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mycotoxicosis in companion animals

Clinical implications of mycotoxicosis in companion animals

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Mycotoxins are secondary metabolites of fungi, which are also commonly known as molds. Fungi that produce mycotoxins of veterinary importance grow on a variety of substrates including grains and grain by-products that may be used as ingredients in pet foods. These fungal metabolites do not serve any known physiologic function in the mold itself. There are several of these secondary fungal metabolites produced by a variety of molds growing on a variety of grains in many climatic regions of the world. Many of these mycotoxins are potent toxins affecting humans, animals, birds and fish. Some of these mycotoxins are produced individually, but Penicillium and Fusarium molds produce multiple mycotoxins simultaneously. This paper will focus on clinical effects of mycotoxins that have caused disease or have high probability of causing disease in pets. These are aflatoxins, deoxynivalenol (vomitoxin), ochratoxin, citrinin, roquefortine and penitrem A. Unfortunately, studies of mycotoxins have almost exclusively addressed individual mycotoxins, which ignores the real field condition where multiple mycotoxins are co-produced.


Aflatoxins

Aflatoxins are highly toxic and carcinogenic metabolites of fungi of genuses Aspergillus and Penicillium. The three major fungi that produce these mycotoxins are Aspergillus flavus, Aspergillus parasiticus, and Penicillium puberulum. These fungi grow on a whole variety of grains, peanuts, and cottonseed and are most common in tropical or subtropical regions. Under ideal conditions of moisture, temperature, oxygen/carbon dioxide, and acid-base balance, these fungi produce four major aflatoxins namely, aflatoxin B1, aflatoxin G1, aflatoxin B2, and aflatoxin G2, listed in the order of potency and abundance (Figure 1).


Figure 1. Structures of the aflatoxins.


Canine aflatoxicosis was first reported in 1952 (Newberne, 1973). Veterinarians were investigating a liver disease called ‘hepatitis X’ in the southeastern United States, which was observed in dogs fed moldy contaminated feed. Experimental feeding of dogs with a commercial dog food reproduced the disease in 1955. In 1966 the disease was reproduced for the first time using purified aflatoxins (Ketterer et al., 1975). Since that time, there has been extensive research that has led to an understanding of the effects of aflatoxins in animals, birds, and humans.

All animals, birds, and fish are susceptible to aflatoxins, with birds and fish being the most sensitive. In pets (dogs, cats, birds and fish), the liver is the primary target organ of aflatoxins. In addition, aflatoxins are immunosuppressive and nephrotoxic. Both dogs and cats are extremely sensitive to aflatoxins. The LD50 of aflatoxin B1 in dogs and cats is 0.5-1.0 mg/kg and 0.3-0.6 mg/kg, respectively. In this regard, dogs and cats are as sensitive to aflatoxins as ducks and rabbits, which have traditionally been regarded as the most sensitive species. Feeds containing aflatoxin B1 concentrations of 60 ppb or greater have caused outbreaks of aflatoxicosis in companion animals (Bastianello et al., 1987; Ketterer et al., 1975; Newberne, 1973). As with other toxic compounds, the sensitivity of companion animals to aflatoxins depends on individual susceptibility, which in turn depends on age, hormonal status (pregnancy) and nutritional status among other factors.

For example, young dogs are more sensitive to aflatoxin B 1 toxicity than adults. Among pet species, birds and fish are the most sensitive to aflatoxins. Feed containing as low 5 ppb aflatoxin B1 can cause acute mortality in birds and fish.

Several combined factors, including improved analytical methods and screening of grains for aflatoxins have tremendously reduced the incidence of aflatoxicosis in companion animals. In the 1990s there was only one documented case of aflatoxicosis in USA. In this particular case, dogs consumed food containing 100-300 ppb aflatoxin B1 for 3-4 months (Devegowda and Castaldo, 2000). In the 1980s, there was also only one documented case of aflatoxicosis in canines. In the latter case, several dogs in South Africa died suddenly or following a short clinical course (Bastianello et al., 1987). Analysis of various batches of feed revealed 100-300 ppb aflatoxin B1. In contrast, several cases of aflatoxicosis in dogs were reported in, or prior to, the 1970s including one where several dogs died in New York after being fed a commercial diet containing 60 ppb aflatoxin B1 (Greene et al., 1977).


CLINICAL AFLATOXICOSIS

The clinical syndrome of canine aflatoxicosis can be categorized as acute, subacute, or chronic. Acute aflatoxicosis occurs when dogs are given feed containing large amounts of aflatoxin B1 (>1 ppm in diet). Clinical signs of acute aflatoxicosis in dogs include sudden death. Usually however, affected animals will vomit within hours of ingesting the contaminated feed. They then become anorexic, severely depressed, drink increased quantities of water more frequently (polydipsia), and have increased urine volume output (polyuria). Death will occur within three days of the onset of clinical signs.

