chapter 5. Effects in food-producing animals CHAPTER 5 CHAPTER Summary ergot alkaloids. In all cases the effect possible involvement of a mycotoxin of mycotoxins on animal performance in an animal production problem. Unexplained disease outbreaks in is potentially a major problem for In conjunction with the information farm and domestic animals have farmers regardless of their scale provided in the other chapters, this suggested the likely presence of of operation. Reduced growth, information will assist farmers in mycotoxins in feeds for many years. decreased egg and milk production, making decisions that will minimize The manifestations of mycotoxicoses lower reproductive efficiency, and losses due to diseases induced by in the field are frequently nondescript increased susceptibility to stress are all mycotoxins. and potentially have many contrib- potentially devastating consequences uting factors, which are often of mycotoxin exposure. Thus, being 1. Introduction difficult to define. Nevertheless, aware of the outward signs that might toxigenic moulds were implicated signal the involvement of a mycotoxin In this chapter, we discuss the in, and sometimes proven to be the in an animal performance problem is effects in farm and domestic animals cause of, animal disease in field the first step to minimizing potential of the most economically important outbreaks long before the toxins adverse impacts. The target organ feedborne mycotoxins. The chapter were discovered. The development affected can provide important clues begins with a summary of field of methods for the chemical analysis to involvement of a specific mycotoxin, outbreaks, followed by sections of mycotoxins in feeds and animal in which case understanding the that describe the toxicokinetics tissues has contributed to an toxicokinetics and toxicology will assist and metabolism of each mycotoxin improved understanding of the dose– in minimizing the cost and maximizing or group of mycotoxins. Of the response relationships of farm animal the effectiveness of interventions. trichothecenes, only deoxynivalenol diseases associated with exposure The primary objective of this chapter is covered in depth; however, it should to aflatoxins, fumonisins, ochratoxin is to provide information that will be recognized that the predominant A, deoxynivalenol, zearalenone, and aid in the field identification of the trichothecene encountered in con-

Chapter 5. Effects in food-producing animals 59 taminated feeds may differ in different to cause animal disease. A major the case for aflatoxins, fumonisins, geographical locations (Starkey et al., problem for the veterinarian in the field deoxynivalenol, zearalenone, and 2007; Miller, 2008; Sugita-Konishi and is that disease expression is seldom ergot alkaloids, where mould- Nakajima, 2010). pathognomonic, i.e. with a sign or contaminated feed was associated Additional information relevant symptom that is so characteristic of a with disease outbreaks before the to the toxicology in animals can be disease as to be diagnostic. Instead, toxins were identified. For example, found in Chapter 6, which focuses multiple interacting factors often in the 1960s the outbreak of a on effects and toxicology in humans. occur that can modify the expression disease known as turkey “X” disease Potential interventions to prevent field of toxicity. Thus, the manifestations led to the discovery of aflatoxins. outbreaks or minimize their adverse of mycotoxicoses in the field are However, before this disease was effects are described in Chapter 9. frequently nondescript and have reported, outbreaks of liver cancer Numerous extensive review articles many potential contributing factors, in farm-raised rainbow trout fed diets and monographs provide additional which are often difficult to define. containing cottonseed (Butler, 1974) information on effects in farm An attempt to apply Koch’s and of liver toxicity in pigs and cattle fed animals (WHO, 2001, 2011; CAST, postulates to demonstrate causality maize contaminated with Aspergillus 2003; Cousin et al., 2005; Roberts requires a bioassay that reproduces flavus were documented in 1935 and et al., 2005; Fink-Gremmels and the disease when a pure compound 1953, respectively (Raisbeck et al., Malekinejad, 2007; Morgavi and is used. Unfortunately, reproducing 1991). Equine leukoencephalomalacia Riley, 2007a, 2007b; Voss et al., the exact conditions that existed (ELEM) was first linked to mouldy 2007; Fribourg et al., 2009; Pestka, in the field is confounded by the maize in 1891 (Haliburton and Buck, 2010a, 2010b; Eaton et al., 2010). potential presence of multiple 1986). ELEM is now known to be To aid in the field identification of the contributing factors. These include, caused by fumonisins. Effects from main observations characterizing but are not limited to, environmental the consumption of maize on which exposure to a particular mycotoxin, stress, multiple toxigenic fungi Fusarium verticillioides had been Table 5.1 summarizes the expected and mycotoxins, nutrient/vitamin cultured were the first indication that toxic effects, species sensitivity, and deficiencies, infectious agents, and mouldy maize might cause porcine potentially useful biomarkers in farm pre-existing conditions. These co- pulmonary oedema (PPE) syndrome animals for each of the major groups occurring factors can influence (Kriek et al., 1981). This was of mycotoxins. the clinical signs, severity, and confirmed only after the discovery progression of the disease (CAST, of fumonisins in 1988 and after the 2. Field outbreaks 2003) in ways that can confound cause of outbreaks of PPE in the both diagnosis and replication of USA in 1989–1990 was confirmed The interest of the scientific and the observed adverse effects. Also, by inducing PPE with pure fumonisin regulatory communities in mycotoxins mycotoxins in feeds are not evenly B1 (Marasas, 2001). began in earnest when aflatoxins were distributed (see Chapter 3); therefore, Feed refusal syndrome in the USA, found to be potent carcinogens that reproducing disease at the dosages most likely caused by deoxynivalenol occurred in several important food found in feed samples analysed from and other trichothecenes, led to an and feed commodities. However, even field outbreaks can be difficult. It has embargo of United States barley by in the absence of any known causal been suggested that 100–200 kg Germany in the 1930s (Hamilton, agent, unexplained disease outbreaks or more of suspect feed should be 1982). The association between in farm and domestic animals, which saved for confirmatory studies in consumption of mouldy feed and often involved mortality or evidence of experimental animals (Osweiler, estrogenism in pigs has been known acute toxicity, served as an indicator 2000). In addition, experimental since 1928 (McNutt et al., 1928), and of the likely presence of mycotoxins in confirmation can require a large estrogenism has been attributed to foodstuffs (Forgacs and Carll, 1962). number of animals if the incidence consumption of feeds contaminated Definitively linking a disease of the disease in the suspected field with zearalenone. The biological outbreak in the field to a specific outbreak is low. activity of ergot (the sclerotia of mycotoxin is very difficult (Hamilton, Despite these difficulties, toxi- Claviceps spp.) was known in China 1982), even though a great deal genic moulds were implicated as more than 5000 years ago even of experimental evidence exists the cause of animal disease in though its involvement in animal to characterize the potential of field outbreaks long before the disease was probably not reported mycotoxins and mouldy foodstuffs toxins were discovered. This was until the Middle Ages (Christensen,

60 Table 5.1. Expected toxic effects, species sensitivity, and potentially useful biomarkers in farm animals for each of the major groups of mycotoxins

Relative sensitivity of Mycotoxin Target organs and major effects Biomarkers species

Aflatoxins Reduced performance, jaundice, pale liver, hepatotoxicity with Ducklings > turkeys Aflatoxin–albumin adducts fatty changes, coagulopathy, and increased susceptibility to > chicks > quail. in serum and DNA adducts internal bruising during handling. Rabbits > swine > cattle > in urine.

Liver tumours in trout. sheep. Aflatoxin M1 in milk and Dogs and mink can also be urine. affected. Young animals > mature animals.

Fumonisins Liver in all species and kidney in many. Brain in horses (ELEM) Horses and rabbits > pigs Fumonisin B1 in urine and and lung in pigs (PPE). and catfish > ruminants and faeces. poultry. Elevated sphinganine and Breeding animals sphinganine-1-phosphate > animals being raised for in tissues, urine, and serum slaughter. and elevated sphinganine- 1-phosphate in red blood cells.

Ochratoxin A Pale and grossly enlarged kidney. Fatty liver in poultry. Pigs and dogs > poultry Ochratoxin A or its Altered performance, including decreased feed consumption, > calves. metabolites in tissues, reduced weight gain, and decreased egg production. Increased Chicks > turkeys > quail. blood, and urine. susceptibility to bruising, decreased tensile strength of the large Mature cattle are intestines, reduced pigmentation, decreased immune response, considered resistant. increased susceptibility to infection, and glycogen accumulation in the liver.

Deoxynivalenol Feed refusal in swine and reduced weight gain and vomiting. Pigs > dogs and cats Deoxynivalenol and its Gastrointestinal problems, soft stools, diarrhoea, increased > cattle, sheep, and glucuronide conjugate in susceptibility to other diseases, and decreased performance. poultry. urine.

Zearalenone Estrogenic effects. Swollen red vulva, vaginal prolapse, rectal Pre-pubertal pigs Zearalenone or metabolites 5 CHAPTER prolapse, and fertility problems in swine. >> cattle and sheep (including glucuronic acid > poultry. conjugates) in urine or faeces.

Ergot alkaloids In cattle, dry gangrene aggravated by cold weather and heat Cattle > horses and sheep. Lysergic acid in urine. intolerance in warm weather. Poultry and swine can also In cattle and horses, neurotoxicity, including tremors, be affected. convulsions, and agalactia. In swine, reproductive problems and agalactia.

ELEM, equine leukoencephalomalacia; PPE, porcine pulmonary oedema.

1980). Ergot was implicated as suggested that multiple mycotoxins In the remainder of this section, the cause of animal production could have been involved, including we provide some examples of problems in domestic animals (mainly aflatoxins and ochratoxin A (Hamilton, the spectrum of documented or cattle) in the USA in the early 19th 1982). Ochratoxin A, unlike aflatoxins, strongly suspected field outbreaks century (Hesseltine, 1979), but the fumonisins, deoxynivalenol, zearale- for aflatoxins, fumonisins, ochratoxin alkaloids responsible for ergotism none, and ergot alkaloids, was A, deoxynivalenol, zearalenone, and were not identified until the 1930s. isolated and characterized (van der ergot alkaloids. The causative agent or agents for Merwe et al., 1965) before it was haemorrhagic syndrome in the USA proven to cause outbreaks of kidney in the 1950s caused by mouldy feed disease in poultry (Hamilton et al., (Forgacs and Carll, 1962) have never 1977) and pigs (Krogh, 1978a, 1978b). been identified. However, it has been

Chapter 5. Effects in food-producing animals 61 2.1 Aflatoxins cases of ELEM in Egypt, Wilson and Outbreaks of mycotoxic nephropathy Maronpot (1971) reproduced ELEM have also been reported in horses Turkey “X” disease was responsible in horses by feeding them maize on (Krogh, 1978b), and there are a for the deaths of > 100 000 turkeys in which this fungus had been grown. few suspected cases in ruminants the United Kingdom in 1960. Mortality Kriek et al. (1981) induced PPE, (Raisbeck et al., 1991). The first was also documented in ducks, a disease that has been known in well-documented and confirmed chickens, pheasant, calves, and Hungary since 1950 (Fazekas et case of ochratoxicosis occurred in pigs (Butler, 1974). In the USA and al., 1998), by feeding pigs maize young turkeys in the south-eastern elsewhere, field outbreaks causing on which F. verticillioides had been USA (Hamilton et al., 1977). In 1976, mortality have been well documented grown. After isolating and chemically about 80% of the marketed turkeys in turkeys, laying hens, pigs, cattle, characterizing the fumonisins, Mara- in North Carolina displayed signs rainbow trout, and dogs (Butler, 1974; sas et al. (1988) induced ELEM in a of ochratoxicosis, and all cases

