Preliminary studies on toxic effects of cyclopiazonic acid alone and in combination with aflatoxin B1 in non-human primates

Jaśkiewicz, K.; Close, Pauline; Thiel, Pieter G.; Cole, Richard

doi:10.1016/0300-483x(88)90134-5

Cited by 18 publications

(7 citation statements)

References 12 publications

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“…In an accompanying experiment when CPA and a atoxin B 1 (AFB 1 ) were administered simultaneously, there was no indication of a synergistic effect when both toxins were administered. Animals treated with AFB 1 only developed more advanced liver lesions and died earlier than those that received high doses of CPA (Jaskiewicz et al 1988).…”

Section: Multiple Dose Studies With Cyclopiazonic Acidmentioning

confidence: 94%

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Review Article: Safety Assessment of the Mycotoxin Cyclopiazonic Acid

Burdock¹,

Flamm²

2000

Int J Toxicol

108

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Cyclopiazonic acid (CPA) is an indol-tetramic acid mycotoxin and is produced by the nearly ubiquitous molds, Aspergillus and Penicillium. CPA produced by these molds has been identified in a number of food sources (including, but not limited to, grain, legumes, meat, milk, and cheese) and from parasitic infections of man and other animals. Few incidents of CPA mycotoxicoses have been reported because of the benign nature of the intoxication, the small amounts present, and its effects may be disguised with concurrent aflatoxicosis (some toxicity data may have been generated using aflatoxin-contaminated CPA). CPA is absorbed in the gastrointestinal tract and following oral administration; it has a half-life of approximately 30 hours and is excreted largely unchanged in the urine and feces. Cyclopiazonic acid is not considered to be a potent acute toxin as its oral LD50 in rodents is in the range of 30 to 70 mg/kg. Multiple dose studies also show a range of effects in several species and among mammalian models, the pig appears to be the most sensitive with a no-observable-effect level (NOEL) in the range of 1.0 mg/kg/day. The preponderance of evidence from the rat and other test animals supports this dose as a defensible estimate of a no effect level. The target organs of CPA toxicity appear to be muscle, hepatic tissue, and spleen, with a localization in the former, although a more apparent toxic change in the latter two. The toxicity and symptoms of CPA poisoning can be attributed to its ability to alter normal intracellular calcium flux through its inhibition of the reticular form of the Ca2+-ATPase pump. CPA was not teratogenic in mice. CPA is not considered a carcinogen and the weight of evidence militates against its characterization as a mutagen. Despite CPA-induced pathological changes ascribed to the spleen or bursa of Fabricius, there does not appear to be an effect on the immune system. In vitro studies imply a potential immunomodulatory effect of CPA, but in all of those reports very high concentrations of CPA were required and none of these findings have been supported with in vivo studies. Therefore, based on a NOEL of 1 mg/kg/day and accounting for species variation, an appropriate acceptable daily intake (ADI) would be approximately 10 μg/kg/day or 700 μg/day. In the context of human exposure, if the uppermost limit of CPA found in cheese is 4 μg/g and the average individual consumes 50 g of cheese daily, this allows an intake of 200 μg, less than one third of a traditionally established ADI.

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Section: Multiple Dose Studies With Cyclopiazonic Acidmentioning

confidence: 94%

“…Monkeys. In a nonterminal pilot study with a single monkey, Jaskiewicz et al (1988) dosed a female vervet monkey with 1 mg CPA/kg per day ve times per week in gelatine intragastrically at the commencement. Thereafter, the dose was doubled every 3rd day to achieve 60 mg/kg/day.…”

Section: Multiple Dose Studies With Cyclopiazonic Acidmentioning

confidence: 99%

Review Article: Safety Assessment of the Mycotoxin Cyclopiazonic Acid

Burdock¹,

Flamm²

2000

Int J Toxicol

108

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“…CPA is not very acutely toxic (Morrissey et al, 1985;Purchase, 1971;Van Rensburg, 1984). CPA toxicity has been studied in several species including rats (Morrissey et al, 1985;Norred et al, 1985;Purchase, 1971), mice (Nishie et al, 1987), pigs (Lomax et al, 1984), dogs (Nuehring et al, 1985), guinea pigs Richard et al, 1990), monkeys (Jaskiewicz, et al, 1988), chickens (Balachandran and Parthasarathy, 1996;Dorner et al, 1983;Gentles et al, 1999;Kubena et al, 1994;Kumar and Balachandran, 2009;Malekinejad et al, 2011;Norred et al, 1988;Venkatesh et al, 2005a,b), laying hen (Cole et al, 1988) and lactating ewe (Cole et al, 1988).…”

