Lecture 11: Circulatory and Hematopoietic Systems

what are fumonisins?

mycotoxins produced by the fungus Fusarium verticillioides

how does fumonisin induced porcine pulmonary edema occur?

ingestion → inhibit sphingosine N acetyltransferase → increase sphingosine → inhibition of L type Ca channel → decrease myocardial contractility → left sided heart failure → pulmonary edema

what do fumonisins cause?

• liver damage in multiple species like pigs, horses, cattle, rabbits, and primates

• species specific target organ toxicity, such as lung in pigs, brain in horses, kidney in rats, rabbits and sheep and esophagus in rats and pigs

what is ergot toxicity known as in humans?

St. Anthony’s Fire

what is the agent of ergot toxicity?

claviceps purpurea

ergot toxicity 

• grains are replaced by ergot sclerotia that contain toxins 

• growing conditions and storage are major factors in the content of ergot containing grain

• grain yields can be downgraded by the content of ergot 

toxic principles of ergot toxicity

ergonovine, ergotamine, lysergic acid amides, ergopeptines

MOA for ergot toxicity

• alpha adrenergic (ex. epinephrine)

• serotonergic - 5HT (serotonin)

• dopaminergic - DA (dopamine)

diagnosis for ergot toxicity

detection of ergot in grain → alkaloids and metabolites in the urine

what is the endophyte that infects tall fescue pastures?

neotyphodium coenophialum 

what is the most prevalent ergopeptine?

ergovaline

fescue toxicity

• cattle in summer time

• panting, drooling, heavy respiration, not eating or moving, not shedding, long periods in water

• fescue foot

black walnut toxicity 

• wood shavings used for bedding for horses can cause laminitis 

• toxic component is juglone → absorbed through coronary band and skin

what can blood and bone marrow toxicity be a result of?

off-target inhibition leading to decreased bone marrow response or a result of peripheral effects leading to destruction of blood cells

bone marrow suppression may result from

direct damage to cell precursors as well as from alterations in the cytokine profile secondary to the drug

major mechanism of toxicity for hematopoietic toxicity 

formation of ROS, including superoxide anion, hydrogen peroxide, and hydroxyl radical 

what is warfarin used for?

• therapeutic to prevent blood clotting

• rodenticide

what happens when warfarin blocks the enzyme vitamin K reductase?

you are left with just oxidized vitamin K because normally you would produce reduced vitamin K to get coagulation factors → without the reduced vitamin K = no coagulation factors

sweet clover toxicity

molding promotes the likelihood of formation of dicumarol in the hay

what do all anticoagulatns have?

the basic coumarin or indanedione nucleus 

first-generation anticoagulants

warfarin (and many others) → require multiple feedings to result in toxicity

intermediate anticoagulants

diphacinone → require fewer feedings than first-generation chemicals, and are more toxic to nontarget species

second-generation anticoagulants 

brodifacoum → highly toxic to nontarget species after a single feeding  

allium species contain a wide variety of

organosulfoxides

what does trauma, like chewing, do to allium?

converts the organosulfoxides to a complex mixture of sulfur-containing organic compounds

MOA for allium toxicity 

oxidative hemolysis → occurs when the concentration of oxidants in the erythrocyte exceeds the capacity of the antioxidant metabolic pathways 

how are heinz bodies formed in allium toxicity?

sulfhemoglobin is less soluble than hemoglobin, so it precipitates, aggregates, and binds to the cell membrane

zinc toxicity causes issues with

red blood cells

circulatory toxicity (acetaminophen)

• presentation → cat with puffy face, puffy paws, pale mucus membranes

• low PCV, methemoglobinemia 

what can be used as potential treatment for acetaminophen toxicity?

N-acetyl cysteine