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CHAPTER 2 Literature Review
2.22 ANIMAL DISEASES ASSOCIA TED WITH CONSUMPTION OF FUMONISIN Bl
indicated that a cytotoxic/proliferative response is required for cancer induction, and that a no-effect threshold exists for cancer induction. The mechanisms proposed for cancer induction include the possible role of oxidative damage during initiation, the disruption of lipid metabolism, integrity of cellular membranes, and altered growth-regulatory responses as important events during promotion (Gelderblom et al., 2001).
Short term in vivo studies have shown that FBI mimics genotoxic carcinogens with respect to the induction of resistant hepatocytes in rat liver (Gelderblom et al., 1992; 1994). This was substantiated by observations that FBI induces GGT and PGST, which are accepted histological markers for putative pre-neoplastic lesions initiated by genotoxic carcinogens.
It is unclear whether the characteristic enzyme phenotype that is associated with the fumonisins in rats indicated an increase in cell proliferation is also likely to playa role in the induction of the "resistant phenotype" as hepatotoxicity, and resultant regenerative cell proliferation is a prerequisite for initiation (Gelderblom et al., 1994). The only difference noticed thus far in the induction of the resistant phenotype between the fumonisins and other genotoxic carcinogens, lies in the kinetics of the cancer initiation step.
2.22 ANIMAL DISEASES ASSOCIA TED WITH CONSUMPTION OF
(Kellerman et al., 1990; Wilson et al., 1992; Ross et al., 1993). Equine leukoencephalomalacia is characterised by liquefactive necrosis of the cerebral hemispheres, causing damage to vascular endothelium of the eNS and, in some cases, hepatocellular necrosis and vacuolisation. The clinical signs associated with the neurologic form of ELEM in horses include apathy, lethargy, head pressing, drowsiness, pharyngeal paralysis, blindness, staggering, hyper-excitability, seizures and eventual recumbency.
Once animals show the neurological signs, death usually occurs within 48-72 hours. If an animal survives the acute syndrome, neurological deficits are observed. The signs associated with the hepatic form include petechial or ecchymotic haemorrhages of the mucous membranes, icterus, oedema of the head and neck, decreased appetite, depression, lingual paralysis, clonic convulsions, and coma. On post-mortem examination, the classic finding is grey to brown areas of malacia and cavitation of the white matter of the cerebral hemisphere. It is usually unilateral, but may be asymmetrically bilateral. Histologically, there is marked, multi focal, liquefactive necrosis, multifocal vascular congestion, and perivascular haemorrhage throughout the white matter of the cerebrum.
Equine leukoencephalomalacia concurrent with significant liver disease was observed in horses and ponies fed feeds naturally contaminated with fumonisins at low concentrations (Wilson et al., 1992; Ross et aI., 1993). The development of brain lesions in the absence of major liver lesions does not preclude biochemical dysfunction in non-brain tissue from contributing to the brain lesions. The length of exposure, levels of contamination, individual animal differences, previous exposure, or pre-existing liver impairment contribute to incidence of clinical disease (Ross et al., 1993). Elevated serum enzyme levels indicative of liver damage (Wilson et al., 1992) are preceded by elevation in the serum Sa: So ratio (Wang et al., 1992; Riley et al., 1997). Serum enzyme levels often return to near normal concentrations, but usually increase markedly immediately prior to, or at the onset of behavioural changes (Kellerman et al., 1990; Wang et al., 1992; Wilson et al., 1992; Ross et al., 1993; Riley et al., 1997). Marasas et al. (1988a) have suggested that high dosage levels of fumonisins induce fatal hepatotoxicity with mild brain lesions, whereas low dosage levels cause mild hepatotoxicity and severe brain lesions.
The causes ofELEM after FBI dose may be divided into direct and indirect effects. Direct action may be mediated by the presence of Sa in brain. An indirect effect of FB I is also possible because FBI-induced hepatotoxicity and nephrotoxicity in rats, disruption of
barrier function of cultured endothelial cells, and damage to the cerebral blood vessels have been reported. Alteration of blood vessels in the CNS and/or disruption of the BBB may have effects on the transfer of FBI or Sa in brain tissue (Kwon et al., 1997a).
