Plant Mycotoxins: Impacts on Health and Production: Australia and New Zealand
Plant toxicoses represent a challenge for producers, researchers, and clinicians. As we have reduced the risks of transmissible and metabolic diseases of cattle, the effects of mycotoxins on performance have become more apparent. Simply, there is a much greater clarity with which the adverse effects of mycotoxins can be observed, when major disorders of cattle are removed.
Arguably, the mycotoxicoses that have been recognized most in Australia and New Zealand are the large group of potential toxins associated with the ryegrass endophyte Neotyphodium lolii. Another mycotoxicosis often associated with grazing ryegrass, facial eczema has also been well described and perennial ryegrass, a disorder of more extensive production regions is also well characterized. However, there is a large number of less well described toxicities that are associated with fungal mycotoxins including Acute Bovine Liver Disorder (ABLD), other recently described hepatotoxic agents, and unusual disorders created by synergistic effects of fungi and bacteria. Surveys of mycotoxin prevalence have identified a remarkably high prevalence of potentially toxic agents in pastures and conserved forages (Reed and Moore, 2009, Loudon et al., 2016 unpublished). Mycotoxicoses conform to a few general principles, including: 1) the cause may not be immediately identified, 2) they are not transmissible from one animal to another, 3) treatment with therapeutic agents or antibiotics has little effect on the course of the disease, 4) outbreaks are often seasonal, because particular climatic sequences may favor fungal growth and toxin production, 5) epidemiological studies indicate a specific association with a particular feed, and 6) examination of feedstuffs may reveal the presence of usually large numbers of fungi; however, this does not necessarily indicate that mycotoxins have been produced (Schiefer, 1990). This paper briefly reviews the effects of ryegrass endophytes, compares aspects of hepatotoxic agents, and highlights the range of toxins that have been identified in Australian pastures.
There are a number of excellent reviews of the effects of ryegrass endophyte on cattle and sheep; however, the complex interactions between plant cultivar and endophyte do not readily allow extrapolation of research findings to field situations and vice-versa.
Production of toxins is greatest when plants are stressed and in summer. There are seasonal changes in the nutritional value and environment that confound field observations of effects of ryegrass toxins on production in cattle. Specifically, ryegrass nutritional quality is poor at the same time as toxin levels are highest. Further, there are possible effects of endophyte toxins and pasture sward composition, specifically reduced clover content and grazing patterns that reduce intake of feed, that make it difficult to measure the effect of specific toxins. Lastly, the role of prolactin (PRL) in cattle in milk production is largely confined to periods during growth and just before calving. Ergovaline acts to decrease PRL concentrations and this may have very substantial effects on production of susceptible cattle. However, such effects will be difficult to detect in the field. Despite these difficulties, there is ample evidence that infection of ryegrass with specific strains of N. lolii has the potential to be a very significant factor reducing dairy production in Australia. This paper provides a review of evidence supporting observed and suggested effects of N. lolii on dairy cattle. Problems that impair effective estimation of the economic and health effects of ryegrass endophyte are discussed and an opinion is provided on the possible magnitude of the toxicosis.
The papers identified in Table 1 have significant flaws in demonstrating a causal relationship between ryegrass endophyte and lower milk production. These flaws include, confounding between pasture composition and outcome. Specifically, pasture swards used in the studies were not identical except for the presence of N. lolii. Often swards differed in botanical composition (Table 1), especially clover content that would have altered digestibility and feed value of dry matter intake. Milk production generally increases in association with increased clover content of pasture. Researchers and labor used in projects were not blinded from group allocation, i.e. they were aware which pasture was which. A lack of documented randomization of cattle and internal replication of pastures means that the observations were more like a comparison than a truly randomized study.
Nonetheless, papers in Table 1 provide significant evidence of associations between the presence of grass infected with N. lolii, especially wild type variants of the fungus, and decreased milk production. There are, despite weaknesses present, a number of strengths of evidence also present in these data. There is also evidence of an underlying biological cause for clinical signs observed. Physiological mechanisms by which N. lolii infection and specifically ergovaline may decrease milk production, that is by vasoconstriction (constriction of blood flow) and lowered PRL concentrations, have been demonstrated in randomized controlled studies.
Fletcher (1998) suggested that concentrations of ergovaline that exceed 0.5 ɸg per gm of dry matter can have marked effects on the health and productivity of livestock. However, conclusions on a dose-response seem premature in the context of the number of potentially adverse effects of ergovaline and the sensitivity of cattle at different stages of development to the ergopeptine alkaloid. It is possible that doses < 0.5 ɸg per gm of dry matter may have a negative effect in some sensitive cattle, for example heifers or cows before calving.