Hamilton, 1982). In the case of poultry, horse by using purified fumonisin B1. involved maize contaminated with pigs, and farm-raised trout, large Serendipitously, in 1989–1990 there OTA (Schaeffer and Hamilton, 1986). numbers of animals were involved were numerous outbreaks of ELEM In a turkey house with 16 000 turkeys, (Butler, 1974; Hamilton, 1982). Acute and PPE syndrome in the USA. mortality was 59%. The first toxicity is easily recognized, but the In 1990, PPE was induced using indication of intoxication was feed more subtle effects are probably pure fumonisin B1 (Harrison et al., refusal (Schaeffer and Hamilton, of greater concern to farmers. 1990). Field outbreaks of PPE have 1986). Death was most commonly For example, decreased rates of not occurred in the USA since the seen in younger birds, whereas weight gain, decreased milk or egg early 1990s, but reports of ELEM older birds developed infections production, increased susceptibility to have persisted. In poultry, reduced with Escherichia coli (air-sacculitis) bruising during processing of poultry performance associated with feeds that did not respond to antibiotics. and pigs, underpigmentation of contaminated with fumonisins Interestingly, in outbreaks in chickens, meat in poultry, and altered immune has been reported, but the effects feed refusal did not occur, whereas function have all been associated seldom involve increased mortality poor pigmentation was common with exposure in the field (Hamilton, (WHO, 2000). (Schaeffer and Hamilton, 1986). 1982; Raisbeck et al., 1991). Pet food Other field cases in chickens have recalls due to aflatoxin contamination 2.3 Ochratoxin A reported decreased egg production resulting in liver toxicity and death in and eggshell quality, increased dogs are not uncommon in the USA. In pigs, mycotoxic nephropathy was susceptibility to intestinal rupture first described in 1928 in Denmark during processing, decreased 2.2 Fumonisins and was reproduced experimentally bone strength, and haemorrhagic using mouldy barley or oats (Krogh, episodes (Schaeffer and Hamilton, In the USA, field outbreaks of ELEM 1992). This disease has also been 1986). In all species, effects on the caused by mouldy maize have been reported in Norway, Sweden, Ireland, kidney were apparent. reported for more than 100 years Finland, Germany, Hungary, Poland, (Haliburton and Buck, 1986). It was the former Serbia and Montenegro, 2.4 Deoxynivalenol reported that about 5000 horses died and Bulgaria (Krogh, 1978a, 1978b; of “mouldy corn poisoning” in Illinois Marquardt and Frohlich, 1992; Stoev Trichothecenes have been implicated in 1934–1935 (Haliburton and Buck, et al., 1998). The main clinical signs in feed refusal by cattle, pigs, and 1986). The disease has also been are renal dysfunction and oedema. In chickens; however, pigs appear to be reported in South America, Hungary, pigs, excessive thirst (polydipsia) and the most sensitive to deoxynivalenol China, Greece, France, Mexico, passage of large volumes of urine (DON) (Rotter et al., 1996; Haschek New Caledonia, Egypt, South Africa, (polyuria) are characteristic signs of et al., 2002). Outbreaks in animals and Germany (Magnol et al., 1983; this disease under field conditions. of “red mould poisoning” from Haliburton and Buck, 1986; Laurent The association of ochratoxin A (OTA) cereals in Japan as far back as 1890 et al., 1998; Rosiles et al., 1998). After with field outbreaks of nephropathy (Miller, 2008) led to the discovery of identifying Fusarium verticillioides in poultry was first reported in DON. It was first isolated in Japan (then known as F. moniliforme) as 1975 (Krogh, 1992) and has been and was originally called Rd-toxin the predominant fungal contaminant reported in many countries since (Moorooka et al., 1972). It was given of mouldy maize that had caused then (Marquardt and Frohlich, 1992). the name vomitoxin (Vesonder et al.,

62 1973) after its isolation from maize Reproductive problems have been problems and neurological effects contaminated with F. graminearum reported in sheep grazing on grasses in horses (staggers, “drunkenness”, because it is associated with emesis contaminated with ZEA (CAST, 2003), and sleep) and reduced reproductive in pigs. Numerous confirmed cases and ZEA was found to interfere with performance, decreased milk produc- have been reported of feed refusal the induction of parturition by oxytocin tion, and reduced growth in cattle or reduced feed intake in pigs in gilts and sows (Alexopoulos, 2001). (Cross, 2003; White et al., 2003). consuming feeds contaminated with In maize contaminated with ZEA, co- In cattle and sheep, increased DON (Osweiler, 2000). The most contamination with DON is likely. body temperature due to peripheral frequently observed effect of DON vasoconstriction is often seen in in farm animals is feed refusal, which 2.6 Ergot alkaloids animals that have ingested grasses may explain why toxic effects are to infected by endophytes (Cross, 2003). a great extent self-limiting (Osweiler, Poisoning resulting from the con- Field cases of fescue foot (necrosis of 2000). There have been unconfirmed sumption of foods contaminated by the extremities) in cattle and laminitis reports of feed refusal in dogs, cats, ergots, which are fungal sclerotia that in horses have been reported to be due and rabbits consuming pet foods replace grass seeds, has been known to peripheral vasoconstriction caused naturally contaminated with DON since the Middle Ages, but it was by ergot alkaloids (Cross, 2003). (Bohm and Razzazi-Fazeli, 2005). not until the 20th century that ergot Environmental conditions appear In ruminants, field disease outbreaks alkaloids from Claviceps purpurea to influence the vasoconstrictive attributed to DON are rare (Raisbeck were determined to be the causative effects of ergot alkaloids in grasses; et al., 1991). agent (Barger, 1931). Ergot alkaloids episodes of fescue foot are most associated with or suspected to common in autumn and early winter, 2.5 Zearalenone be involved in diseases of farm and the condition known as summer animals include ergoline alkaloids, slump is most common in warm Estrogenism in pigs consuming which contain the lysergic acid ring weather (Raisbeck et al., 1991). mouldy feed was first reported in structure, and ergopeptine alkaloids, 1928 (McNutt et al., 1928); since which contain a tripeptide moiety. 3. Toxicokinetics and then, field outbreaks of reproductive In farm animals, ergot poisoning is metabolism problems, including vulvovaginitis usually associated with grazing on CHAPTER 5 CHAPTER and anestrus, and enlargement of seed heads of grasses contaminated Mycotoxins are chemically diverse, the mammae in males have been with ergots of Claviceps spp. or and therefore their uptake, distribution, attributed to consumption of feeds grasses colonized by groups of fungi metabolism, and excretion are equally contaminated with zearalenone that occur as endophytic symbionts diverse. Galtier (1998) summarized (ZEA) (Aucock et al., 1980; Raisbeck (Neotyphodium spp. and Epichloë the kinetics and biological fate of et al., 1991), which was previously spp.; Roberts et al., 2005) or with the most of the economically important called F-2 toxin (Mirocha et al., consumption of feeds contaminated mycotoxins. Uptake from the 1968). Field outbreaks of estrogenic with ergot (CAST, 2003). Outbreaks gastrointestinal tract depends to a syndrome in pigs have been reported of ergot poisoning have also been large extent on the water solubility in North America, Europe, Africa, reported in pigs and cattle consuming or lipophilicity of the particular Asia, and Australia (Christensen, sorghum-based feeds. Consumption mycotoxin. Metabolism by microbes 1979). ZEA-induced abortions in of feeds based on small grains, in the gut can also have a profound pigs have also been reported and such as rye and barley, or foraging effect on uptake and toxicity. are probably a result of embryo on infected grasses contaminated Some mycotoxins, like OTA, are implantation failure (Osweiler et al., with ergots has caused lameness well absorbed, whereas others,

1986). Suggestions that reproductive or necrosis of ears, tails, and feet like fumonisin B1, are very poorly problems in ruminants can be attri- in cattle (CAST, 2003). Endophytes absorbed. Binding of mycotoxins buted to ZEA are considered to be (Neotyphodium spp. and Epichloë to plasma proteins can influence controversial (Raisbeck et al., 1991). spp.) that occur in pasture grasses uptake, distribution, and the half-life The semisynthetic ZEA analogue such as tall fescue and ryegrass are in the blood. Again, some mycotoxins, zeranol is used in cattle as a growth known to produce ergot alkaloids, including OTA, are tightly bound, promoter, and its estrogenic effects which have caused a diverse array whereas others, including fumonisin have caused reduced performance of toxic syndromes in grazing B1, are not bound. Metabolism and in bulls (Raisbeck et al., 1991). animals, including reproductive excretion are important considerations

Chapter 5. Effects in food-producing animals 63 for determining whether residues 3.1.3 Bioavailability 1993a). Low levels of aflatoxin B1 and will remain in tissues and also for aflatoxin M1 (< 1 µg/kg) were detected developing biomarkers for exposure. Aflatoxin B1 is rapidly absorbed from in the liver and kidneys of lactating

For example, aflatoxin B1 is extensively the small intestines, and the rate of cows fed diets containing 1250 µg/ metabolized in the liver and elsewhere, absorption is much higher in suckling kg aflatoxin B1 for 2 weeks (Busby and significant amounts can be and young animals than in adults and Wogan, 1981a). Pigs fed diets excreted as metabolites in milk. For (Kumagai, 1985). The process of containing 100–400 µg/kg aflatoxin

DON, most of the absorbed toxin is absorption from the small intestines is B1 for 4 weeks had detectable levels excreted in urine, whereas only very passive and complete. For example, of aflatoxins B1 and M1 in the liver, small amounts of fumonisin B1 are the time needed to reduce aflatoxin B1 muscle, kidney, and blood. At 400 µg/ excreted in urine. Fumonisin B1 is in the intestinal lumen by 50% is about kg aflatoxin B1 in feed, the detected not metabolized in the liver or other 7 minutes (Ramos and Hernández, levels of aflatoxins B1 and M1 were tissues and therefore is recovered 1996). Aflatoxins B1 and B2 are more as high as 4 µg/kg and 1.5 µg/kg, intact or partially hydrolysed (probably rapidly absorbed than are aflatoxins respectively (Busby and Wogan, by microbes in the gastrointestinal G1 and G2, ensuring that their 1981a). In chickens, maximal levels tract) in faeces. Although mycotoxin bioavailability is high (Ramos and were attained in plasma and the liver residues can be carried over into Hernández, 1996). Aflatoxin B1 is also within 6 hours after oral dosing, and milk and eggs (Galtier, 1998), only absorbed slowly through the skin, and levels declined rapidly thereafter aflatoxin M1 and OTA have been intratracheal absorption is more rapid (Hirano et al., 1994). After either a detected naturally in cow’s milk. than via the oral route (IARC, 1993a). single oral dose or daily oral dosing

