultry feeds, respectively (Figure 2).

0%

10%

20%

30%

Other Fungi

Fumonisins are capable of inducing

40%

50%

60%

70%

80%

90%

Fusarium species

both acute and chronic toxic effects in poultry and livestock.

Figure 2. Per cent frequency of animal and poultry feeds showing contamination of Fusarium and other fungi.

These effects are dependent on: The type of mycotoxin The level and duration of exposure The animal species that is exposed and the age of the animal (D’mello et al., 1999) Acute toxicity generally leads to rapid onset and an obvious toxic response, while chronic toxicity is characterized by a low-dose toxin exposure for a long time period, leading to cancer and other

Tricarballylic esters

generally irreversible effects.

Chemically, fumonisins are toxic, cancer-promoting secondary metabolites that have: A linear, 20-carbon long backbone An amine group at carbon atom 2 (C-2) Methyl groups at C-12 and C-16 Tricarballylic esters at C-14 and C-15

O

O

FUMONISIN

OH O

HO

CH₃

H₃C CH₃

HO O HO

O

CH₃

O

Methyl groups

Amine group

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Absorption: FB1 is poorly absorbed

Fumonisins are divided into four groups based on structural differences: A, B,

in the gastrointestinal tract and is

C and P (Musser and Plattner, 1997).

extensively retained unmetabolized in tissues such as the liver and kidneys.

The most abundantly found and the most toxic fumonisin is fumonisin B1 (FB1):

Excretion: FB1 is eliminated in bile through some enterohepatic recirculation

Toxicity: FB1 is a Group 2B carcinogen

while exerting its toxicity. The toxin

(possibly carcinogenic to humans)

may also end up in the faeces and

(IARC, 2002). It has been associated

as trace contaminants in urine.

with hepatotoxic, neurotoxic, nephrotoxic and immune-suppressing effects in animals and in humans.

Fumonisin B1 mode of action The molecular aspects of FB1-induced toxicity are poorly understood and the

This leads to the intracellular accumulation of sphingoid bases, increased phosphate

downstream toxic cellular mechanisms of

adducts, and a reduced ceramide

FB1 have been deduced to be complex,

concentration resulting in growth

involving many molecular sites.

inhibitory effects, cytotoxicity, apoptosis, cell proliferation, carcinogenicity, DNA

1. Studies have ascribed FB1-induced toxicity to the structural similarity between fumonisins and the sphingoid bases (sphinganine and sphingosine) of sphingolipid layer in cell membrane.

FB1 has a primary amino group at C-2 that competitively inhibits ceramide

damage (Riley et al., 2001; Voss et al., 2007) , disruption of normal cell cycling (Ramljak et al., 2000) , alteration of signalling by cAMP and protein kinase C (Huang et al., 1995) , and oxidative stress (Poersch et al., 2014; Abdellatef and Khalil, 2016; Deepthi et al., 2017).

synthase, resulting in the disruption of de novo biosynthesis of ceramide and thus deregulating the sphingolipid complex formation (Merrill et al.,

2001; Riley et al. 2001; Enongene et al. 2002; Riley and Voss, 2006).

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Sphingolipids

2. It has been also reported that FB1 inhibits other intracellular enzymes such as protein phosphatases and arginosuccinate synthetase (Jenkins et al., 2000).

2. Inhibition of intracellular enzymes

1. Ceramide synthase inhibition FB1

3. In addition, Domijan and Abramov

(2011) demonstrated that FB1 inhibits Complex I of the mitochondrial electron transport chain in the cell cultures of rat primary astrocytes and human neuroblastoma (SH-SY5Y).

Ceramide synthase FB1-associated toxic cellular mechanisms

This leads to a reduction in the rate of mitochondrial and cellular respiration, depolarization of mitochondrial membrane, over-production of reactive oxygen species (ROS) in mitochondria and deregulation of calcium signalling.

Accumulation of sphingoid bases

3. Inhibition of Complex I of the mitochondrial electron transport chain

Increased phosphate adducts Reduced ceramide concentration Reduced mitochondrial and cellular respiration Depolarization of the mitochondrial membrane Excess of ROS Deregulation of calcium signalling

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Toxic effects of Fumonisin B1 Fumonisin B1 intoxication is evident in different domestic and laboratory animals and differences in sensitivity and clinical symptoms have been described (Figure 3).

Contaminated feed

Affects alimentary value & organoleptic features Decreased nutritive value of feed Decreased animal performance and productivity

FB1

Immune suppression Neurotoxicity Hepatotoxicity Nephrotoxicity Carcinogenicity

Figure 3. Toxic effects of FB1 in poultry and livestock.

The first syndrome attributed to fumonisin B1 was ELEM, equine leukoencephalomalacia in the 1980s, characterized by fatal necrotic lesions in the cerebrum of horses (Marasas et al., 1988).

Fumonisin B1 induced cardiovascular dysfunction in horses with decreased heart rates, lower cardiac output, and right ventricular contractibility, which may be involved in the pathogenesis of the lesions in the central nervous system (Smith et al., 2002).