Milk production is strongly influenced by mammary blood flow (Bequette et al., 1998). The action of ergovaline as a vasoconstrictor, therefore, may influence milk production by reducing blood flow to the mammary gland and splanchnic bed, and by increasing heat stress. As important to the industry is the potential for ergovaline, a dopamine agonist, to decrease PRL concentrations. Prolactin does not play an important role in maintenance of lactation in dairy cattle, but is a major mediator of mammary tissue differentiation and development before lactation. In my opinion, the potential for ergovaline from ryegrass to influence mammary development and reduce milk production potential in autumn calving cows, in spring calving cattle fed silage and in growing heifers is very substantial and may explain some of the lower milk production observed in Australasia. At present, it is impossible to determine the amount of loss, because critical studies are not available.
There is a vast array of potential toxins, including neurotoxic alkaloids that may be present in ryegrass infected with N. lolii (Lane, 1999). One of the challenges in researching this area is that the presence of a causal agent may not always be demonstrated during a study (e.g. Auldist and Thom, 2000, Table 2). Further, it can be argued that causal agents may be present that have either not yet been identified in the example of neurological disorders and immune suppression or have not been, to date, associated with specific conditions observed in cattle. One example is the lysergyl group alkaloids that could influence behavior of cows.
While a comprehensive review of other putative effects of endophyte toxins was not conducted, there is ample evidence of effects of the toxins on health (Table 2). Strong evidence, from many sources, is available on the effects of Lolium alkaloids on neurologic disorders and especially grass staggers. There is also evidence that other neurologic disorders may arise. Behavioral problems with either Lolitrem or other neurotoxic alkaloids are regularly observed by producers. These toxins can be present at the same time as Fusarium toxins are very prevalent (Loudon et al., 2016 unpublished).
The evidence of effects of endophyte toxins on immune function, polio-encephalomalacia (PEM), fat necrosis, and somatic cell count are weak, although potential pathways exist for effects to be exerted.
There are few studies in dairy cattle on reproductive performance in relation to endophyte toxins, but basic studies in beef cattle with fescue endophytes and ergovaline provide evidence of potential to cause harm. However, the evidence is more robust in regard to the adverse actions of the Fusarium fungal toxin Zearalenone on reproductive performance. There is field evidence of lower fertility in cows and heifers, of physiological effects consistent with pathways that impair fertility and in vitro and intervention studies (Weaver et al., 1986) that show impaired fertility. There is evidence from surveys conducted by Reed and Moore (2009) who examined 4 groups of pastures submitted from cattle and sheep farms of a substantial risk to exposure of cattle to zearalenone. Zearalenone exceeded the tolerance concentration > 1.0 mg/kg DM in 3 of 22 winter pastures; and 12 of 24 samples of silage that were submitted by farmers for nutritional assessment but were not suspected of toxicity in the range 1.0–80 mg/kg. In a separate investigation of 28 feed samples submitted for mycotoxin screening by nutritionists and veterinarians, zearalenone concentrations exceeded 1.0 mg/kg in 6 of 28 samples (Reed and Moore, 2009).
There is strong evidence that ergovaline and Lolitrem produced by N. lolii cause heat stress in cattle (Table 1). Lastly, there is moderate evidence of scouring, weight loss, selective appetite, lameness, and reduced clover content and again good physiological evidence for these putative effects. One remarkable case possibly supporting a role of ryegrass endophytes in scouring are observations and a trial of a Max P infected fescue and deaths in horses associated with marked edema of the bowel (Burke et al. 2009, Lean et al., unpublished).
It appears more likely that the potential effect of these toxins has been significantly underestimated than overestimated in our production system. It is clear from the magnitude of milk loss in some studies (Table 1) that the disorder may be of substantial magnitude in the summer and autumn and due to costs associated with behavioral problems. The potential for interactions between ergovaline and heat stress should not be under-estimated in the summer months, especially in irrigation districts. Of particular concern is the potential for ergovaline to influence mammary gland development, through effects around calving on dam and calf and during puberty and gestation in the heifer.