Once absorbed, aflatoxin B1 is non- for 2 weeks, aflatoxin residues were 3.1 Aflatoxins covalently bound to albumin and is detected in various organs and in transported to other tissues. muscle tissue in laying hens (Busby 3.1.1 Absorption and Wogan, 1981a). Aflatoxins can 3.1.4 Distribution cross the placenta and accumulate

Aflatoxin B1 absorption, distribution, in developing fetuses (IARC, 1993a). and elimination is rapid. Aflatoxin B1 Early distribution studies focused on Unmetabolized aflatoxin B1 can is well absorbed; it accumulates in the extraction of the parent compounds accumulate in tissues rich in melanin liver and is extensively metabolized in or non-polar aflatoxin metabolites and pigment and the upper respiratory the liver and other tissues. The binding ignored the water-soluble metabolites tract (Larsson and Tjälve, 1993). of metabolites to macromolecules, (Busby and Wogan, 1981a). In sheep including proteins and nucleic acids, and other animals, aflatoxin B1 is 3.1.5 Excretion also occurs soon after absorption. immediately transported to the liver Unbound water-soluble metabolites after absorption from the gut (Wilson After intraperitoneal or intravenous are excreted in urine and other fluids, et al., 1985). The half-life of aflatoxin dosing of aflatoxin B1, excretion and the parent compound is excreted B1 in plasma after intravenous is rapid and most of the dose is in faeces; however, some metabolites dosing is < 1 hour (Wong and Hsieh, eliminated in faeces and urine (Wong bound to nucleic acids can persist for 1980), whereas after intratracheal and Hsieh, 1980; Busby and Wogan, relatively long periods in tissues. or oral dosing it is about 90 hours 1981a). The relative retention of

(Coulombe and Sharma, 1985). aflatoxin B1 is greater than that of

3.1.2 Gastrointestinal As with absorption from the small aflatoxin B2 due to greater urinary metabolism intestines, aflatoxin B1 is rapidly taken excretion of aflatoxin B2 (Busby and up by the liver with a half-life of < 5 Wogan, 1981a). A large percentage Little published information is avail- minutes (Busby and Wogan, 1981a). of the intraperitoneal dose is able about the ability of micro- Aflatoxin B1 is widely distributed in recovered in bile (Busby and Wogan, organisms in the gastrointestinal the body, with most accumulating in 1981a). In sheep, aflatoxin residues, tract to metabolize or bind aflatoxins. the liver, kidney, and lung. Maximal mainly aflatoxin M1, are excreted It is known, however, that certain levels in tissues, and especially primarily in urine within 48 hours bacteria can bind aflatoxin B1 in vitro, the liver, are reached quickly, and after oral dosing (Busby and Wogan, and it has been suggested that they the relative retention of aflatoxin B1 1981a). Aflatoxin M1 is the main may aid intestinal excretion (Oatley is greater than that of aflatoxin B2 unconjugated metabolite of aflatoxin et al., 2000). (Busby and Wogan, 1981a; IARC, B1 excreted in the milk of sheep,

64 goats, and cows. In sheep and cattle, microsomal systems to aflatoxins P1, al., 2010). For example, domestic aflatoxin B1 is the main component in M1, and Q1 and, most importantly, turkeys, one of the most susceptible faeces. In laying hens, aflatoxin B1 the highly reactive aflatoxin B1-8,9- species to aflatoxicosis, are known to excretion is primarily in faeces and epoxide. In the liver, cytochrome be deficient in the GST that mediates is maximal 24 hours after a single P450 enzymes are responsible for detoxification of the aflatoxin B1-8,9- oral dose, a finding similar to that activation of aflatoxins B1, M1, and epoxide (Klein et al., 2000), and that seen in laboratory animals dosed P1, all of which can form nucleic deficiency results in high levels of intravenously (Wong and Hsieh, acid adducts or undergo conjugation hepatic aflatoxin B1 epoxidation (Yip 1980). In laying hens, the body to glutathione, conversion to and Coulombe, 2006; Rawal et al., half-life of aflatoxin B1 was 67 hours dihydrodiols, or binding to serum 2009). after a single oral dose (Busby and proteins or other macromolecules.

Wogan, 1981a). Aflatoxin M1 is the main unconjugated 3.2 Fumonisins metabolite in the urine of cows, 3.1.6 Transmission pigs, and sheep. In rodents, and 3.2.1 Absorption presumably in farm animals,

Approximately 1–15% (IARC, 2002a) aflatoxin B1–nucleic acid adducts are In most animals, fumonisin B1 of the aflatoxin B1 dose is recovered also found in urine, and 80% of the absorption, distribution, and elim- as aflatoxin M1 in the milk of sheep, depurinating adducts are excreted ination is rapid. Fumonisins are goats, and cows (IARC, 1993a). within 48 hours after dosing. A close poorly absorbed, and although some The conversion rate is > 1% when correlation has been established evidence exists that fumonisins can the aflatoxin B1 dose is low (IARC, between levels of adducts in urine be partially metabolized in the gut, 2002a). Extensive evidence has and levels in the liver (IARC, 1993a), metabolism by the liver or other been found for the lactational transfer and correlations have also been tissues has not been convincingly of aflatoxin M1 and its accumulation observed between dietary intake and demonstrated (WHO, 2000, 2001, in the livers and lungs of offspring levels of adducts in urine and serum 2012; IARC, 2002b; Shephard et al., (IARC, 1993a). Low levels of aflatoxin (IARC, 2002a). 2007; Voss et al., 2007). metabolites can be detected in The relative sensitivity of animals the liver and other tissues several to the toxic effects of aflatoxin B1 3.2.2 Gastrointestinal CHAPTER 5 CHAPTER weeks after animals are exposed is closely linked to differences metabolism to high levels of aflatoxin B1 (Busby in metabolism among species and Wogan, 1981a; Coulombe (IARC, 2002a). The susceptibility of Microbial metabolism most likely and Sharma, 1985). However, the animals to aflatoxin B1 toxicity and occurs in the gut of monogastric levels retained in edible tissues are carcinogenicity depends to a large animals, because partially hydrolysed generally low; feed-to-tissue ratios extent on the type of metabolites fumonisin B1 (lacking one tricarballylic range from 800:1 to 14 000:1 (IARC, produced and the rate of formation acid side chain) and, to a lesser

2002a). Aflatoxin B1 can be detected and detoxification of the aflatoxin B1- extent, fully hydrolysed fumonisin in eggs of laying hens fed diets 8,9-epoxide. Risk factors contributing B1 (lacking both side chains) were containing aflatoxin B1, with a feed- to an individual’s sensitivity to liver recovered in faeces but not in bile of to-tissue ratio ranging from 2200:1 tumours and hepatotoxicity include vervet monkeys (WHO, 2000). Most to 5000:1 (Oliveira et al., 2000; level of exposure to aflatoxin B1; (60–90%) of the total fumonisin B1 IARC, 2002a). With the exception of expression of enzymes in the found in ruminant faeces was present milk, transmission to edible animal aflatoxin activation and detoxification as the partially hydrolysed form. In products should pose little health risk pathways; nutritional status; co- non-ruminants, the parent compound to consumers. exposure to other mycotoxins, es- was the dominant species present pecially fumonisin; and exposure to (WHO, 2000). However, studies 3.1.7 Metabolism infectious agents (see Chapter 6). in pigs have reported significant Evidence suggests that the critical amounts of fully hydrolysed and

The metabolism of aflatoxin B1 has factor determining species sensitivity partially hydrolysed fumonisin B1 been extensively reviewed (IARC, is the rate at which the aflatoxin B1- in faeces and tissues (Fodor et al., 1993a, 2002a; see also Chapter 6). 8,9-epoxide can be conjugated 2008). Whether the hydrolysed

Briefly, in the liver and other tissues, to glutathione by glutathione fumonisin B1 was produced in the aflatoxin B1 is metabolized in S-transferase (GST) (Eaton et tissues was not determined.

Chapter 5. Effects in food-producing animals 65 3.2.3 Bioavailability been detected in the brains of pigs Several studies have confirmed this (Prelusky et al., 1996a), but little or finding using the persistence of free In all animals studied, including pigs, no fumonisin has been detected in sphinganine as a biomarker in the laying hens, turkey poults, ducks, and the brain tissue of horses, although kidney and liver to show that although dairy cows, the fumonisin absorption the brain is a known target organ fumonisin B1 is rapidly eliminated, that does occur is rapid and the quantity (Haschek et al., 2002). Until recently the biomarker remains elevated for of fumonisin B1 detected in plasma it was believed that fumonisins a much longer period. Although the and tissues after oral administration is could not cross the placenta and half-life after oral dosing is not known, very low (negligible to < 4% of dose) enter the developing embryo (WHO, the oral half-life is probably between (WHO, 2000, 2001, 2012; IARC, 2001). However, recent studies have 8 hours and 48 hours based on what 14 2002b; Fodor et al., 2008; Tardieu et detected [ C]fumonisin B1 in embryos is known from the parenteral routes, al., 2008, 2009). The bioavailability of and placentas, an observation the time required to reach peak levels fumonisin B2 may be less than that of confirmed by the presence of in plasma (1–7 hours) after gavage, fumonisin B1. Feeding studies have elevated levels of free sphinganine, and the estimated time for complete shown that, in the liver and kidney, a biomarker for fumonisin inhibition clearance from the liver and kid- fumonisin B1 is accumulated to a of ceramide synthase (Gelineau-van ney (2 weeks) (WHO, 2000). much greater extent than expected Waes et al., 2005). based on the relative amounts in feed 3.2.6 Transmission of fumonisin B1, fumonisin B2 (Riley 3.2.5 Excretion and Voss, 2006; Fodor et al., 2008; Little evidence exists to suggest Gazzotti et al., 2010), and fumonisin After intraperitoneal or intravenous significant transfer of fumonisins

B3 (Riley and Voss, 2006). Although dosing of fumonisin B1, initial elim- through milk (WHO, 2000). No diets containing predominantly ination from tissues is rapid, with no fumonisin B1 was detected in the milk fumonisin B2 from culture material evidence of metabolism (Shephard of lactating sows fed diets containing induced liver toxicity in both rats and et al., 2007; Voss et al., 2007), but nonlethal levels of fumonisin B1, and horses (Riley et al., 1997; Voss et extensive enterohepatic circulation no evidence was found of toxicosis al., 1998), pure fumonisin B2 did not occurs (Prelusky et al., 1996a). After in their suckling pigs. In a study with induce liver toxicity in mice in one oral dosing, peak plasma levels lactating cows administered fumonisin feeding study (Howard et al., 2002). occur within 1 hour to several hours. B1 intravenously, the carry-over of

In a cultured intestinal epithelial cell Several studies using different routes fumonisin B1 into the milk was either model, hydrolysed fumonisin B1, of exposure and different animal very small or not detected. The fact but not fumonisin B1, was found to species have shown that fumonisins that very little fumonisin B1 is retained cross the monolayer (primarily from are excreted primarily in faeces, in any tissue, milk, or eggs has led basolateral to apical), suggesting a either unchanged or with loss of one to the conclusion that fumonisin carrier-mediated efflux process (De or both of the tricarballylic acid side residues in food products derived

