Integumentary System Toxicology

Question 1

What are the 2 pathways of toxicant absorption through the skin?

Answer 1

1. transappendageal - through hair follicles
2. epidermal

Question 2

What are the 4 oxidation states of selenium?

Answer 2

1. -2 = selenides
2. 0 = elemental
3. +4 = selenites
4. +6 = selenates

Question 3

Why is selenium an essential nutrient? What roles does it play?

Answer 3

component of >30 selenoproteins

• iodothyronine deiodinases: activates/deactivates thyroid hormones
• glutathione peroxidase, thioredoxin reductase: oxidative stress defense

immune function, reproduction, biotransformation reactions, neurotransmitter turnover

Question 4

What are the 3 major plant sources of selenium?

Answer 4

1. obligate indicators - require high concentrations of Se to grow (woody aster, goldenweed, prince’s plume, locoweeds)
2. facultative indicators - survive in high Se and accumulate high levels, but do not require high levels to grow (other asters, saltbush, ironweed, snakeweed)
3. non-accumulators - other plants that grow on seleniferous soils

Question 5

Why is Canadian maritime province soil deficient in selenium? Where are levels high?

Answer 5

acidic soil renders Se unavailable

western Canada, AZ, CO, SD, ND, ID, KS, NE, NV, NM, UT due to low rainfall and alkaline soils

Question 6

What is a common cause of iatrogenic selenium toxicity? What are 2 other additional (rare) causes?

Answer 6

Se use for prevention of musculoskeletal disorders (white muscle disease)

1. errors in food formulation
2. mine wastes from cooper or silver mines

Question 7

Where is selenium absorbed? How does absorption vary based on chemical form?

Answer 7

duodenum (some jejunum and ileum)

• elemental Se = low absortion
• selenomethionine, selenocysteine, selenite = high absorption

Question 8

How are selenite, selenate, selenomethionine, and selenocysteine absorbed?

Answer 8

passive diffusion via brush-border membranes

sodium cotransport system

SM/SC = amino acid transport mechanisms

Question 9

How is selenium mostly eliminated? What is indicative of this?

Answer 9

urine (+ feces, expired air)

garlic odor due to dimethylselenide

Question 10

What are the 3 mechanisms of toxicity selenium? What cells are most susceptible? What does this lead to?

Answer 10

1. reacts with thiols leading to generation of ROS, oxidative stress, and cellular damage (lipid peroxidation)
2. depletes GSH and S-adenosylmethionine
3. replaces sulfur in proteins, impairing enzyme activity and cellular function (decreases cell division and growth)

keratinocytes and sulfur-containing keratin —> weakening of hooves and hair

Question 11

What mechanisms of toxicity of selenium were noted in birds and swine?

Answer 11

BIRDS = embryotoxicity due to DNA and RNA polymerase inhibition

SWINE = focal symmetrical poliomyelomalacia of ventral horns of the spinal cord

Question 12

What species are most susceptible to selenium toxicity? What are some clinical signs of acute selenosis?

Answer 12

horses

• depression, weakness, anorexia
• dyspnea, cyanosis
• garlicky odor (dimethylselenide) to breat
• nasal discharge, salivation, teeth grinding
• watery diarry
• incoordination, sweating, tachycardia, tetanic spasms
• dog-sitting (pigs)

Question 13

In what species does subchronic selenosis occur? What are some clinical signs?

Answer 13

pigs —> symmetrical poliomyelomalacia

• ataxia, posterior paralysis
• quadriplegia, sternal recumbency
• coronary band separation
• alopecia

Question 14

What species commonly develop chronic selenosis (alkali disease)? What are some clinical signs? What is not seen?

Answer 14

cattle, horses (also sheep, pigs, poultry)

• lameness (animals graze on knees)
• hair loss in tail and mane
• horn and hoof deformities (horizontal rings and cracks)
• vitality, anemia, joint stiffness

anorexia

Question 15

How are waterfowl and poultry affected by selenium toxicity? What are 3 common manifestations?

Answer 15

teratogenesis

1. underdeveloped feet
2. underdeveloped or missing lower/upper beaks
3. underdeveloped or missing eyes

Question 16

How is acute selenium toxicosis treated?

Answer 16

• terminate exposure
• IV fluids, oxygen, ventilation
• administer vitamin E or N-acetylcysteine
• treat symptoms

Question 17

How is chronic selenium toxicosis treated? How should the diet be altered?

