Impact of a Single Oral Acute Dose of Aflatoxin B1 on Liver Function/Cytokines and the Lymphoproliferative Response in C57Bl/6 Mice

Ishikawa, Angélica Tieme; Hirooka, Elisa Yoko; Silva, Paula Leonello Álvares e; Bracarense, Ana Paula Frederico Rodrigues Loureiro; Flaiban, Karina Keller Marques da Costa; Akagi, Claudia Yuri; Kawamura, Osamu; Costa, Márcio Paulino; Itano, Eiko Nakagawa

doi:10.3390/toxins9110374

“…Indeed, reactive aflatoxin metabolites can directly bind nucleic acids, disrupt protein synthesis and ultimately cause widespread cellular damage 7,32,33 . Consistent with prior reports 34,35 , elevated levels of TNF-α and IFN-γ were observed. Coupled with an excess of reactive oxygen species (ROS), TNF-α has been shown to cause hepatocyte apoptosis [36][37][38] .…”

Section: Discussionsupporting

confidence: 92%

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1

Ruggeberg

¹

,

O’Sullivan

²

,

Kovacs

³

et al. 2020

Sci Rep

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Mycotoxins, such as aflatoxin B 1 (AFB 1), pose a serious threat as biological weapons due to their high toxicity, environmental stability, easy accessibility and lack of effective therapeutics. This study investigated if blood purification therapy with CytoSorb (CS) porous polymer beads could improve survival after a lethal aflatoxin dose (LD 90). The effective treatment window and potential therapeutic mechanisms were also investigated. Sprague Dawley rats received a lethal dose of AFB 1 (0.5-1.0 mg/ kg) intravenously and hemoperfusion with a cS or control device was initiated immediately, or after 30, 90, or 240-minute delays and conducted for 4 hours. The CS device removes AFB 1 from circulation and significantly improves survival when initiated within 90 minutes of toxin administration. Treated subjects exhibited improved liver morphology and health scores. changes in the levels of cytokines, leukocytes and platelets indicate a moderately-severe inflammatory response to acute toxin exposure. Quantitative proteomic analysis showed significant changes in the level of a broad spectrum of plasma proteins including serine protease/endopeptidase inhibitors, coagulation factors, complement proteins, carbonic anhydrases, and redox enzymes that ostensibly contribute to the therapeutic effect. Together, these results suggest that hemoadsorption with cS could be a viable countermeasure against acute mycotoxin exposure. Aflatoxins are toxic secondary fungal metabolites (mycotoxins) produced by fungus from the genus Aspergillus that cause severe acute reactions that can be lethal. Aspergillus species are important human pathogens and the toxic metabolites appear to act as virulence factors to suppress the immune system in invasive aspergillosis 1. Aflatoxins cause damage to the liver resulting in hemorrhagic liver necrosis, steatosis, bile duct proliferation and subsequent organ failure and have been detected in pulmonary lesions of immune-compromised patients with systemic aspergillosis 2. Aflatoxin B 1 (AFB 1), the most potent toxin of the 14 naturally occurring aflatoxin variants, is extremely cytotoxic, genotoxic, and carcinogenic 3,4. In the liver, cytochrome P450-modified AFB 1 forms DNA adducts that lead to impaired cellular function, carcinogenesis and/or cell death and organ failure 5,6. Acute aflatoxin poisoning from mold contaminated foods has been linked with numerous deaths in several instances 7,8. Importantly, mycotoxins pose a serious threat as potential biowarfare agents due to their inherent stability and ease of manufacture. The toxins can be readily weaponized into aerosol form and dispersed over a wide area to elicit mass casualties through both inhalation and dermal exposure 9. There have been several reported incidents of use of mycotoxins as bioweapons in Southeast Asia and the Gulf States 10,11. Early symptoms of mycotoxin exposure in bio-warfare manifest rapidly in minutes to hours and can include burning, pain, wheezing, nausea, vomiting, tearing, weakness, bleeding and a host of other symptoms...

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“…In animals, the lethal dose varies greatly among species, as suggested by the wide variation in their LD50 values ranging between 0.3 and 18.0 mg/kg bw [176], although values as low as 0.2 mg/kg bw or as high as 60 mg/kg bw were occasionally reported ( Table 2). Animals like ducks, sheep, turkeys, dogs, pigs, and rats are the most susceptible, whereas monkeys, chickens, mice, and ruminants the most resistant [138,177]. The higher susceptibility of the first group of animals was explained by their ability to metabolize rapidly AFB1 via the phase II metabolism driving towards the formation of aflatoxin-albumin adducts [178].…”

Section: Aflatoxicosesmentioning

confidence: 99%

“…The higher susceptibility of the first group of animals was explained by their ability to metabolize rapidly AFB1 via the phase II metabolism driving towards the formation of aflatoxin-albumin adducts [178]. In a study on the impact of an orally administered single dose of AFB1 to mice, 0.66 mg/kg bw induced severe tissue injury 5 days after the ingestion [177]. In poultry, the AFB1 doses that killed all tested birds varied between 0.8 and 4.0 mg per animal, with turkeys being the most sensitive (0.8 mg) and gooses the most resistant (4.0 mg), whereas no death was observed in chicken at the highest doze of 4.0 mg [176].…”