Angelis et al., 2005). chains. Low levels of fumonisin B1 can from animals are insufficient to render be detected in the urine of animals them injurious to consumers (WHO, 3.2.4 Distribution exposed experimentally to fumonisin, 2000). However, in a study in weaned including rabbits (Orsi et al., 2009), piglets fed diets containing fumonisin

Although fumonisins are distributed rats (Cai et al., 2007), pigs (Fodor et B1 at 10 mg/kg or 30 mg/kg diet, the to most tissues, the liver and kidney al., 2008; Dilkin et al., 2010), horses livers contained 306 μg/kg or 830 μg/ retain the highest concentrations of (Tumbleson et al., 2003), and vervet kg of fumonisin B1, respectively, after the absorbed material in all animals monkeys (Shephard et al., 2007). In 28 days (Dilkin et al., 2003). At the studied (reviewed in Voss et al., pigs, < 1% of the oral dose is recovered higher level of contamination, a 70 kg

2007). Fumonisin B1 persists in the in urine (Prelusky et al., 1996a; Dilkin person would need to consume kidney much longer than in plasma or et al., 2010). It has been estimated that 170 g of liver to exceed the Joint the liver, and in male Sprague Dawley pigs exposed to dietary fumonisin B1 WHO/FAO Expert Committee on (Riley and Voss, 2006) and Wistar at 2–3 mg/kg body weight (bw) in feed Food Additives (JECFA) provisional rats (Martinez-Larranaga et al., would require a withdrawal period of maximum tolerable daily intake

1999), the levels of fumonisin B1 in the at least 2 weeks for the fumonisin B1 (PMTDI) of 2 μg/kg bw/day. Pigs fed kidney can be 10 times the amount in to be eliminated from the liver and diets containing low levels (1.66 mg/ the liver. Radiolabeled fumonisin has kidney (Prelusky et al., 1996a, 1996b). animal/day) of fumonisins for 7 weeks

66 had detectable, but much lower, acylation of the free primary amino the intestinal microbial population can levels of fumonisins (15–43 μg/kg) in group prevents toxicity and reduces also reduce the hydrolysis of OTA to the liver (Gazzotti et al., 2010). Levels the ability of the fumonisin to inhibit its non-toxic metabolite, ochratoxin of fumonisin detected in the muscle ceramide synthase (Norred et al., α, leading to increased blood of pigs or poultry orally dosed with 1997, 2001). The two tricarballylic concentrations of OTA (WHO, 2001). fumonisin were either very low or acid side chains are also important for In pigs, ochratoxin B is metabolized below the detection limits (Prelusky toxicity, as demonstrated by reduced much more efficiently to ochratoxin et al., 1996a; Tardieu et al., 2008). or no toxicity, or evidence for disruption β than OTA is to ochratoxin α. The of sphingolipid metabolism, when rate of disappearance of OTA from 3.2.7 Metabolism fumonisin is hydrolysed (Howard et rumen fluids and its gastrointestinal al., 2002; Collins et al., 2006; Voss et metabolism depend on diet (Müller Fumonisins do not appear to be al., 2009; Grenier et al., 2012). et al., 2001) and are affected by the metabolized in vitro or in vivo by animal amount of feed concentrates (feed tissues (WHO, 2001), even though 3.3 Ochratoxin A additives with a high nutrient density) they are clearly excreted in bile, and added to the diet (Höhler et al., 1999). hydrolysed and partially hydrolysed 3.3.1 Absorption fumonisin B1 has been reported in 3.3.3 Bioavailability tissues (Fodor et al., 2008). The source Comprehensive reviews of the of hydrolysed fumonisins in tissues pharmacokinetics and metabolism OTA is well absorbed from the is unknown. However, formation of OTA are available (Marquardt and gastrointestinal tract, presumably of hydrolysed fumonisin during Frohlich, 1992; WHO, 2001; Dietrich from the small intestines, and it is also alkaline processing (nixtamalization) et al., 2005; Pfohl-Leszkowicz and well absorbed from the lungs, with and by microbial metabolism in Manderville, 2007). OTA is rapidly a calculated bioavailability of 98% the gastrointestinal tract has been absorbed. The half-life in plasma (WHO, 2001). Bioavailability from the demonstrated (see Section 3.2.2). One depends on the extent of binding oral route is reported as ranging from study suggested that a cytochrome to plasma proteins. OTA is widely 40% to 70% in chickens, rabbits, and P450 isoform is capable of producing distributed; in pigs, it is accumulated pigs. Absorbed OTA is rapidly and a fumonisin B1 metabolite (Marvasi et in the kidney and other tissues and tightly bound to serum proteins and CHAPTER 5 CHAPTER al., 2006), but no convincing evidence can occur in edible tissues. OTA in that form is only slowly transferred has been reported of in vivo or in vitro and its metabolites are reabsorbed from the bloodstream to the liver and metabolism by cytochrome P450, the by the kidney and excreted in urine kidney. The high affinity of OTA for microsomal esterase, or any other and also undergo enterohepatic serum albumin results in a higher microsomal enzyme (WHO, 2001, circulation and excretion in faeces. concentration in plasma than in the 2012). However, studies have shown The potential exists for extensive gut (Kumagai, 1988). The maximal that cytochrome P450 activity can metabolism by microbes to less toxic concentration in serum after a single be altered as a result of the inhibition metabolites in the gastrointestinal oral dose is attained in < 1 hour in of the enzyme ceramide synthase tract. Ochratoxins A and B can also chickens and in 10–48 hours in pigs by fumonisin (WHO, 2001). Both be metabolized by cytochrome P450 (WHO. 2001). The plasma half-life of B fumonisins and their hydrolysed enzymes in various tissues. OTA is quite variable, ranging from a counterparts can react with ceramide few hours in chickens to 5 days in pigs. synthase; hydrolysed fumonisin B1 3.3.2 Gastrointestinal is a substrate for this enzyme, produc- metabolism 3.3.4 Distribution ing the compound N-palmitoyl-AP1 (Seiferlein et al., 2007). Studies using In cows and sheep, OTA is degraded In pigs, chickens, and goats, the hydrolysed fumonisin B1 have shown by the rumen flora and protozoa (WHO, relative tissue distribution of OTA is that it is much less toxic than the parent 2001). However, some portion is not usually kidney > liver or muscle > fat compound (Howard et al., 2002; metabolized and can accumulate in (WHO, 2001; Biró et al., 2002; Collins et al., 2006; Voss et al., 2009; serum, tissues, and milk (IARC, 1993b; Dietrich et al., 2005). In rabbits, the Grenier et al., 2012). Höhler et al., 1999). The enzymes relative distribution is kidney > liver Even though little evidence responsible for the metabolism > mammary gland > muscle (Ferrufino- has been found for metabolism of are carboxypeptidase A and Guardia et al., 2000). OTA has been B fumonisins in tissues, chemical chymotrypsin. Antibiotics that inhibit shown to cross the blood–brain

Chapter 5. Effects in food-producing animals 67 barrier in rats and the placenta in 3.3.7 Metabolism 3.4.2 Gastrointestinal rats and pigs (WHO, 2001). The rate metabolism of disappearance of OTA from the In addition to gastrointestinal degra- blood is much slower than that from dation by microbes, microsomal A great deal of information has the kidney or liver and other tissues, preparations from rabbits and pigs been published about the ability of indicating the importance of binding containing various cytochrome P450 microorganisms in the gastrointestinal to serum proteins and enterohepatic enzymes can oxidize OTA to less tract to metabolize DON. In some recirculation in the overall fate of OTA toxic hydroxyochratoxin A (WHO, studies, incubation with cultures or once it has been absorbed. In cells, 2001). At least 20 OTA derivatives extracts from the gastrointestinal tract OTA is accumulated via a multispecific have been identified after incubation has resulted in extensive conversion organic anion transporter (O’Brien and with liver microsomes or cultured cells, of DON to the de-epoxy metabolite, Dietrich, 2005). The accumulation and and hydroxylated metabolites have DOM-1 (WHO, 2001). Near-complete persistence of OTA in the kidney is been detected in pig kidney (Pfohl- de-epoxidation has been shown due to its reabsorption by the organic Leszkowicz and Manderville, 2007). using intestinal contents from pigs and anion transporter (Zingerle et al., Metabolism by cyclo-oxygenases and chickens and bovine rumen fluid. Pigs 1997; Welborn et al., 1998). The ability other oxidative enzymes can produce lacking the ability to carry out intestinal of the kidney to accumulate OTA plays reactive oxygen species, leading to de-epoxidation can acquire the ability an important role in its nephrotoxicity. oxidative damage to tissues. OTA through contact with faeces from In pigs fed OTA for 1 month, the half- has been suggested to induce DNA pigs capable of making the de-epoxy life of residues in the kidney, liver, and adducts (see Pfohl-Leszkowicz and metabolite (Eriksen et al., 2003). It has muscle was 3.5–4.5 days (Busby and Manderville, 2007, and Chapter 6). also been shown that de-acetylation Wogan, 1981b). of 3-acetylDON to DON occurs in the 3.4 Deoxynivalenol pig gastrointestinal tract before DON is 3.3.5 Excretion absorbed. Whereas the de-epoxides of 3.4.1 Absorption DON and NIV are less cytotoxic than Elimination of OTA is primarily via the parent compounds, de-epoxidation, the urine, but significant amounts Depending on geographical location, unlike de-acetylation, appears to occur can also be excreted in faeces. the predominant trichothecenes may primarily in the distal portion of the OTA is eliminated slowly because be DON, nivalenol (NIV), or one of digestive tract, where DON absorption it undergoes enterohepatic recir- their acetylated precursors. However, is low (Eriksen et al., 2003). culation, is reabsorbed by the kidney, DON is the focus of this section. For and binds tightly to serum protein more information specific to NIV and 3.4.3 Bioavailability (WHO, 2001). The extent of albumin acetylated derivatives of DON and binding also markedly decreases the NIV, see Pestka (2010a) and Sugita- DON is rapidly absorbed from the uptake of OTA by transporters (Bow Konishi and Nakajima (2010). gastrointestinal tract in sheep, cows, et al., 2006). The elimination half-life Absorption, distribution, and elim- and pigs (WHO, 2001). In sheep, is much shorter for ochratoxins B and ination of DON are rapid after either the bioavailability is low (< 10%). C than for OTA and its metabolites oral or parenteral dosing. No evidence Bioavailability in cows also appears to (Li et al., 1997). has been found for DON accumulation be low, whereas one study estimated in tissues or transmission to eggs that the systemic bioavailability in pigs 3.3.6 Transmission or milk at the DON levels normally was 55%. After a single intragastric encountered in animal feed (Prelusky dose in pigs, the peak plasma level OTA has been shown to be transferred et al., 1994). The potential for extensive occurred at 15–30 minutes and the efficiently to milk in rodents and metabolism in the gastrointestinal plasma half-life was 7.1 hours. The rabbits (WHO, 2001). At high levels tract via de-epoxidation reactions plasma half-life after intravenous of exposure, OTA can accumulate in results in the formation of de-epoxy dosing was 3.9 hours in pigs and eggs of chickens and quail (WHO, DON (DOM-1) (reviewed in WHO, 100–125 minutes in sheep. When 2001). Detectable levels have been 2001; Pestka, 2010a, 2010b). pigs were fed diets containing reported in pig kidney and liver, blood 3-acetylDON for 3 days, DON was products, and other meat products detected in plasma 20 minutes after for human consumption (WHO, 2001; the first feeding (Eriksen et al., 2003). CAST, 2003). The maximal plasma level occurred