Answer 17

• ARSENIC SALT to accelerate biliary excretion in poultry, cattle, and pigs
• selenium antagonists

provide Se-deficient rations with increased proteins to bind free Se

Question 18

What are the 2 major functions of molybdenum?

Answer 18

1. component of metalloenzymes responsible for purine metabolism, uric acid (antioxidant) production, sulfur-containing amino acids metabolism, and drug/toxicant metabolism —> xanthine oxidase/dehydrogenase, aldehyde oxidase, sulfide oxidase
2. binds to alpha-macroglobulin on RBC membranes to enhance resistance to rupture

Question 19

What are 3 major sources of molybdenum? When does toxicosis occur?

Answer 19

1. naturally found in copper, lead, and tungsten ores
2. combustion of fossil fuels
3. in high amounts in the soil and forage in FL, OR, NV, and CA, where Mo fertilizers are used to increase nitrogen fixation in legumes, and pastures near production plants

if copper deficiency is present

Question 20

What commonly competitively inhibits molybdenum uptake? In what 3 ways is it commonly excreted?

Answer 20

sulfate —> shares a common transport pathway in the intestine and kidney

1. bile - cattle
2. urine - lab animals
3. milk - ruminants

Question 21

In what species is molybdenum toxicosis most common? What factor drives toxicosis?

Answer 21

ruminants, especially cattle (and younger animals)

dietary Cu:Mo ratio (4:1 or 10:1) —> high dietary sulfur levels exacerbate toxicity because it decreases Cu absorption

Question 22

What is the three-way interaction of Mo-Cu-S?

Answer 22

1. dietary S is converted to sulfide in the rumen, which bind Cu, decreasing its absorption (increased Mo in diet increases conversion)
2. Mo and S form thiomolybdates in the rumen that bind Cu, making it insoluble and decreases absorption
3. when rumen Cu is low, thiomolybdates are absorbed and impair systemic Cu metabolism by increasing/urinary loss of Cu and depleting activities of Cu-dependent enzyes

Question 23

What Cu-dependent enzymes are typically affected by molybdenum toxicity? What are 2 results?

Answer 23

• ceruloplasmin: Cu-transport and Fe metabolism
• lysyl oxidase: collagen synthesis
• tyrosinase: melanin synthesis
• cytochrome C oxidase: mitochondrial electron transport (aerobic metabolism)
• dopamine-beta-hydroxylase: catecholamine metabolism
• superoxide dismutase: oxidant defense

1. impairment of myeline maintenance and function = enzootic ataxia in lambs
2. alteration of Zn metabolism

Question 24

In what species is acute molybdenum toxicosis most common? What are the main clinical signs? Lesions?

Answer 24

cattle and sheep

• feed withdrawal, lethargy weakness
• hind limb ataxia progresses to front, recumbency
• profuse salivation, ocular discharge, mucoid feces

hydropic degeneration of hepatocytes and renal tubules

Question 25

What are the main 5 clinical signs of chronic molybdenum toxicosis?

Answer 25

1. severe, persistent diarrhea (peat scours) - green, liquid feces containing gas bubbles 2. achromotrichia and alopecia due to tyrosinase depletion that reduces melanin synthesis 3. emaciation, decreased milk production, delayed puberty, bone fractures, lameness, limb deformities, muscular degeneration 4. swayback/enzootic ataxia in lambs with stiff backs and legs making it difficult to rise 5. microcytic hypochromic anemia

Question 26

What is important in the diagnosis of suspected molybdenum toxicosis? How is it diagnosed?

Answer 26

distinguishing between primary copper deficiency and secondary copper deficiency related to excessive molybdenum exposure - clinical signs in a herd and concentrations of Mo in blood, liver, and kidneys - levels of Cu and Mo in feeds/forages - levels of Cu and Mo in tissues (poor correlation between tissue levels of Cu and clinical disease)

Question 27

What are the 3 major differentials to rule out for molybdenum toxicosis?

Answer 27

1. emaciation or unthriftiness - parasites, selenosis, fluorosis, ergotism 2. diarrhea - metal poisonings, GI infections 3. lameness or bone abnormalities - fluorosis, selenosis, ergotism, lead poisoning

Question 28

What are the 2 major treatments for molybdenum toxicosis?

Answer 28

1. addition of Cu to diets to achiecve 4:1 to 10:1 Cu:Mo ratio (additional Cu necessary to counter S effects - S:Mo should be <100:1) 2. administer Cu - injectable copper glycinate or copper edetate (Cu-EDTA)

Question 29

What is photosensitization? What are the 4 classifications?