FB1 toxicosis in pigs was characterized by pulmonary, cardiovascular and hepatic symptoms. Affected animals become anorexic, showing signs of encephalopathy, loss of body weight and hepatic nodular hyperplasia.

The symptoms in swine have been referred to as Porcine Pulmonary Edema (PPE) and as “mystery swine disease� (Hollinger and Ekperigin, 1999).

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For a long time, poultry has been considered to be less susceptible to fumonisins, probably because of the lack of strong clinical symptoms of impairment even with high contamination levels.

The clinical features of the disease include diarrhea, weight loss, increased liver weight and poor performance.

Recent studies have focused on the subclinical effects of fumonisins and reveal that the intestinal tract of the birds is very sensitive to the exposure to fumonisins.

Dombrink-Kurtzman et al., (1992, 1993) demonstrated that FB1 and FB2 produced cytotoxic effects on lymphocytes of turkey, and morphologically changed the peritoneal macrophages, and diminished their viability and phagocytic potential.

Chronic fumonisin-exposure in poultry has shown to have adverse effects on the immune system leading to increased pathogen susceptibility and lowered vaccinal response (Voss et al., 2007).

Additionally, ingestion of fumonisins affects the expression of proteins related to pro- and anti-inflammatory responses in the intestinal tract of broilers

(Grenier and Applegate., 2013).

Rats and mice have been used extensively for decades as a model organism to study human mycotoxicosis, especially with regard to the carcinogenic potential of mycotoxins.

Pozzi et al., (2000) have reported apoptosis in the liver cells, by studying the effects of prolonged oral administration of fumonisin B1 and aflatoxin B1 in rats.

Theumer et al., (2002) have detected immunobiological alterations produced by the ingestion of FB1 in a model of experimental subchronic mycotoxicosis in rats.

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Cattle, sheep, and goats are known to be less sensitive to fumonisins.

However, a negative impact on the production of milk/wool, reproduction and growth can be noticed when animals are exposed to FB1 for longer periods of time.

An in vitro study by Bernabucci et al. (2011) showed an increased production of malondialdehyde (MDA) in bovine peripheral blood mononuclear cells treated with 35 and 70 Âľg/mL of FB1.

A study by Goel et al., (1994) showed an increase in Sa:So ratios in serum, liver, kidney and muscle of catfish fed with ≼10 mg FB1/kg feed after 12 weeks of treatment.

An increase in serum enzymes, urea and creatinine were reported by Orsi et al. (2009) and Gbore et al. (2010) in rabbits administered oral doses of FB1.

Epidemiological incidences of esophageal cancer in humans due to the consumption of fumonisin-contaminated food have been reported from various parts of the globe such as South Africa, Central America, Asia (Rheeder

et al., 1992; Chelule et al., 2001; Marasas et al., 2004) and among the dark population in Charleston, South Carolina (Sydenham et al., 1991) .

Similar observations were also documented from China (Yoshizawa et al., 1994; Abnet et

al., 2001), Italy (Franceschi et al., 1990), and Brazil (Van der Westhuizen et al., 2003).

An outbreak of FB1 -associated illness due to consumption of sorghum and maize contaminated with high levels of fumonisins was also reported from India characterized by acute onset of abdominal pain and diarrhea (Bhat and Krishnamachari, 1977).

Consumption of FB1 contaminated maize has also been associated with neural tube defects (due to reduction in the uptake of folic acid via folate receptor) in human infants of the rural population in South Africa and Northern China (Marasas et al., 2004) .

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Environmental stress factors related to mycotoxin occurrence The critical difficulty in assessing the risk of different mycotoxins to animal and human health is the multiple factors affecting fungal colonization and production of mycotoxins in foods or feeds.

Environmental conditions (physical factors) are often conducive to rapid spoilage of feeds by fungi and production of harmful mycotoxins resulting in a significant decrease in the quality of feeds.

Abiotic factors or stress conditions determine

Optimum conditions for fungal growth are not necessarily optimum for toxin production.

the extent of fungal colonization and mycotoxin biosynthesis in crops, foods and feeds. They include: Relative humidity Temperature fluctuations (heat,

Under natural conditions, the combination

cold, chilling, freezing)

of two or more factors such as drought and salinity, relative humidity and temperature,

Salinity Drought Nutrients Light intensity

heat and salinity, extreme temperature and high light intensity, etc., may have an impact on fungal infestation.

These environmental factors influence the fungal growth, metabolism and mycotoxin biosynthesis and are essential to understand

Ozone pH

the overall process and to prevent mycotoxin production and spoilage of food or feed.

Anaerobic stresses

(Wang et al., 2003; Mitchell et al., 2004; Agarwal and Grover, 2006; Hirel et al., 2007; Cavanagh et al., 2008; Munns and Tester, 2008; Chinnusamy and Zhu, 2009; Marin et al., 2010b; Mittler and Blumwald, 2010; Faneli et al., 2012)

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Management of fumonisin contamination The negative effects of consuming

However, a wide gap still persists

Safe elimination of fumonisins from

food or feed contaminated with

globally when it comes to

feed is of paramount importance as

mycotoxins have gained much

implementing these practices.

the poultry/livestock sector suffers

attention in the public and scientific arena in the recent years.