68 2.8 hours after feeding, suggesting 3.4.6 Transmission 3.5.2 Gastrointestinal that absorption started in the stomach metabolism or the upper part of the duodenum. DON was not detected in milk from cows fed a diet containing maize naturally ZEA can be degraded in the rumen. 3.4.4 Distribution contaminated with DON at up to 12 mg/ In both sheep and cattle, rumen kg dry diet for 10 weeks (WHO, 2001). fluid reduces ZEA to its more The little information available on the Low levels of DON (< 1.7 mg/egg) were easily excreted metabolites, α- and distribution of DON in tissues suggests detected in eggs from chickens fed β-zearalenol (Raisbeck et al., 1991). that this compound is rapidly and widely diets containing DON at 5.5 mg/kg distributed but is not accumulated. In diet for 65 days. Other studies 3.5.3 Bioavailability chickens, 3 hours after a single oral also indicate that transmission to dose of radiolabelled DON, the relative milk is small in sheep and cows. ZEA is poorly absorbed from the gut accumulation was bile >> kidney > blood/ Transmission of DON to edible animal of chickens (Christensen, 1979). For plasma > liver >> other tissues (WHO, products should pose little health risk example, in chickens, 12 hours after 2001). At later time points (72 and to consumers. oral dosing, 0.08% of the dose was 96 hours), very little or no DON was recovered in tissues and organs, detected. In pigs, 3 hours after a 3.4.7 Metabolism whereas 99% was recovered in single intravenous dose, DON was excreta, bile, and the digestive distributed to all tissues examined and No evidence has been found that tract plus its contents (Christensen, the relative accumulation was kidney DON is metabolized by microsomal 1979). Peak plasma concentrations > plasma > liver > fat >> other tissues enzymes. However, evidence for occurred 2–6 hours after a single (WHO, 2001). At 24 hours after dosing, glucuronide conjugation in sheep oral dose in broilers (Bernhoft et the levels in all tissues were reduced and pigs is well documented (WHO, al., 2001). Oral bioavailability may by > 90% relative to those at 3 hours 2001; Eriksen et al., 2003). In some be much greater in other species; after dosing. studies with sheep, the glucuronide for example, in rats the oral conjugate of DON can account for a bioavailability was reported as 2.7% 3.4.5 Excretion large percentage of the total plasma of the dose (Shin et al., 2009). In pigs DON. In pigs fed diets containing orally dosed with ZEA, the half-life CHAPTER 5 CHAPTER DON is rapidly eliminated in urine and 3-acetylDON, 42% and 33% of in plasma was 87 hours (Biehl et al., faeces in chickens, sheep, and pigs the DON in plasma and urine, 1993) due to extensive enterohepatic (WHO, 2001). In chickens, 79%, 92%, respectively, was conjugated to the recirculation. and 98% of an oral dose could be glucuronide (Eriksen et al., 2003). In accounted for in excreta at 24, 48, and that study, a significant portion of the 3.5.4 Distribution 72 hours after dosing, respectively. In DON in faeces was the de-epoxide. sheep, 36 hours after a single oral dose, In rats orally dosed with ZEA, only 6.9%, 0.11%, and 64% of the dose was 3.5 Zearalenone very low levels were detected in recovered in urine, bile, and faeces, tissues (Christensen, 1979). The respectively. In ewes, 91% and 6% of a 3.5.1 Absorption liver contained the highest levels single intravenous dose was recovered in of ZEA of the tissues examined urine and bile, respectively, after 24 hours, ZEA is rapidly absorbed and elim- (Christensen, 1979; Bernhoft et and a similar result was seen in pigs. inated. It is metabolized in the liver al., 2001). ZEA and its metabolite Pigs consuming wheat naturally (and possibly the intestinal mucosa) α-zearalenol can cross the placenta contaminated with DON excreted 50– and excreted in urine and faeces as and enter the fetus (Bernhoft et al., 62% of the DON in their urine (Goyarts the glucuronide after considerable 2001). and Dänicke, 2006). In a feeding study enterohepatic recirculation. It is with 3-acetylDON, 45% and 2% of metabolized by rumen microbes. 3.5.5 Excretion the dose was recovered in urine and Accumulation in tissues is minimal. faeces, respectively, 48 hours after the Comprehensive reviews of the The half-life of ZEA in pigs dosed pigs were taken off the contaminated toxicokinetics of ZEA in animals either intravenously or orally was diets, and the remainder of the dose are available (Fink-Gremmels and 87 hours (Biehl et al., 1993). When was unaccounted for (Eriksen et al., Malekinejad, 2007; Zinedine et al., bile was removed, the half-life 2003). 2007). was reduced to 3 hours, indicating

Chapter 5. Effects in food-producing animals 69 that enterohepatic cycling of ZEA the substrates for these enzymes fluids are quickly degraded by rumen (principally as the glucuronide) is include natural steroid hormones microorganisms to metabolites such extensive in pigs. Excretion in bile is (reviewed in Fink-Gremmels and as lysergic acid (Moyer et al., 1993; rapid in broilers; peak concentrations Malekinejad, 2007). The intestinal Hill, 2005; Ayer et al., 2009). In cattle, occur 2–6 hours after a single mucosa may also actively reduce the main ergot alkaloid found in urine oral dose (Dänicke et al., 2001). In ZEA to α-zearalenol and mediate is lysergic acid (Stuedemann et al., chickens orally dosed with ZEA, conjugation to glucuronic acid (Biehl 1998). Gastrointestinal metabolism 75% of the administered dose was et al., 1993). The rapid conversion of in monogastrics is probably limited recovered in excreta after 24 hours ZEA to the more easily excreted α- (Hill, 2005). (Christensen, 1979). Zearalenol and β-zearalenol derivatives in cattle, can be detected as the glucuronide along with microbial metabolism in 3.6.3 Bioavailability in urine and faeces of pigs and in the rumen, could explain the relative excreta of chickens (Christensen, resistance of cattle to the reproductive Gastrointestinal absorption of ergot 1979; CAST, 2003). α-Zearalenol effects of ZEA, compared with pigs alkaloids is low (< 5%), and clearance is glucuronide appears to be the major (Raisbeck et al., 1991). rapid (Haschek et al., 2002). However, metabolite detected in pig urine and physiological effects can be persistent, serum after prolonged exposure to 3.6 Ergot alkaloids suggesting either that metabolites are ZEA (Dänicke et al., 2005). tightly bound or that an undiscovered 3.6.1 Absorption reservoir exists in the body. The 3.5.6 Transmission bioavailability of ergot alkaloids appears The absorption and metabolism of to be a function of solubility. The ZEA is poorly transferred to milk as ergot alkaloids may be quite different ergopeptine alkaloids are less soluble zearalenol derivatives (< 1% of dose) in monogastrics and ruminants. than the ergoline alkaloids and when and may induce signs of estrogenism Water-soluble alkaloids appear to administered orally must be dissolved in female piglets (Osweiler, 2000). be more strongly absorbed than in lipophilic carriers or chemically In the liver, α-zearalenol is detected lipophilic ones, and rumen microbes modified to improve solubility (Hill, more frequently than β-zearalenol. appear to play an important role in 2005). In sheep rumen and omasal Trace amounts of ZEA and its the release and intestinal availability tissue, transport of alkaloids appears metabolites can be detected in muscle of soluble alkaloids in the rumen to be an active process, and lysergic tissues of pigs fed oats contaminated (Hill, 2005; Ayer et al., 2009). The acid and lysergol are transported much with ZEA; however, residues do not more soluble alkaloids, such as more effectively than are ergopeptine persist (Zöllner et al., 2002). lysergic acid, are excreted in urine, alkaloids (Hill et al., 2001). and the less soluble alkaloids can 3.5.7 Metabolism undergo enterohepatic recirculation 3.6.4 Distribution and are excreted primarily in bile. After considerable enterohepatic re- Transmission is unlikely, and accu- Ergot alkaloids are widely distributed, circulation, ZEA is metabolized in mulation in tissues, if any, is low. as evidenced by the fact that most of the liver and excreted in urine and Once absorbed, ergot alkaloids such the physiological effects involve direct faeces as the parent compound, as ergotamine can be metabolized interaction with dopamine receptors the metabolites α-zearalenol by cytochrome P450 enzymes. in the peripheral vasculature and, in and/or β-zearalanol, or their some cases, in the brain and other respective glucuronide conjugates 3.6.2 Gastrointestinal neuronal tissue (see Section 4.6). (reviewed in Fink-Gremmels and metabolism Malekinejad, 2007; Zinedine et al., 3.6.5 Excretion 2007). The enzymes responsible Studies in sheep and cattle suggest for the conversion of ZEA to α- that rumen microorganisms can Once ergot alkaloids are absorbed, and β-zearalenol are 3-α- and degrade plant material and release clearance is very rapid. For ex- 3-β-hydroxysteroid dehydrogenase, the more soluble ergoline alkaloids ample, intravenously administered respectively. These two microsomal (Hill, 2005; Ayer et al., 2009). The ergovaline was shown to have a enzymes are important in steroid small amounts of less soluble plasma half-life of 24 minutes in metabolism, so ZEA has the potential ergopeptine alkaloids (ergonovine sheep (Jaussaud et al., 1998) and a to disrupt steroid metabolism because and ergovaline) present in rumen half-life of 56 minutes in horses (Bony