Answer 29

abnormal sensitivity of the skin to UV light common in herbivores (NOT SUNBURN) - TYPE I = primary* - TYPE II = aberrant endogenous pigment synthesis (porphyria) - TYPE III = secondary/hepatogenous* - TYPE IV = idiopathic

Question 30

What is the pathogenesis of photosensitization?

Answer 30

- photodynamic compounds in nonpigmented skin are activated by UV absorption, leading to higher energy states and reactions with biological substrates or molecular oxygen and production of ROS - ROS cause oxidative damage of macromolecules and organelles - damage results in increased permeability and release of lytic enzymes and cytoplasmic extrusion - edema, cell death, ulceration with superficial blood vessels and epidermis as the primary targets ---> skin sloughs off

Question 31

What is primary photosensitization? How can it be chemically induced?

Answer 31

photodynamic compounds are ingested, injected, or absorbed through the skin and react with light in non-pigmented skin to cause severe dermatitis - phenothiazines in antipsychotics and antihistamines - polycyclic aromatic hydrocarbons - sulfonamides - tetracyclines - antifungals - NSAIDs

Question 32

What 3 plants cause primary photosensitization? What are the toxic principles?

Answer 32

1. Fagopyrum esculentum (buckwheat) - fagopyrin 2. Hypericum perforatum (St. John's wort) - hypericin 3. Ammi majus (bishop's weed) - furnocoumarins (seeds are most phototoxic)

Question 33

What causes aberrant pigment metabolism? In what animals does this cause photosensitization?

Answer 33

porphyrin arises from inherited or acquired defective functions of enzymes involved in heme synthesis (TYPE II) cattle and cats - congenital erythropoietic porphyria, bovine erythropoietic protoporphyria

Question 34

What causes secondary/hepatogenous photosensitization (III)? In what animals is this most common?

Answer 34

phylloerythrin, a microbial breakdown product of chlorophyll in the GIT ---> hepatic disease/dysfunction or biliary occlusion prevents its excretion, causing concentrations in circulation to increase, reach the skin, and activate by light livestock ---> poor prognosis

Question 35

What 2 plants most commonly cause secondary/hepatogenous photosensitization? What species are most affected? What is the toxic principle?

Answer 35

1. Panicum virgatum (switch/panic grass) - sheep, lithogenic saponin (diosgenin) 2. Agave (lecheguilla) - goats and sheep, diosgenin

Question 36

What additional 2 plants also contain diosgenin?

Answer 36

1. puncture vine (Tribulus terrestris) 2. beargrass (Nolina texana) (secondary/hepatogenous photosensitization - III)

Question 37

What skin areas are most commonly affected by photosensitization?

Answer 37

areas of little to no hair and light-colored skin - lips, nose, eyes, coronary bands - white skin on face, back, and legs - udders, teats, tongue - *severe phylloerythrinemia and bright sunlight can induce lesions in black-coated animals*

Question 38

What are the initial and later clinical signs of photosensitization? What is commonly seen in the hepatogenous form?

Answer 38

- INITIAL: photophobia, excessive tearing, swelling, redness, increased sensitivity of nonpigmented skin - LATER: pruritis, blisters, ulceration, exudation, scabs, cutaneous edema, fissuring epithelium, sloughing of non-pigmented skin, secondary bacterial infection, licking behavior (cattle, sheep, deer) results in glossitis, corneal edema, and blindness signs of liver disease - icterus

Question 39

Photosensitization:

Answer 39

Question 40

Photosensitization, sheep:

Answer 40

whole body can be affected if it has recently been sheared

Question 41

What causes facial eczema during photosensitization?

Answer 41

mycotoxin sporidesmin produces severe cholangitis and pericholangitis, which leads to biliary obstruction and restriction of phylloerythrin excretion

Question 42

How is photosensitization diagnosed? How can Type II and Type III be diagnosed?

Answer 42

- history or evidence of exposure to photosensitizing agents or hepatotoxins - clinical signs/lesions restricted to lightly pigmented areas with sparse hair cover - liver serum enzymes TYPE II = porphyria levels in blood, feces, and urine, signalment, clinical signs TYPE III = liver serum enzymes and histologic signs of liver disease

Question 43

How is photosensitization treated?

Answer 43

- provide ample shape/sheltering - grazing only allowed in darkness - parenteral corticosteroids - basic wound management: lavage, debridement, closure, and antibiotics to avoid secondary bacterial infections