Section: Cyclopiazonic Acid Toxicity Hazard Assessment Of Cyclopiazonmentioning

confidence: 99%

Cyclopiazonic acid: 50th anniversary of its discovery

Ostrý¹,

Toman

Grosse

et al. 2018

WMJ

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In 1968, the mycotoxin cyclopiazonic acid (CPA) was first discovered and characterised as a chemical substance. Within the following five decades, much has been learned from the results of CPA research. CPA is produced by several Penicillium species (P. griseofulvum, P. camemberti, P. commune, P. dipodomyicola) and Aspergillus species (A. flavus, A. oryzae and A. tamarii). It is widespread on naturally contaminated agricultural raw materials. CPA has been reported to occur in food commodities (e.g. oilseeds, nuts, cereals, dried figs, milk, cheese and meat products) and to possess toxicological significance. CPA is also frequently detected in peanuts and maize; the presence of CPA and aflatoxins in maize and peanuts contaminated with A. flavus suggests that synergism may occur. CPA is toxic to several animal species, such as rats, pigs, guinea pigs, poultry and dogs. After ingesting CPA-contaminated feeds, test animals display severe gastrointestinal upsets and neurological disorders. Organs affected include the liver, kidney, heart, and digestive tract, which show degenerative changes and necrosis. Biologically, CPA is a specific inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPase. Data from toxicological evaluation of aflatoxins and CPA in broiler chickens demonstrate that both aflatoxins and CPA alone and the aflatoxin-CPA combination can adversely affect broiler health. The effects of aflatoxins and CPA combination were additive in most cases.

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“…Jaskiewicz et al found low toxicity of CPA in nonhuman primates but also confirmed that CPA caused pathological changes in the liver, blood vessels, and myocardium. 12 Cellular studies showed that CPA is cytotoxic to hematopoietic stem cells, monocytes, and intestinal cancer cells, and also interferes with monocyte differentiation at noncytotoxic concentration levels. 13 It is necessary to investigate their combined toxic effects, considering the high exposure concentration and the high detection rate of CPA and the suggestion that the toxic effects of AFB1 and CPA are likely to be additive.…”

Section: Introductionmentioning

confidence: 99%

Coexposure of Cyclopiazonic Acid with Aflatoxin B1 Involved in Disrupting Amino Acid Metabolism and Redox Homeostasis Causing Synergistic Toxic Effects in Hepatocyte Spheroids

Sun

et al. 2022

J. Agric. Food Chem.

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Cyclopiazonic acid (CPA), an emerging toxin, has been found in various foods such as corn, peanuts, and figs.Aspergillus flavus can produce CPA, leading to coexposure with highly toxic aflatoxin B1 (AFB1), but the mechanism of their combined action is not clear. In this study, cocultured hepatocyte spheroids were used as the evaluation model, and two concentration settings of isotoxicity and different toxicity ratios were used to investigate the combined toxic effects. Metabolomics was subsequently used to analyze the potential mechanisms underlying the effects of their exposure. AFB1 and CPA might exhibit stronger cytotoxicity, with significant combined effects on mitochondrial morphology, activity, and reactive oxygen levels. The gene expression analysis revealed that the overexpression of AKT genes could mitigate the combined effects of AFB1 and CPA to some extent. Metabolomics analysis indicated that AFB1 and CPA significantly downregulated the metabolism of L-aspartate and antioxidant substances (e.g., penicillamine, myricetin, and ethanolamine). The pathway enrichment analysis also revealed a large impact on amino acid metabolism, likely affecting intracellular redox homeostasis. In addition, the presence of CPA affects intracellular glucose metabolism and lipid metabolism pathways. This study suggested a direction for future research on relevant toxic pathways and provided possible ideas for inhibiting or mitigating toxicity.

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Preliminary studies on toxic effects of cyclopiazonic acid alone and in combination with aflatoxin B1 in non-human primates

Cited by 18 publications

References 12 publications

Review Article: Safety Assessment of the Mycotoxin Cyclopiazonic Acid

Review Article: Safety Assessment of the Mycotoxin Cyclopiazonic Acid

Cyclopiazonic acid: 50th anniversary of its discovery

Coexposure of Cyclopiazonic Acid with Aflatoxin B1 Involved in Disrupting Amino Acid Metabolism and Redox Homeostasis Causing Synergistic Toxic Effects in Hepatocyte Spheroids

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