70 et al., 2001). Ergopeptine alkaloids cannot model the uncontrolled reduced weight gain and decreased are excreted in bile and ergoline exposure of farm animals to naturally feed efficiency. The effects on alkaloids in urine (Hill et al., 2001). In contaminated feeds and foods in growth are dose-dependent and at cattle grazing on tall fescue infected the field, where multiple factors low levels may be barely discernible. by endophytes, the urine contained contribute to the expression of Other performance effects include approximately 96% of the total ergot disease. Thus, the potential for tox- decreased reproductive performance, alkaloid excreted, and after 2 days of icity revealed in controlled experi- abortion, and reduced egg or milk grazing on grass free of endophytes, ments is often not predictive of the production. In turkeys, a sensitive the urinary alkaloids were reduced levels of exposure in feeds associated species, reduced weight gain is seen to control levels (Stuedemann et al., with suspected field outbreaks of at a dose of 125 µg/kg diet, impaired 1998). The maximal levels of ergot disease. One explanation for the immune response and increased alkaloids in urine were attained within difficulty in equating dose–response mortality at 250 µg/kg, and acute 48 hours, and the main alkaloid was in laboratory studies with dose– mortality at 500 µg/kg (Norred, lysergic acid. response in the field is the inability 1986). A similar relative dose– to identify all the environmental, response occurs in pigs but at higher 3.6.6 Transmission nutritional, and genetic factors that levels of exposure because they are contribute to disease expression. less affected by aflatoxins. In cattle There are no reports that ergot Nevertheless, information gained and chickens, much higher levels alkaloids are transferred to milk or from in vitro studies and studies are required to induce a decrease accumulate in tissues. with laboratory animals is predictive in performance, and in chickens of the possible contribution of impaired immune response can 3.6.7 Metabolism mycotoxins in altering immune occur at levels that have no effect function (Bondy and Pestka, 2000), on the growth rate. In all species, Ergopeptine alkaloids are metab- thereby contributing to unexplained aflatoxins are hepatotoxic, with fatty olized in the liver via cytochrome animal diseases and performance changes, hepatocyte degeneration, P450 enzymes such as CYP3A, and problems in farm animals (Osweiler, necrosis, and altered liver function. hydroxylated metabolites are excreted 2000). Several excellent reviews A common clinical sign is jaundice. in bile (Moubarak and Rosenkrans, have documented the toxicology Grossly, the liver appears pale and CHAPTER 5 CHAPTER 2000; Haschek et al., 2002). Ergoline of mycotoxins in farm animals and swollen or fatty with variable texture. alkaloids (i.e. lysergic acid), which provided extensive descriptions of In chickens, fatty liver syndrome is are more water soluble, are excreted the clinical manifestations (Oltjen, believed to be caused by aflatoxin in urine (Hill, 2005; Ayer et al., 2009) 1979; Richard and Thurston, 1986; (Norred, 1986), although OTA can and faeces in amounts greater than Raisbeck et al., 1991; WHO, 2001; also cause fatty liver in poultry that consumed, suggesting that Haschek et al., 2002; CAST, 2003; (Trenholm et al., 1988). Liver damage ergovaline and possibly other ergot Cousin et al., 2005; O’Brien and ultimately can lead to coagulopathy, alkaloids are metabolized in tissues Dietrich, 2005; Fink-Gremmels and as evidenced by haemorrhaging and to lysergic acid (Schultz et al., 2006). Malekinejad, 2007; Pestka, 2007, anaemia (Fig. 5.1). In poultry and 2010a, 2010b; Pfohl-Leszkowicz and pigs, coagulopathy contributes to 4. Toxicological effects Manderville, 2007; Voss et al., 2007; the appearance of internal bruising Zinedine et al., 2007; Steyn et al., during handling. In pigs, this may Only a few known mycotoxins pose 2009). In this section, we describe occur at levels as low as 150 µg/kg a measurable health risk to farm the main clinical signs in farm animals diet (Edds, 1979). animals, for several reasons. First, exposed to the levels of mycotoxins The mechanism of action of a fundamental tenet of toxicology encountered in field outbreaks. We aflatoxins involves metabolism to re- is “the dose makes the poison”. also present postulated responses to active intermediates and their binding Thus, even though farm animals are low levels of mycotoxins. to macromolecules (nucleic acids and exposed to mycotoxins every day proteins) and consequent disruption through their feed, the dose is usually 4.1 Aflatoxins of transcriptional and translational insufficient to make the contaminated processes and regulatory pathways feed acutely poisonous. Second, the The overt symptoms of aflatoxin critical for repair of damaged DNA, for doses and routes of exposure used poisoning are not definitive. Animals cell growth, death, and differentiation, in controlled laboratory experiments do not eat well and therefore have and ultimately for toxicity and

Chapter 5. Effects in food-producing animals 71 carcinogenicity (Wild and Gong, head pressing, and decreased feed In equids, the minimum toxic level

2010; Eaton et al., 2010; Kensler et intake, followed by convulsions of fumonisin B1 in feed for inducing al., 2011). Some evidence has been and death after several days. Early ELEM appears to be between 15 mg/ found that aflatoxin B1 produces clinical signs include hindlimb ataxia, kg and 22 mg/kg diet (WHO, 2000, reactive oxygen species, resulting in delayed forelimb placing reactions, 2001). Analysis of feeds from oxidation of DNA bases (Guindon et and tongue paresis (Fig. 5.2), which confirmed cases of ELEM indicated al., 2007). are all mild signs of proprioceptive that a diet containing a fumonisin

The response of an animal to dysfunction (Foreman et al., 2004). B1 concentration of > 10 mg/kg diet aflatoxin depends to a large extent Elevation in levels of serum enzymes presented an increased risk of devel- on the rate of metabolism and the indicative of liver damage occurs oping ELEM (WHO, 2000, 2001). type of metabolites that are produced soon after elevation in levels of free Like ELEM, PPE syndrome is a (see Section 3.1.7 and Chapter 6). sphingoid bases and sphinganine-1- rapid-onset disease that is often fatal For example, quail and turkeys are phosphate in serum. The elevation in to affected animals. Clinical signs sensitive to aflatoxin toxicity and have sphinganine levels is also seen in the typically occur 2–7 days after pigs a high rate of epoxide formation and liver and kidney (Riley et al., 1997) start consuming diets containing large a low rate of glutathione conjugation. and other tissues (Tumbleson et amounts of fumonisins. Clinical signs In resistant species, even if the rate al., 2003). Sphinganine-1-phosphate include decreased feed consumption, of epoxidation is high, a high rate of is also greatly elevated in serum of dyspnoea, weakness, cyanosis, and glutathione conjugation is protective. horses treated with pure fumonisin B1 death. When animals are examined However, the resulting clinical (Constable et al., 2005). The elevated at necropsy, varying amounts of signs are similar although the dose serum and tissue levels of free clear yellow fluid are seen in the dependence may be quite different. sphingoid bases and sphinganine- pleural cavity together with varying Aflatoxin adducts in urine and blood 1-phosphate are biomarkers for degrees of interstitial and interlobular of farm animals may be very useful exposure to potentially toxic levels oedema, with pulmonary oedema as a biomarker for exposure during of fumonisins (Riley et al., 2011) and hydrothorax (Fig. 5.3). Toxic suspected field outbreaks (Riley et and have been used in studies in hepatosis usually occurs concurrently al., 2011). horses, pigs, rabbits, poultry, and with pulmonary oedema, and in some other farm animals (WHO, 2000). In animals that consume high levels of 4.2 Fumonisins horses, serum enzyme levels often fumonisins, toxic hepatosis appears return to near-normal concentrations without signs of pulmonary oedema. Consumption of feeds contaminated but usually increase markedly im- Nodular hyperplasia has been with fumonisins is a proven cause mediately before, or at the first signs observed in some pig livers (WHO, of two farm animal diseases and a of, behavioural changes indicative 2000, 2001). suspected cause of others. ELEM of the onset of ELEM (WHO, 2000, As with ELEM, fumonisin con- is a fatal neurotoxic disease that 2001). centration in maize screenings occurs only in equids (horses and In addition to the brain lesions, obtained from different farms was related species). The disease is histopathological abnormalities in the closely correlated with outbreaks of characterized by the presence of liver and kidney have been reported PPE in the USA in 1989–1990. The liquefactive necrotic lesions in the in horses, and these are also minimum dose necessary to induce white matter of the brain; the grey correlated with elevation in levels this disease has not been clearly matter may also be involved (WHO, of free sphinganine (Tumbleson et established, but in diets containing

2000). All aspects of the disease can al., 2003). ELEM concurrent with fumonisin B1 from culture material, be reproduced experimentally. The significant liver disease and fatal concentrations as low as 17 mg/ brain lesions are caused by vasogenic liver disease in the absence of any kg diet induced pulmonary oedema cerebral oedema (Haschek et al., brain lesions have been observed in in 5 days, whereas concentrations 2002; Foreman et al., 2004) and horses and ponies. The appearance of 150–170 mg/kg diet for up to are accompanied by increased of the clinical disease is likely to 210 days caused liver effects early protein in the cerebrospinal fluid depend on multiple factors, including on but no evidence of pulmonary and other changes consistent with the length of exposure, level of oedema (WHO, 2000). Pigs fed a vasogenic cerebral oedema (Smith contamination, individual animal dif- diet containing fumonisin B1 at 45 et al., 2002; Foreman et al., 2004). ferences, previous exposure, and mg/kg diet for 10 days developed Early symptoms include lethargy, pre-existing liver impairment. mild signs of pulmonary oedema,

72 including the accumulation of fluid in Fig. 5.1. (a) Liver from a chick fed a diet containing 7.5 mg/kg of aflatoxin B1; (b) a the pleural cavity, which persisted in normal liver. Similar results are seen in turkey poults fed the same diets. Photograph courtesy of Timothy Phillips, Texas A&M University. several animals 10 days after removal from the contaminated diets (Fodor et al., 2008). Pigs given a single oral dose of 5 mg/kg bw of fumonisin B1 (equivalent to 83 mg/kg diet) did not develop pulmonary oedema but did show behavioural and clinical signs of toxicity suggestive of its onset (Dilkin et al., 2010). In pigs, tissues other than the liver and lung that have been reported to be targets for fumonisins include the pancreas, heart, kidney, spleen, pulmonary intravascular macro- phages, and oesophagus. Altered Fig. 5.2. (a) A horse in the initial stage of equine leukoencephalomalacia. Photograph growth and changes in selected courtesy of Walter F.O. Marasas, Programme on Mycotoxins and Experimental haematological parameters in pigs Carcinogenesis (PROMEC Unit), South African Medical Research Council. (b) A have been reported at dietary levels weanling Appaloosa filly administered fumonisin B1 intravenously at 0.20 mg/kg bw/ as low as 1 mg/kg diet (WHO, day for 7 days. Note the severe displacement of the tongue after manual exteriorization by the examiner. From day 4 through day 7, this filly developed progressive tongue 2000). In weaned pigs, growth, paresis, proprioceptive deficits, and ataxia in all four limbs, hind limb spasticity and attainment of sexual maturity, and paresis, and forelimb hypermetria. On the day of euthanasia, it kept its tongue out sperm production were impaired in of its mouth for periods of up to 1 minute at a time. Source: Foreman et al. (2004); animals consuming diets containing reproduced with the permission of the publisher. fumonisin B1 at > 5 mg/kg diet (Gbore, 2009). The physiological basis for performance problems induced in CHAPTER 5 CHAPTER pigs by fumonisin is unclear; however, several in vitro and in vivo studies have shown that fumonisin exposure can have deleterious effects on intestinal integrity and function, which can lead to altered intestinal immune responses and possibly other effects on intestinal physiology (Bouhet et al., 2004; Bouhet et al., 2006; del Rio Garcia et al., 2007; Loiseau et al., 2007; Devriendt et al., 2009; Lessard et al., 2009). Oral exposure to feed contaminated with fumonisins also has effects on other immune responses, Clinical features include diarrhoea, (75–644 mg/kg diet) because poultry including sex-specific decreased weight loss, increased liver weight, appeared to be unusually resistant antibody titres after vaccination and poor performance, and increased to dietary fumonisins (WHO, 2000, increased susceptibility to secondary susceptibility to infectious diseases. 2001). However, toxicity and altered pathogens (Halloy et al., 2005; Marin Several studies have confirmed that haematological parameters have et al., 2006). F. verticillioides, F. proliferatum, been observed in broiler chicks fed