This has generated a hitherto unprecedented interest towards the development of new detoxification procedures.

from health-related issues and great Furthermore, mycotoxin

economic losses due to fumonisins.

contamination can be partially prevented by adapting proper processing methodologies and storage facilities of cereals, grains, food and feedstuffs.

Good Agricultural Practices (GAP) and Good Manufacturing Practices (GMP) are possible methods to minimize mycotoxin occurrence in field conditions.

However, detoxification of toxins cannot be fully achieved as their production is modulated by environmental factors.

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Most physical and chemical strategies followed to reduce mycotoxin contamination have been shown to be rather ineffective or are difficult to implement into the production process (Pearson et al., 2004).

Moreover, fungal resistance to chemical treatments has now become widespread (Davidson, 2001).

Therefore, a biological control method

The most commonly employed detoxification

would be an efficient

method in the poultry/livestock industry is the use of

alternative for the

mycotoxin binders (sequestering agents) in feed, but

management of

they are usually aflatoxin-binders and have much

fumonisins (Figure 4).

less affinity towards fumonisins or other mycotoxins.

Good Agricultural Practices (GAP) Growing disease resistant crops Insects and fungal treatments

AT HARVEST

Growing cultivars with geographic region and climatic conditions

Proper sanitation Maturity of the crop (yield)

PRE-HARVEST

Weather Climate conditions Moisture content

POST-HARVEST PROCESSING AND TRANSFORMATION Physical approaches – solvent extraction, thermal inactivation, photochemical, irradiation, toxin adsorbents/binders

STORAGE

Chemical approaches – acidic agents, alkalies, aldehydes, oxidizing agents, reducing agents

Drying

Biological approaches – plants extracts, antioxidants, essential oils, enzymatic degradation by microbial taxa, probiotic lactic acid bacteria

Proper sanitation Sorting

Figure 4. Mycotoxin management strategies in the poultry and livestock industries.

Shelling Grading

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Many species of bacteria and

Among the biocontrol agents,

The possible mechanisms

fungi such as Flavobacterium

probiotic lactic acid bacteria (LAB)

involved in the antifungal

aurantiacum, Corynebacterium rubrum, Candida lipolitica, Aspergillus niger, Trichoderma viride, Armillariella tabescens, Nuerospora species, Rhizopus species, Mucor species, etc., have been shown to enzymatically degrade mycotoxins (Bata and Lasztity, 1999; Ciegler et al., 1966).

represent a potent and interesting

efficiency of LAB include:

application as they are widely used in fermented food products and feed to extend the shelf life of food/feed.

Moreover, lactic acid bacteria are GRAS “Generally Regarded as Safe� (USFDA, 2017) organisms having wide metabolic versatility and ability to produce a broad range of metabolic end products.

Production of organic acids

Competition for nutrients

Enzymes capable of degrading fumonisins have been isolated from a filamentous

Production of antagonistic compounds

saprophytic fungus growing on maize and the corresponding genes have been cloned and transferred in transgenic maize

ANTIFUNGAL PROPERTIES OF LAB

(Blackwell et al., 1999).

1. Isolation of fumonisin-degrading enzymes

Saprophytic filamentous fungus 2. Cloned DNA 3. Transfer to transgenic maize

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The inhibition of mycotoxin production by LAB is due to microbial competition, depletion of nutrients, low pH, and the production of heat-stable low-molecularweight secondary metabolites (Batish et al., 1997; Gourama and Bullerman, 1997; Laitila et al., 2002).

The mechanism by which LAB detoxifies mycotoxin remains to be elucidated. However, several reports suggest the binding nature of LAB to the mycotoxin moieties.

Lactobacilli also produce antifungal metabolites

The majority of studies on mycotoxins are aflatoxin-oriented, with less attention being paid to Fumonisin B1 contamination in food/ feed and their toxicity in humans/ animals.

Having a clear understanding of fumonisin interference

such as organic acids, hydrogen peroxide,

with the living system followed by the development

proteinaceous compounds, hydroxyl fatty acids and

of chronic disorders is of immense value.

phenolic compounds, offering valuable opportunities in food preservation as well as feed supplements or in

Furthermore, exploration of probiotic LAB as potent

veterinary medicine (Magnusson et al., 2003;

antifungal agents and as a tool to biodegrade fumonisins

Kecerova et al., 2004; Gerez et al., 2009; Bilkova et al., 2011; Cortes-Zavaleta et al., 2014; Deepthi et al., 2016).

will guard food/feeds from fungal infestation.

Bacteriocin-like substances and other low and medium molecular weight compounds produced

by Lactobacillus have also shown antifungal properties (Rouse et al., 2008; Kos et al., 2011; Al Kassaa et al., 2014).

These probiotic species also act as biopreservatives of food/feed and also have additive effects on health, performance and production.

Subsequently this leads to increased food/feed production, as well as improved food/feed quality and trade/economy conditions for the countries.

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