Section: Aflatoxicosesmentioning

confidence: 99%

Aflatoxins: Production, Structure, Health Issues and Incidence in Southeast Asian and Sub-Saharan African Countries

Benkerroum¹

2020

Preprint

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This review aimed to update the main aspects of aflatoxin production, occurrence and incidence in selected countries, and associated aflatoxicosis outbreaks. Means to reduce aflatoxin incidence in crops were also presented with an emphasis on the environment-friendly technology using atoxigenic strains of Aspergillus flavus. Aflatoxins are unavoidable widespread natural contaminants of foods and feeds with serious impact on health, agricultural and livestock productivity, and food safety. They are secondary metabolites produced by Aspergillus species distributed on three main sections of the genus (section Flavi, section Ochraceorosei, and section Nidulantes). Poor economic status of a country exacerbates the risk and the extent of crop contamination due to faulty storage conditions that are usually suitable for mold growth and mycotoxin production: temperature of 22 to 29°C and water activity of 0.90 to 0.99. This situation paralleled the prevalence of high liver cancer and the occasional acute aflatoxicosis episodes that have been associated with these regions. Risk assessment studies revealed that Southeast Asian and Sub-Saharan African countries remain at high risk and that, apart from the regulatory standards revision to be more restrictive, other actions to prevent or decontaminate crops are to be taken for adequate public health protection. Indeed, a review of publications on the incidence of aflatoxins in selected foods and feeds from countries whose crops are classically known for their highest contamination with aflatoxins, reveals that despite the intensive efforts made to reduce such an incidence, there has been no clear tendency, with the possible exception of South Africa, towards sustained improvements. Nonetheless, a global risk assessment of the new situation regarding crop contamination with aflatoxins by international organizations with the required expertise is suggested to appraise where we stand presently.

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“…In animals, the lethal dose varies greatly among species, as suggested by the wide variation in their LD50 values ranging between 0.3 and 18.0 mg/kg bw [187], although values as low as 0.2 mg/kg bw or as high as 60 mg/kg bw were occasionally reported ( Table 2). Animals like ducks, sheep, turkeys, dogs, pigs, and rats are the most susceptible, whereas monkeys, chickens, mice, and ruminants the most resistant [150,188]. The higher susceptibility of the first group of animals was explained by their ability to metabolize rapidly AFB1 via the phase II metabolism driving towards the formation of aflatoxin-albumin adducts [189].…”

Section: Aflatoxicosesmentioning

confidence: 99%

“…The higher susceptibility of the first group of animals was explained by their ability to metabolize rapidly AFB1 via the phase II metabolism driving towards the formation of aflatoxin-albumin adducts [189]. In a study on the impact of an orally administered single dose of AFB1 to mice, 0.66 mg/kg bw induced severe tissue injury 5 days after the ingestion [188]. In poultry, the AFB1 doses that killed all tested birds varied between 0.8 and 4.0 mg per animal, with turkeys being the most sensitive (0.8 mg) and gooses the most resistant (4.0 mg), whereas no death was observed in chicken at the highest doze of 4.0 mg [187].…”

Section: Aflatoxicosesmentioning

confidence: 99%

Aflatoxins: Production, Structure, Health Issues and Incidence in Southeast Asian and Sub-Saharan African Countries

Benkerroum¹

2019

Preprint

View full text Add to dashboard Cite

This review aimed to update the main aspects of aflatoxin production, occurrence and incidence in selected countries, and associated aflatoxicosis outbreaks. Means to reduce aflatoxin incidence in crops were also presented with an emphasis on the environment-friendly technology using atoxigenic strains of Aspergillus flavus. Aflatoxins are unavoidable widespread natural contaminants of foods and feeds with serious impact on health, agricultural and livestock productivity, and food safety. They are secondary metabolites produced by Aspergillus species distributed on three main sections of the genus (section Flavi, section Ochraceorosei, and section Nidulantes). Poor economic status of a country exacerbates the risk and the extent of crop contamination due to faulty storage conditions that are usually suitable for mold growth and mycotoxin production: temperature of 22 to 29°C and water activity of 0.90 to 0.99. This situation paralleled the prevalence of high liver cancer and the occasional acute aflatoxicosis episodes that have been associated with these regions. Risk assessment studies revealed that Southeast Asian and Sub-Saharan African countries remain at high risk and that, apart from the regulatory standards revision to be more restrictive, other actions to prevent or decontaminate crops are to be taken for adequate public health protection. Indeed, a review of publications on the incidence of aflatoxins in selected foods and feeds from countries whose crops are classically known for their highest contamination with aflatoxins, reveals that despite the intensive efforts made to reduce such an incidence, there has been no clear tendency, with the possible exception of South Africa, towards sustained improvements. Nonetheless, a global risk assessment of the new situation regarding crop contamination with aflatoxins by international organizations with the required expertise is suggested to appraise where we stand presently.

show abstract

Impact of a Single Oral Acute Dose of Aflatoxin B1 on Liver Function/Cytokines and the Lymphoproliferative Response in C57Bl/6 Mice

Cited by 38 publications

References 27 publications

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1

Aflatoxins: Production, Structure, Health Issues and Incidence in Southeast Asian and Sub-Saharan African Countries

Aflatoxins: Production, Structure, Health Issues and Incidence in Southeast Asian and Sub-Saharan African Countries

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