Leukoencephalomalacia was induced in two horses by the oral administration of FB I. A filly received 59.5 mg.kg-I of a 50% preparation of FBI isolated from corn cultures of F moniliforme MRC 826, administered in 21 doses of 1.25-4 mg.kg-I over 33 days (the other 50% was inorganic matter that co-eluted during purification), and a colt received 44.3 mg.kg-1 of95% pure FBI in 20 doses of 1-4 mg.kg-1 in 29 days. Gross necropsy of the filly revealed a sunken area (2cm in diameter) in the lateral part of the anterior frontal lobe of the left cerebral hemisphere. The white matter on the cut section of this focus was softer than normal and reddish-brown. Microscopic examination revealed necrosis of the white matter, numerous macrophages, aggregates of mineralisation, and small haemorrhages. At the periphery of the necrotic area, the blood vessels showed hypertrophy and hyperplasia of endothelial cells, fibrinoid changes of their cell walls, and perivascular mononuclear cell infiltration. The white matter close to the focal lesion had mild status spongiosis and mild to moderate proliferation of astrocytes. Necropsy of the colt showed swelling of the cerebral hemisphere and flattening of the gyri. A yellowish-brown focus was seen in the subcortical white matter of the left dorsal frontal lobe, and extended posteriorly to the occipital lobe. A smaller, gelatinous focus was found in the white matter of the right occipital lobe. Microscopic examination of the lesions revealed partial loss of cellular detail of the white matter, swelling and proliferation of astrocytes, infiltration of macrophages, and swelling ofaxons. The blood vessels around the foci had hyperplasia and hypertrophy of endothelial cells, as well as perivascular oedema. The white and grey matter of the rest of the left side of the brain showed moderate oedema, and the right side showed only a mild oedema. These authors concluded that these results unequivocally prove that FBI can induce LEM in horses (Kellerman et al., 1990). There is no specific therapy for ELEM. By the time clinical signs are noted, it is usually too late in the course of the disease. Removal of the contaminated feed from susceptible animals is very important and avoidance is the only way to prevent the disease.
2.22.2 Porcine pulmonary oedema syndrome
Kriek et al. (1981) were the first to report porcine pulmonary oedema (PPO) syndrome.
When culture material of F. verticillioides (MRC 826) was fed to horses, pigs, sheep, rats and baboons; lung oedema occurred only in pigs. Clinical signs ofPPO typically occur two to seven days after pigs consume diets containing large amounts of fumonisins over a short period of time. Clinical signs include dyspnoea, weakness, cyanosis and death (Kriek et aI., 1981; Osweiler et aI., 1992; Casteel et aI., 1993; 1994; Diaz and Boermans, 1994; Rotter et al., 1996; Fazekas et aI., 1998; Gumprecht et aI., 1998). At necropsy, the animals exhibit varying degrees of interstitial and interlobular oedema, with pulmonary oedema and hydrothorax (Colvin and Harrison, 1992; Colvin et aI., 1993). It has been hypothesised that cardiovascular alterations are a consequence of sphingoid base induced inhibition of L-type calcium channels (Smith et aI., 1996), and that cardiovascular dysfunction in pigs, subsequent to increased free sphingoid base concentration in the heart, is the cause of PPO (Haschek et aI., 1995; Smith et aI., 1996; 1999;
Haschek-Hock et aI., 1998).
2.22.3 Vervet monkeys
Riley et al. (1996) recommended that quantitative detection of high concentrations of free Sa in urine, serum or tissues be used in conjunction with other clinical tools in situations where toxicity to animals resulting from exposure to fumonisins is suspected.
Shephard et al. (1996b) studied the Sa:So ratio in serum of Vervet monkeys over 60 weeks.
These animals consumed diets such that their total daily fumonisin intake was -0.3 and 0.8 mg. kg-l bodyweight per day of F. moniliforme culture material. Serum Sa levels in the experimental groups (mean of 219nM and 325nM, respectively) were significantly elevated above the levels in controls (mean 46nM; p=O.02). The Sa:So ratio was significantly elevated from a mean of 0.43 in the control group to 1.72 and 2.57 in the experimental groups, respectively (p=0.003). Hence, the disruption of sphingolipid biosynthesis in vervet monkeys induced by fumonisins in their diet, can effectively be monitored in the serum as an elevation of the Sa: So ratio (Shephard et aI., 1996b).