Several published reports sug- fumonisin B1, and moniliformin are diets containing only 10 mg/kg of gest the involvement of Fusarium toxic to poultry (broiler chicks, turkeys, pure fumonisin B1 and 30 mg/kg of verticillioides in diseases of poultry, turkey poults, quail, and ducklings). fumonisin B1 from F. verticillioides and by implication the presence of The levels of fumonisin used in many culture material (WHO, 2000, fumonisin contamination in feed. of the early studies were quite high 2001). Like other poultry, ducks are

Chapter 5. Effects in food-producing animals 73 Fig. 5.3. (Left) A lung with severe oede- pathway (Wang et al., 1991). (Haschek et al., 2002). The elevation ma from a pig with porcine pulmonary Fumonisins are structurally similar of free sphingoid bases and sphingoid oedema after being fed fumonisin- to sphingoid bases and especially base 1-phosphates and the depletion contaminated feed and (right) a normal lung. Photograph courtesy of Wanda 1-deoxysphinganine, which lacks a of more complex sphingolipids in Haschek, University of Illinois. hydroxyl group on carbon 1 (Zitomer tissues, serum, and urine have proven et al., 2009). Sphingoid bases are to be useful biomarkers for exposure essential components of the chemical and the effects of fumonisin in farm backbone of all sphingolipids in animals (Riley et al., 2011). animals. When toxicity associated with fumonisins is observed in 4.3 Ochratoxin A laboratory or farm animals, the onset and severity of the pathology The primary effect of OTA in all farm is closely correlated with evidence animals is nephrotoxicity. In pigs of disrupted sphingolipid metabolism and poultry, the proximal tubules are (Riley et al., 1996, 2001; WHO, mainly affected and the kidney is 2000, 2001, 2012; Riley and Voss, pale and grossly enlarged (Fig. 5.4). 2006; Voss et al., 2011). Disrupted Fatty liver can occur in poultry. sphingolipid metabolism can also be The most sensitive indicator of evident at dosages that do not cause acute ochratoxicosis in chickens overt toxicity (NTP, 2001). This is is the reduction in total serum especially true in resistant species proteins and albumin. A decrease in such as ducks (Tardieu et al., phosphoenolpyruvate carboxykinase relatively resistant to the toxic effects 2006). The major biochemical and in the kidney is a sensitive and of fumonisins (Tran et al., 2005). cellular consequences resulting from specific indicator in pigs (Krogh, However, increased mortality and blockage of ceramide biosynthesis 1992; Marquardt and Frohlich, 1992). toxicity have been observed in ducks are the accumulation of free In pigs, large increases in levels force-fed diets containing 20 mg/kg sphingoid bases and sphingoid base of proteins excreted in urine are of fumonisin B1 (Tardieu et al., 2009). 1-phosphates (Riley and Voss, 2006; indicative of glomerular proteinuria As in pigs, fumonisin can also alter Zitomer et al., 2009), the depletion of and correlate with histological obser- immune response and susceptibility more complex sphingolipids (Voss et vations of renal damage. to infectious agents in poultry (Tessari al., 2009), and the global disruption of In poultry and pigs, exposure to et al., 2006; Deshmukh et al., 2007). lipid metabolism (WHO, 2001). The OTA at lower levels can result in altered Other farm animals that have changes in concentrations of impor- performance, including decreased been studied using pure fumonisins, tant lipid mediators lead ultimately feed consumption and reduced weight contaminated maize screenings, to perturbation of the signalling gain, and at higher levels can result in or maize culture material from F. pathways and altered regulatory and delayed response to immunization and verticillioides include carp, catfish, physiological processes (Lemmer increased susceptibility to infection lambs, goats, trout, cattle, mink, et al., 1999; Bondy et al., 2000; (Stoev et al., 2000a, 2000b). Other and rabbits. Rabbits are especially Merrill et al., 2001), which are the effects in poultry include decreased sensitive to nephrotoxicity (Voss basis for the observed clinical signs egg production, coagulopathy (in- et al., 2001; Ewuola, 2009). In all associated with the diseases induced creased susceptibility to bruising during cases where toxicity was evident, it by fumonisins. ELEM is associated processing), decreased bone strength, involved the liver and/or kidney or the with alterations in cardiovascular decreased tensile strength of the large equivalent organs in fish. function induced by sphingolipids, intestines, underpigmentation, and Disruption of lipid metabolism i.e. deregulation of cerebral arteries glycogen accumulation in the liver. appears to be the underlying responsible for autoregulation of blood The mechanism of action in mechanism by which fumonisins flow to the horse’s brain (Haschek et farm animals is unclear. However, cause toxicity to animals (WHO, al., 2002; Foreman et al., 2004). PPE is the structural similarity of OTA to 2000, 2001). The initial mechanism hypothesized to be a result of acute left- phenylalanine and the fact that it of action of fumonisin is inhibition of sided heart failure as a consequence inhibits many enzymes and processes ceramide synthase, a key enzyme in of inhibition of L-type calcium that are dependent on phenylalanine the de novo sphingolipid biosynthesis channels induced by sphingoid bases strongly suggest that OTA acts at least

74 Fig. 5.4. Examples of pig kidneys taken at slaughter, showing increasing degrees the mechanism appears to be indirect of mycotoxic nephropathy, with enlarged and mottled or enlarged and pale kidneys. (Miller, 2008; Pestka, 2010a). In pigs, Mycotoxic nephropathy in these animals was attributed to exposure to ochratoxin A feed refusal occurs even when DON and other mycotoxins (primarily, fumonisin and penicillic acid); however, mycotoxic nephropathy has also been reported in pigs exposed primarily to ochratoxin A (Elling is administered intraperitoneally, and Moller, 1973; Krogh, 1974). Source: Stoev et al. (2010); reproduced with the so feed refusal cannot be due permission of the publisher. to taste or learned responses (Prelusky, 1997). Clinical signs include gastrointestinal problems, soft stools, diarrhoea, increased susceptibility to other diseases, and decreased performance. In pigs, mild renal nephrosis, reduced thyroid size, gastric mucosal hyperplasia, increased albumin-to-α-globulin ratio, and sometimes mild changes in other haematological parameters have been reported (WHO, 2001). Numerous studies in laboratory animals have demonstrated alter- ations in immune function induced by DON (Bondy and Pestka, 2000; Pestka, 2010a), but conclusive evidence that DON induces altered resistance to infectious diseases in the field is still lacking (Osweiler, partially by disrupting phenylalanine 4.4 Deoxynivalenol 2000). Nevertheless, the mechanism metabolism (CAST, 2003; Riley of action in laboratory animals et al., 2011). Several studies have Many reviews on the toxicity of DON suggests, and controlled studies in CHAPTER 5 CHAPTER shown that supplementation of feed have been published (Beasley, 1989; the laboratory setting support, the with L-phenylalanine or proteins Prelusky et al., 1994; Rotter et al., 1996, potential for involvement by DON in protects against the toxic effects of WHO, 2001; Pestka, 2010a, 2010b). altered immune response. OTA, including mortality (Marquardt Although DON is not considered to The mechanism of action of DON and Frohlich, 1992; WHO, 2001). be acutely toxic to farm animals, it is complex. Disruption of ribosomal In addition to inhibition of protein is considered to be a major cause and endoplasmic reticulum function synthesis via binding to phenylalanine- of economic losses due to reduced as a consequence of DON binding tRNA synthetase, recent studies performance (Miller, 2008). In the field, to ribosomes is clearly a key event have demonstrated the ability of OTA concentrations as low as 1 mg/kg in disease causation in animals to induce oxidative stress, reduce have been associated with feed (Pestka, 2010a, 2010b). Binding of cellular defence, and alter signalling refusal in pigs; however, more typically DON to ribosomes is known to inhibit pathways involved in various aspects concentrations of > 2–5 mg/kg are translation by preventing polypeptide of cellular and mitotic regulation (Mally required for decreased feed intake and chain initiation or elongation in and Dekant, 2009). The ultimate reduced weight gain and concentra- animals (Ueno, 1984). However, consequence of generalized disruption tions of > 20 mg/kg for vomiting and several other ways exist in which DON of these metabolic and regulatory feed refusal (Trenholm et al., 1988; can interfere with protein synthesis, pathways is increased cell death, and Haschek et al., 2002; Fig. 5.5). all involving disrupted ribosomal the kidney is the most sensitive target Dogs and cats are also sensitive function (Pestka, 2010a). The because of its ability to accumulate to the emetic effects of DON, and downstream cellular consequences OTA to high levels. Because OTA binds acetylated DON also induces of disrupted ribosomal function tightly to albumin and serum proteins, emesis. Feed refusal and emesis appear to be dose-dependent, with serum OTA is a useful biomarker for appear to be due to neurochemical low doses being cytostimulatory exposure in pigs. imbalances in the brain, and although and high doses cytotoxic (Pestka, the emetic centre is clearly involved, 2010a). For example, DON is

Chapter 5. Effects in food-producing animals 75 Fig. 5.5. Reduced weight gain in pigs, an example of the effects of deoxynivalenol. of ZEA to estrogen receptors, These pigs are littermates, but the pig in the foreground was fed a diet containing the complex interacts with genes deoxynivalenol at 5 mg/kg diet for 7 weeks after weaning. Note also the white, rat-like controlling both estrogen-like and hair of the pig fed the deoxynivalenol-containing diet. Source: Trenholm et al. (1988), Fig. 3, p. 15; reproduced with the permission of the Minister of Public Works and antiestrogen-like responses (Boehme Government Services Canada, 2012. et al., 2009; Parveen et al., 2009). ZEA is also a ligand for the pregnane X receptor, which controls the expression of genes in some pathways that regulate biotransformation of endobiotics and xenobiotics (Ding et al., 2006). ZEA, and its metabolites and their conjugates, are detectable in urine and faeces and have been used as exposure biomarkers in animal studies (reviewed in Zinedine et al., 2007). Clinical signs of oestrus can be induced in ovariectomized sows. Doses of ZEA as low as 1–5 mg/ kg bw can induce vulvovaginitis, tenesmus, vaginal prolapse, and rectal prolapse in young female pigs (Osweiler, 1986; Fig. 5.6). Effects on pre-pubertal boars known to increase expression of as mechanism-based biomarkers have also been reported, and these pro-inflammatory cytokines, affect (Amuzie and Pestka, 2010) could include reduced libido, decreased transcription factors for many genes prove useful as markers of DON plasma testosterone, and other related to immunity and inflammation, involvement in disease outbreaks in effects (Osweiler, 1986). In sows, increase mRNA expression, in- farm animals (Riley et al., 2011). dietary levels of 3–10 mg/kg of ZEA crease mRNA stabilization, affect can induce anoestrus, reduced MAP kinase signalling, and induce 4.5 Zearalenone litter size, fetal reabsorption, and the ribotoxic stress response, all implantation failure. Cattle are more of which contribute to its biological The species that is the most sensitive resistant to the estrogenic effects; effects in animals (Pestka, 2010b). to the effects of ZEA is the pig. The however, conception rates can be It has also recently been shown that observed effects of ZEA on pigs reduced. DON disrupts the growth hormone involve primarily the reproductive axis; this finding provides a credible system (Fitzpatrick et al., 1989; Fink- 4.6 Ergot alkaloids explanation for growth retardation in Gremmels and Malekinejad, 2007; animals. Specifically, DON induces Zinedine et al., 2007). The sensitivity Based on major signs, ergotism in expression of pro-inflammatory of the pig appears to involve the way in farm animals can be divided into the cytokines, which leads to upregulation which this species metabolizes ZEA. gangrenous form and the convulsive of suppressors of cytokine signalling, Metabolism depends primarily on form (Robbins et al., 1985; Raisbeck which leads ultimately to reduced two hydroxysteroid dehydrogenases, et al., 1991). Livestock consuming feed levels of both insulin-like growth factor which produce the two main me- grains containing small seed grasses 1 and insulin-like growth factor acid- tabolites α- and β-zearalenol. The or foraging on pasture grasses are at labile subunit in the blood (Amuzie α-zearalenol isomer has a much particular risk. Cattle are at greatest and Pestka, 2010). The combined greater uterotropic activity than ZEA risk, and sheep and horses are less use of urinary DON glucuronide level does, and in pigs the predominant frequently affected. The symptoms of as an exposure biomarker (Turner, form of hydroxysteroid dehydrogenase ergotism and toxic alkaloids (Oliver, 2010) and changes in plasma levels of is the one that yields primarily 2005) include lameness, gangrene, insulin-like growth factor 1 and insulin- α-zearalenol (Fink-Gremmels and agalactia, reduced weight gain, abortion, like growth factor acid-labile subunit Malekinejad, 2007). After binding hypersensitivity, ataxia, convulsions,

