Mycotoxins Introduction Relatively low number of medically important fungi for humans, when compared to plant and insect pathogens Mycotoxins: low-molecular weight natural products produced as secondary metabolites by filamentous fungi Grouped depending on their disease causing ability in vertebrates Mycotoxicoses: Diseases produced by the exposure to toxic fungal metabolites Dietary, Respiratory, Dermal…… Definitions & Generalities Mycotoxin Gold Rush 1960-1975 Many scientists joined the well-funded search for toxigenic agents produced by fungi 300-400 compounds now recognized as mycotoxins; 12+ groups “Poisoning by natural means” Similar to exposure to pesticides or heavy metal residues Usually accidental exposure Mycotoxicoses… Severity of the poison depends on: Vitamin deficiency Caloric deprivation Alcohol abuse Infectious disease status Symptoms of disease depend on: Type of mycotoxin Amount and duration of exposure Age, health and sex of exposed individual Poorly understood factors: Genetics Dietary status Interactions with other toxic substances Mycotoxicoses… The biggest problems with mycotoxicoses Heighten vulnerability to microbial diseases Worsen the effects of malnutrition Interact synergistically with other toxins. Definitions & Generalities All mycotoxins are of fungal origin (microfungi) BUT, not all toxic compounds produced by fungi are called mycotoxins… Examples: Mycotoxins versus vertebrates and other animals Mycotoxins - LOW conc. vs Ethanol - HIGH conc. Antibiotics versus Bacteria Phytotoxins versus Plants Mushroom Poisons – macroscopic fungi, ingestion because of misidentification Who is at risk to being exposed to mycotoxins? Places of the world… with poor methods of food handling and storage where malnutrition is a problem where few regulations exist to protect exposed populations In the US (and other developed countries) ? Hispanic populations – consume more corn products than the rest of the population Inner city populations – more likely to live in buildings harbor high levels of molds Control of Mycotoxins Good agricultural practice Sufficient drying of crops after harvest before storage Prevent pre-harvest contamination by increasing/developing host resistance by: Plant breeding Genetic engineering – enhance antifungal genes Use of biocontrol agents that target regulatory genes in the mycotoxin development Improved government screening and regulation programs Major Mycotoxins Alphabetical listing—NOT potency 1. 2. 3. 4. 5. 6. 7. 8. 9. Aflatoxins* Citrinin Ergot Alkaloids* Fumonisins* Ochratoxins Patulin Trichothecenes* Zearalenone Etc… Aflatoxin Isolated after Turkey X Disease Consumption of a mold-contaminated peanut meal Four major aflatoxins B1, B2, G1 and G2 B1 is the most potent natural carcinogen known, unfortunately major aflatoxin produced by toxigenic strains Major producers: Aspergillus flavus and Aspergillus parasiticus Aflatoxin Natural contamination of agricultural products: Cereals, figs, oilseeds, nuts, tobacco, etc. Contaminated in field before harvest More problems during storage – moist & humidity Contamination of grain causes: Increased mortality in farm animals Lowers the value of exported grain as animal feeds Location of biggest problem is countries where the population is facing starvation or regulations non-existent or not enforced Aflatoxin Mechanism of action: Cytochrome enzymes convert to an epoxide that binds to N7 of guanine Eventual mutation of G/C to A/T Extrapolate test animal results to human Difficult because different enzymes Human carcinogen– liver cancer China, Philippines, Thailand, and many African countries Risk factor: Hepatitis B Ergot Alkaloids Produced by Claviceps, primarily a grass pathogen Associated with disease since 600 BCE Common in Europe during Middle Ages “..noxious pustule in the ear of grain” Eating cereals infected with a toxic cocktail of alkaloids with ergoline ring systems St Anthony’s Fire – bread from contaminated flour Gangrenous – blood supply to the extremities Convulsive – affect CNS Ergot Alkaloids Currently a veterinary problem Cattle, sheep, pigs, chicken Symptoms Gangrene, abortions, convulsions, suppression of lactation, hypersensitivity Mechanism of action: Induce smooth muscle contraction Midwives administer to women in labour as a natural product to accelerate uterine contractions Ergot Alkaloids - History 1943 – Birth of LSD Hoffman - research involved varying the amino alcohol of lysergic acid Developed Methergine – control hemorrhaging after childbirth Continued research… Accidentally ingested compound #25 and discovered the hallucigenic properties of lysergic acid diethylamide (LSD) Marketed as Delysid – unsuccessful treatment of schizophrenia Ergot Alkaloids - Uses MK-ULTRA code name After WWII - CIA used as a truth serum for interrogating suspected communists Hypothesized Salem witchcraft affair probably the result of convulsive ergotism related to consumption of rye with Claviceps ergot alkaloids cocktail Ergotamine – used to treat migraine headaches Ergot derivatives – used in the treatment of Parkinsonism Fumonisin Produced by: Fusarium spp. Alternaria alternata Economical importance: Fusarium verticillioides A corn endophyte in vegetative and reproductive tissue; usually plant is asymptomatic Cause seedling blight, stalk and ear rot ALL corn has resident fungus, most strains do not produce the toxic compound Fuminosin Medical Importance: Interferes with sphingolipid metabolism in animals and vertebrates Cause leukoencephalomalacia (hole in head syndrome) in birds and rabbits Humans: Can cause neural tube defects Linked to esophageal cancer Charleston, SC – 7 samples Isolated high concentration in corn meal and corn grits US city with highest incidence of esophageal cancer among African-Americans Trichothecenes Nonmacrocyclic Macrocyclic Type A Group Type B Group AKA Vomitoxin Trichothecenes Over 60 compounds produced by: Fusarium, Phomopsis, Trichoderma, Myrothecium, Stachybotrys, Trichothecium… Common food & feed contaminants Consumption: Alimentary hemorrhaging and vomiting Skin contact: Dermatitis Collective problem: Extreme potent inhibitors of eukaryotic protein synthesis, specifically peptidyl transferase Eating mold grain Trichothecenes, Deoxynivalenol Most common mycotoxin found in grain Especially barley A.k.a. Vomitoxin or food refusal factor Farm animal – nausea, vomit, diarrhea, weight loss and food refusal Trichothecenes, T-2 & diacetoxyscirpenol Cytotoxic activity Immunosuppressive effect Human disease: Alimentary toxic aleukia Inflammation of skin, vomiting, necrosis of oral cavity, bleeding (nose, mouth & vagina), and CNS problems Trichothecenes, Stachybotrys Wet building material harbor organism Gypsum board, ceiling tiles, wood fiber board, dust lined A/C vents Mycotoxin people talk about when referring to Sick-building Syndrome Shown to cause pulmonary bleeding in infants when exposed for prolonged times Described as the 10th plague visited on Egypt Hurricane Katrina, New Orleans Stchybotyrs growing above flood line Carpet Monsters Killer Spores Interesting e-book in USF Library (Chap 8) Author is N.Money who studies biophysics Basidiospore discharge Explains basics of immunology/allergies Addresses indoor air quality/role of fungi Addresses mycotoxin of Stachybotrys in neonatal hospital unit Additional Reading: POISONS of the PastMolds, Epidemics and History By Mary Kilbourne Matossian References