Because the liver is the primary target organ, the animal may be jaundiced and urine will have increased bilirubin. There is a significant increase in serum liver enzymes especially AST, ALT, and LDH. Another significant observation in acute canine aflatoxicosis is disseminated intravascular coagulation (DIC). This usually occurs as a terminal event. Severe bleeding occurs in body cavities and in the submucosal and subserosal surfaces.

There is hematochezia, and dogs may vomit blood (Greene et al., 1977). The bleeding disorder is characterized by hypofibrinogenemia, increased one-stage prothrombin times (PT), prolonged activated partial thromboplastin times (PTT) and by severe thrombocytopenia. Because of bleeding, dogs are usually anemic. Fever is not a characteristic of aflatoxicosis in companion animals.

Subacute cases of aflatoxicosis in companion animals occur following exposure to moderate amounts of aflatoxin B1 over a few weeks (2-3 weeks). Affected dogs or cats will present with lethargy, anorexia, polyuria, polydipsia, elevated liver enzymes, and jaundice. Death usually follows DIC. Dietary aflatoxin B1 concentrations of 500-1000 ppb may cause these signs.

Chronic aflatoxicosis is caused by consumption of diets containing small to moderate amounts of aflatoxins continuously or intermittently. Dietary concentrations of aflatoxin B1 between 50-300 ppb over a period of 6-8 weeks may cause chronic aflatoxicosis. Dogs or cats will show clinical signs similar to subacute aflatoxicosis with a prominence of jaundice.

The best way to distinguish between acute, subacute, and chronic aflatoxicosis is by histopathology (Bastianello et al., 1987). Grossly, in acute aflatoxicosis the liver is swollen. Histologically there is severe fatty degeneration of the liver with distinct vacuolation of hepatocytes. Bile canaliculi are distended with bile. The portal and central veins are congested. In subacute cases, the liver may or may not be swollen. Histologically, the distinctive feature is bile duct proliferation. There is also evidence of liver regeneration. In chronic cases there is extensive fibrosis of the liver. As in subacute cases, there is bile duct proliferation. Grossly, livers of chronically affected dogs are small in size and shrunken because of fibrosis.

Chronic intake of low amounts of aflatoxin B1 in feed (20-100 ppb) may also cause immunosuppression. This is followed by nonspecific clinical signs including increased susceptibility to viral, bacterial, fungal, or parasitic infections. Immunosuppression is due to the ability of aflatoxins to cause low white blood cell counts and to reduce antibody production. Immunosuppressed pets will not respond to regular immunizations.

Cancer is another long-term effect of aflatoxins. Exposure to a large amount of aflatoxins has the potential to lead to liver cancer in pets that recover from the effects of acute, subchronic, or chronic aflatoxin exposure. Therefore, exposure to aflatoxins can have long-term health implications. Clinical cases of aflatoxicosis have been reported in dogs, pet birds and fish. It is also important to remember that aflatoxins can be produced in storage in the owner’s home if feed is not stored under ideal conditions. As a precaution, it is best to buy moderate quantities of pet food which will not last for months if the storage conditions are inadequate or questionable.


Deoxynivalenol (Vomitoxin)


Deoxynivalenol (DON) is a member of the trichothecene group of mycotoxins produced by Fusarium fungi (Figure 2). Fusarium fungi are most prevalent in temperate regions of the world. This mycotoxin was first detected in 1972 in corn that caused vomiting and feed refusal in pigs. Clinical signs of acute DON toxicity in most species, including companion animals and pet birds, include skin irritation, feed refusal, vomiting/ regurgitation, diarrhea, hemorrhages, abortion (animals), and death.

Biochemically, DON inhibits protein and DNA synthesis. In this regard, DON is immunosuppressive (may predispose affected animals to infectious diseases) and causes reduced growth rate. In swine diets DON is toxic in concentrations >2ppm. Data on the toxicity of DON in companion animals are scarce. There is only one documented study of DON toxicity in dogs (Hughes et al., 1999) and this summary is based on findings from this study.