Photosensitizing and Hepatotoxic Syndromes
Perhaps the most recognized single mycotoxicosis in Australia and New Zealand is the facial eczema syndrome which is caused by sporidesmin intoxication produced from fungal spores of Pithomyces chartarum. This condition causes secondary photosensitization through hepatic damage, lowers milk production, and results in body weight loss. Pithomyces chartarum grows on litter at the base of pasture and sporulates profusely under warm, moist conditions in late summer and autumn. The toxicosis results in marked inflammation of the bile ducts caused by sporidesmin that, in turn, results in a failure to excrete phylloerythrin, a breakdown product of chlorophyll. The initial course of the disease is not dramatic; however, the resulting photosensitization can be severe and results in skin loss, edema of inflamed white pigmented areas, and decreased milk production. Chronic disorder is detectable by evaluation of gamma glutamyl transferase (GGT) and glutamate dehydrogenase (GDH) activities in blood (Collett, 2014). The hepatic pathology is markedly different to that of the other agents compared in Table 4. Surveys of GGT activities in cattle and monitoring of spore production indicate that the risk of cattle being exposed to this condition is very high in New Zealand and the condition is well-recognized in Australia.
Acute bovine liver disease, is an acute hepatopathy reported in beef and dairy cattle in southern Australia, but has yet to be described in New Zealand (Vermunt et al., 2010). The disorder has a high morbidity, which can exceed 50% and mortality is often 10 to 20% but can be as high as 50% (Vermunt et al., 2010). Peracute cases can be very depressed, recumbent, and die (Vermunt et al., 2010). In milder cases, the following signs may be observed: neurological signs, jaundice after 24 hours, severe photosensitization, weight loss, marked discomfort, dehydration, rumen stasis, bloated appearance, and photophobia (Vermunt et al., 2010).
The cause of ABLD is unknown, but the epidemiology suggests a mycotoxicosis. However, there are no known mycotoxins, with the exception of amatoxins from some mushroom species, that produce hepatic peri-portal necrosis (Lancaster et al., 2006). The histopathology of ABLD is unique and Gunn and Clarke (2003) suggest that the presence of peri-portal necrosis is required for a definitive diagnosis. Lancaster et al. (2006) produced a description of ABLD in Australia based on 15 clinical reports. Peri-portal necrosis in the liver was prominent and consistently present, leading to early death (Lancaster et al., 2006). There are no incidence or prevalence data for ABLD in Australia for this disorder. Outbreaks appear to be associated with recent rain, autumn, the presence of Cynosurus echinatus (rough dog’s tail) and calm, warm, sunny weather with heavy morning dews (Lancaster et al., 2006).
Recently, an outbreak of severe hepatic damage and photosensitization affected a herd in Tasmania (Golder et al., 2016 in press). There is evidence that the condition was not unique to the herd, but the outbreak was extremely severe with morbidity, based on the number of treated cases within 72 hours of clinical onset of 24.3% and 21.8% if based on cows with ≥20% milk drop between 72 hours before and after clinical onset. Nineteen cows from a herd of 678 died over the first 30 days of the outbreak. Within 2 days of ingestion of feed suspected of causing the outbreak cattle variably showed recumbency, per-acute photosensitization, inflamed coronary bands, conjunctival erythema, distress indicated by kicking at the flank, bruxism, discomfort, weight shifting, vocalization indicating pain, depression, low hung heads, and hunching, but no cattle died. Cattle later in the outbreak had severe erosions of skin, nasal epithelium, and intestinal mucosa. The photosensitization was very severe with damage to skin of the udder and unpigmented areas. Many cows affected badly developed mastitis associated with lesions near the teats. While the cattle had been treated with non-steroidal anti-inflammatory agents, the widespread epithelial lesions suggested the presence of an agent capable of causing epithelial erosion. The condition was associated with the presence of a leaf smut, Jamesdicksonia dactylidis, from a sample of Hordeum murinum (barley grass) which has not been previously reported in Tasmania but it is not known whether the smut produced toxins. Fifty-five mycotoxins were detected from the same sample of H. murinum obtained from the presumably contaminated pasture and B-trichothecenes, fumonisins, and zearalenone metabolites were detected in high concentrations. Ergot alkaloids were detected at medium concentration, while aflatoxins and ochratoxin A were not detected (Golder et al., 2016 in press).
Plant poisonings pose a challenge for diagnosis. Toxins, may not always be present or may not be well characterized, leading to difficulties in conducting studies on a dose-response basis. Interactions occur among potential toxic agents. Randomization, controlling for confounding effects (e.g. more fertile paddocks, effects on other plant species) and blinding are difficult when dealing with herds of lactating cows and the somewhat unique instances that lead to toxicity. Physiological studies demonstrate mechanism, but not necessarily magnitude of effect in the field. Notwithstanding these problems, it appears that there is ample evidence that ryegrass endophyte and other mycotoxins can be major factors limiting pastoral production.