76 Fig. 5.6. Vulvas of pre-pubertal gilts fed control diet (left) or zearalenone-contaminated 5. Sensitive or target species feed (right). Note swelling and oedema due to zearalenone consumption. Photograph and confounding factors courtesy of Walter F.O. Marasas, Programme on Mycotoxins and Experimental Carcinogenesis (PROMEC Unit), South African Medical Research Council. Although acute disease outbreaks from exposure to mycotoxins are not uncommon, definitively linking exposure to effects is not easy at the low levels of exposure most commonly encountered in the field. The observed physiological effects usually involve subtle changes in animal performance or behaviour and increased susceptibility to infectious disease, all of which are relatively nonspecific effects. Nevertheless, when changes in animal performance are observed and can be linked to the feed, exposure to low levels of mycotoxins in feed should be suspected as a contributing factor, at the very least. Young animals are more sensitive than adults to the adverse effects of mycotoxins, in part because of a higher metabolic rate. Factors and, in sheep, intestinal inflammation. In much of their time seeking shade or that can influence susceptibility cattle grazing on tall fescue, syndromes standing in ponds (Raisbeck et al., to performance problems and known as fescue foot, summer slump, 1991). Fat necrosis is characterized disease due to mycotoxins are sex, CHAPTER 5 CHAPTER and fat necrosis have been described by hard fat masses in the adipose genetic strain, reproductive status, (Robbins et al., 1985). Fescue foot tissue of the abdominal cavity. Fat pre-existing conditions, nutritional is characterized by gangrene of the necrosis is believed to require long- factors such as vitamin- or protein- extremities (feet, ears, and tail) and is term consumption (for years) of tall deficient diets, environmental caused by vasoconstriction resulting in fescue, whereas summer slump and stress, concurrent exposure to reduced blood flow and ischemia in the fescue foot may occur within weeks infectious agents, and exposure to peripheral tissues (Oliver 2005; Fig. 5.7). of exposure (Raisbeck et al., 1991). other toxins, including mycotoxins. This is usually accompanied by In all cases, it is the vasoconstrictive Target-organ specificity and species increased core body temperature in action of the ergot alkaloids and their sensitivity are known largely from cattle. Necrosis and loss of the tip metabolites (Hill et al., 2001; Ayer et laboratory studies in which a single of the tail is a common sign. Cold al., 2009) that is the underlying cause species has been studied using a weather aggravates the problem of the three common fescue toxicities. single toxin. Comparative studies of fescue foot, whereas summer In horses, reproductive problems are quite rare, so dose–response slump is commonly associated with resulting from consumption of ergot relationships comparing species, warm conditions. Summer slump alkaloids in tall fescue include longer sex, and exposure to multiple toxins is characterized by reduced milk gestation, stillborn foals, agalactia, at low levels – a scenario that is likely production, heat intolerance, rough placental retention, and reduced in field situations – are also rare. In hair coat, increased respiration rate, breeding efficiency (Cross, 2003). this section, we briefly describe the decreased feed intake, reduced Laminitis can also be caused by susceptibility of farm and domestic serum prolactin levels, and reduced consumption of toxic tall fescue and, animals to mycotoxins and the target conception rates (Robbins et al., 1985; like fescue foot in cattle, it is believed organs for aflatoxins, fumonisins, Raisbeck et al., 1991; Spiers et al., to be caused by vasoconstriction OTA, DON, ZEA, and ergot alkaloids 2005). A common sign in herds with in the extremities induced by ergot (summarized from WHO, 2001; summer slump is that the cattle spend alkaloids (Cross, 2003). Haschek et al., 2002; CAST, 2003).

Chapter 5. Effects in food-producing animals 77 Fig. 5.7. A field case of fescue toxicity. acute toxicity is the duckling (death), al., 2001). Studies have shown that The cow’s tail switch has fallen off and and the most sensitive species for pigs treated with fumonisins have a prominent ring has formed, produced chronic toxicity is the rainbow trout increased susceptibility to intestinal by ergot alkaloids in tall fescue. In this animal, the foot is also affected (not (liver cancer). Domestic turkeys infection with Escherichia coli shown) with reddening and swelling; this and quail are also very sensitive. (Oswald et al., 2003) and decreased is common with gangrenous ergotism. Reproductive effects have been specific antibody response during Photograph courtesy of Charles Bacon, reported in mink at low dietary levels vaccination (Taranu et al., 2005). United States Department of Agriculture, Agricultural Research Service. (10 µg/kg), and dogs are also quite Fumonisins frequently co-occur with sensitive to acute toxicity. In poultry, aflatoxins in maize and have been the relative sensitivity is ducklings shown to promote aflatoxin-initiated > turkey poults > goslings > chicks liver tumours in rainbow trout (IARC, > quail. In other farm animals, the 2002b). Fumonisins also cause liver relative sensitivity is rabbits > young toxicity in catfish, poultry, mink, pigs > calves > mature cattle > sheep. goats, and cattle (WHO, 2001). It However, these comparisons depend has been suggested that mycotoxic very much on the experimental nephropathy in pigs and chickens conditions under which the studies is a result of concurrent exposure were carried out. For example, young to multiple mycotoxins, including pigs are much more sensitive than fumonisin, OTA, and penicillic acid older pigs. The susceptibility of a (Stoev et al., 2010). The relative species to aflatoxin toxicity depends sensitivity, based on the United on its ability to metabolize aflatoxin States Food and Drug Administration efficiently and quickly to less toxic or (FDA) Guidance to Industry, is nontoxic metabolites (see Section equids and rabbits > pigs and catfish 3.1.7). Because maize is an important > ruminants, poultry, and mink, and source, exposure to both aflatoxins breeding animals are considered to and fumonisins is likely in animals be more sensitive than animals being consuming maize-based feeds. raised for slaughter (FDA, 2001). 5.1 Aflatoxins 5.2 Fumonisins 5.3 Ochratoxin A The liver is the primary target organ for aflatoxins, for both acute and chronic Fumonisins cause liver damage in The kidney and, to a much lesser toxicity. The kidney can also be all farm animals tested and also extent, the liver are the main targets affected in pigs and goats. However, kidney damage in rabbits, cattle, of OTA. Cattle (but not calves) anecdotally the most commonly and sheep. In addition, fumonisins are considered resistant due to suspected indicator of exposure to induce species-specific toxicities, metabolism of OTA to nontoxic aflatoxins is decreased performance in the brain in horses and the lung ochratoxin α by rumen microbes. and/or increased susceptibility to en- in pigs, that are a consequence of Other ruminants may also show vironmental and microbial stressors. cardiovascular dysregulation (WHO, resistance; however, dietary factors Conversely, undernourished or 2001; Haschek et al., 2002). Because can affect the extent of rumen stressed animals will be more fumonisins inhibit sphingolipid bio- metabolism (Höhler et al., 1999). sensitive to aflatoxin toxicity, and synthesis, it is likely that receptors Pigs and dogs are the most sensitive studies in rodents show that exposure and processes that are dependent domestic animals, and poultry are to bacterial endotoxins augments liver on sphingolipids are affected. For less sensitive than pigs. The relative injury induced by aflatoxin (Barton example, glycosphingolipids are sensitivity in poultry is chicks > turkeys et al., 2000). Cyclopiazonic acid and necessary for the proper functioning > quail (Newberne and Rogers, 1981). aflatoxins frequently occur together of many membrane receptors, in groundnuts and maize, and the including those for some vitamins original outbreaks of turkey “X” (i.e. folate) and for the recognition disease in the United Kingdom in 1960 of numerous microbial pathogens may have involved both toxins (Cole, and microbial toxins (i.e. Shiga-like 1986). The most sensitive species for toxins and cholera toxin) (Merrill et

78 5.4 Deoxynivalenol 5.5 Zearalenone 5.6 Ergot alkaloids

In farm animals, the primary target Pre-pubertal female pigs are the The vasoconstrictive properties organ for DON toxicity is uncertain. most susceptible farm animal to of ergot alkaloids are the primary The reason is that the most sensitive the estrogenic effects of ZEA. The cause of problems in farm animals. effects are reduced weight gain sensitivity of pigs may be due to Sensitive species are those that in the mouse, presumably due to a higher affinity of their estrogen graze on pasture grasses (especially reduced feed intake, and feed refusal receptors for α-zearalenol (Fitz- tall fescue) or consume feeds and emesis in pigs (WHO, 2001). patrick et al., 1989; Fink-Gremmels comprised of small seed grasses There is evidence that feed refusal and Malekinejad, 2007). Cattle and (such as ryegrass). Cattle are and emesis are due to a central sheep are much less sensitive than probably the most sensitive, followed serotoninergic effect. Cattle, sheep, pigs, and poultry are considered to by sheep and horses. Environmental and poultry are resistant to the be resistant (Haschek et al., 2002). factors (especially temperature) are emetic effects of DON, but reduced Cycling mares also appear to be very important in determining the feed intake is seen at 10–20 mg/kg relatively insensitive to the estrogenic nature of the observed effects in diet in ruminants (Osweiler, 2000). effects of ZEA at low doses cattle (Raisbeck et al., 1991; Oliver, Horses are resistant, but shrimp (equivalent to natural contamination) 2005). are very sensitive to the effects on (Juhász et al., 2001). An interaction body weight gain, whereas dogs and between ZEA and oxytocin (an ergot cats are also sensitive to the emetic alkaloid derivative) has been reported effects of DON (WHO, 2001). DON in pigs (Alexopoulos, 2001). Grains and ZEA frequently occur together, contaminated with DON are frequently making exposure to both likely. also contaminated with ZEA. CHAPTER 5 CHAPTER

Chapter 5. Effects in food-producing animals 79 References

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