CLINICAL RESPONSES TO DEOXYNIVALENOL

Hughes et al. (1999) showed that extrusion processing does not destroy DON. Therefore, DON-contaminated corn will result in presence of vomitoxin in feed. The researchers exposed groups of dogs to manufactured feed containing DON concentrations ranging from 0-10 ppm. The most significant finding was feed refusal in dogs given feed containing greater than 4.5 ppm DON. Cats were less sensitive than dogs; and in this species, feed refusal was observed at DON concentrations greater than 7.7 ppm DON. These results suggest that dogs may be as sensitive as pigs (the most sensitive animal) to DON with regard to feed refusal. Another finding in dogs and cats given DON-contaminated feed was vomiting. The net effect of these clinical responses to vomitoxin in dogs was reduced feed intake and loss of body weight. If pets are presented with hemorrhagic gastroenteritis, feed refusal and loss in body weight when fed cereal diets, DON should be on the rule-out list. As mentioned earlier, Fusarium molds have a tendency to produce multiple toxins including T-2, HT-2, and zearalenone. T-2 and HT-2, which are very irritating mycotoxins, have the potential to synergistically interact with DON.




Figure 2. Toxins produced by Fusarium species.


Ochratoxin A

The ochratoxins are a group of mycotoxins that contain an isocoumarin moiety linked to L-ß-phenylalanine (Figure 3). They are produced by Penicillium and Aspergillus molds. The major producers are P. verrucosum and A. ochraceus (alutaceus), which are species of storage fungi but can also grow in the field. Therefore these fungi have the potential to produce ochratoxins in a pet owner’s home after purchase of feed if the feed is not stored properly. These fungi are most prevalent in Europe. Ochratoxin A (OA) has been isolated from cereals, especially corn, oats, wheat and barley.

Feed surveys of natural grain contamination in North America and Europe have revealed OA concentrations ranging from 5-27,000 ppb. In Europe, OA is implicated in Balkan endemic nephropathy. It is also a potent rodent carcinogen.


Figure 3. Structure of ochratoxin A.


CLINICAL RESPONSE TO OCHRATOXIN A

The author was unable to find a dietary toxic level of OA in dog feed. The most extensive study of OA toxicosis in dogs was by Kitchen et al. (1977a,b,c); and this summary is based on findings in that study. As in other species, the kidney is the primary target organ of OA toxicosis in dogs.

Clinical signs of OA toxin toxicosis in dogs include anorexia, emesis, retching, tenesmus, polydipsia, polyuria, and prostration. The minimum oral toxic dose of OA was 0.2 mg/kg. Immediately after dosing dogs became restless, paced, and vomited within 15-20 minutes. Ochratoxin A toxicosis also increased serum lactic dehydrogenase. In urine there was slight proteinuria. Other clinical signs noted in dogs given OA included tonsillitis and melena.

Gross findings in dogs given 0.2 to 3.0 mg OA/kg included severe mucohemorrhagic enteritis of the cecum, colon, and rectum. Lymph nodes were enlarged, edematous, and hyperemic. Histologically, OA caused degeneration and desquamation of tubular epithelial cells, primarily in the straight segment of the proximal tubule. In addition, OA caused necrosis of lymphoid tissues in the spleen, tonsil, thymus, and peripheral lymph nodes.


Citrinin

Citrinin is a metabolite of fungal species of the genera Penicillium and Aspergillus (Figure 4). Citrinin may be co-expressed with OA because it is produced by similar types of fungi. The primary target organ in citrinin toxicosis is the kidney. However citrinin is at least 10 time less nephrotoxic than OA. Citrinin is a very strong emetic in dogs, which is a protective mechanism in this species. It is very unlikely that dogs will be poisoned by citrinin alone naturally because high amounts of this toxin will induce emesis and feed refusal. Dogs given citrinin experimentally had tenesmus and prominent serous nasal discharge and lacrimation (Carlton et al., 1974; Kitchen et al., 1977a). If dogs are offered food containing a high amount of citrinin the most prominent expected clinical sign is weight loss because they will vomit and refuse to eat. Oral experimental citrinin toxicity studies in dogs have involved use of gelatin capsules. In one study, two dogs given 40 mg citrinin/kg daily were found dead on day 3 and the rest were humanely killed when they became moribund. These dogs had elevated blood urea nitrogen, decreased specific gravity, glucosuria, mild proteinuria and urinary casts. At necropsy, prominent gross alterations were found in kidneys, which were pale and swollen. Histologic changes were characterized mainly by necrosis of renal tubular epithelium.


Figure 4. Structure of citrinin.


Tremorogenic mycotoxins

Penitrem A and roquefortine are two tremorogenic mycotoxins of importance in companion animals. Penitrem A is produced by fungi of the genus Penicillium, especially P. crustosum. This fungus grows on cereal grains and on rotting organic matter. Roquefortine is also produced by fungi of the genus Penicillium. Originally it was identified to be produced by P. roqueforti, a fungus used in the manufacture of blue cheeses, but several other species of Penicillium have recently been shown to produce this mycotoxin on several substrates including grains, spoiled soups, and garbage.

They can therefore be regarded as storage fungi because they can grow on any kind of improperly stored pet food . In almost all cases, penitrem A and roquefortine are produced concurrently. Because the fungi that produce both mycotoxins grow on cereals used in the manufacture of food for companion animals, it is important that feed manufacturers are aware of the dangers of these mycotoxins.


CLINICAL TREMOROGENIC MYCOTOXICOSIS

Clinical signs associated with tremorogenic mycotoxicosis in dogs include muscle tremors, ataxia, seizures and death (Lowes et al., 1992; Puls and Ladyman, 1988; Hocking et al., 1988; Hayes et al., 1976). This disease is often misdiagnosed as strychnine poisoning or poisoning by pesticides and other compounds which cause tremors and seizures in dogs. Penitrem A is a potent tremorogenic mycotoxin. In the only published experimental study, the lowest dose of 0.125 mg/kg caused clinical signs of penitrem A toxicosis in dogs (Hayes et al., 1976). Large oral doses of penitrem A (>2.5 mg/kg) cause hepatic necrosis with elevated liver enzymes especially LDH and ALT. There is also increased serum creatinine kinase, most likely as a result of muscle tremors. The mechanisms of action of these tremorgenic mycotoxins have not been investigated. This is unfortunate because roquefortine and penitrem A poisoning is presently the most common mycotoxicosis of pets encountered in clinical practice.


References

Bastianello, S.S., J.W. Nesbit, M.C. Williams and A.L. Lange. 1987. Pathologic findings in a natural outbreak of aflatoxicosis in dogs. Ondesport J. Vet. Res. 54:635.

Carlton, W.W., G. Sansing and G.M. Szczech. 1974. Citrinin mycotoxicosis in beagle dogs. Food Cosmet. Toxicol. 12:479.

Devegowda, G., and D. Castaldo. 2000. Mycotoxins: Hidden killers in pet foods. Is there a biological solution? In: Proceedings of the Technical Symposium on Mycotoxins, Pet Food Institute, Chicago IL, 2000.

Greene, C.E., J.A. Barsanti and B.D. Jones. 1977. Disseminated intravascular coagulation complicating aflatoxicosis in dogs. Cornell Vet. 67:29.

Hayes, A.W., D.B. Presley and J.A. Neville. 1976. Acute toxicity of penitrem A in dogs. Toxicol. Appl. Pharm. 35:311

Hocking, A.D., K. Holds and N.F. Tobin. 1988. Intoxication by tremorogenic mycotoxin (penitrem A) in a dog. Aust. Vet. J. 65:82.

Hughes, D.M., M.J. Gahl, C.H. Graham and S.L. Grieb. 1999. Overt signs of toxicity to dogs and cats of dietary deoxynivalenol. J. Anim. Sci. 77:693.

Ketterer, P.J., E.S. Williams, B.J. Blaney and M.D. Connole. 1975. Canine aflatoxicosis. Aust.Vet. J. 51:355.

Kitchen, D.N., W.W. Carlton and J. Tuite. 1977a. Ochratoxin A and citrinin induced nephrosis in beagle dogs: I. Clinical and Clinicopathological features. Vet. Path. 14:154.

Kitchen, D.N., W.W. Carlton and J. Tuite. 1977b. Ochratoxin A and citrinin induced nephrosis in beagle dogs: II. Pathology. Vet. Path. 14:261.

Kitchen, D.N., W.W. Carlton and E.J. Hinsman. 1977c. Ochratoxin A and citrinin induced nephrosis in beagle dogs: III. Terminal renal ultrastructural alterations. Vet. Path. 14:392.

Lowes, N., R.A. Smith and B.E. Beck. Roquefortine in stomach contents of dogs suspected of strychnine poisoning in Alberta. 1992. Can. Vet. J. 33:535.

Newberne, P.M. 1973. Chronic aflatoxicosis. JAVMA 163:1262. Puls, R. and E. Ladyman. 1988. Roquefortine toxicity in dogs. Can. Vet. J. 29:569.



Author: WILSON K. RUMBEIHA
Animal Health Diagnostic Laboratory, Michigan State University, East Lansing, Michigan, USA


(2666)
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Edgar Islas
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Queretaro, Queretaro de Arteaga, Mexico
Doctor of Veterinary Medicine
Re: Clinical implications of mycotoxicosis in companion animals
05/23/2007 | Great information. I write from Mexico, one of the main challenges is to count with the service of laboratory capable of determining the whole variety of mycotoxins affecting petfood.
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Dr. Karki Kedar
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, Bagmati, Nepal
Doctor of Veterinary Medicine
Re: Clinical implications of mycotoxicosis in companion animals
07/01/2009 | Thanks for very exciting and new information
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