Page 1042 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

974 SECTION | XIV Poisonous Plants

VetBooks.ir to gossypol toxicity until proven otherwise. In general, its long elimination half-life and tissue sequestration, gos-
sypol is generally regarded as a cumulative toxin.
monogastric animals and preruminant stage sheep, goats
Important features of gossypol-induced overt toxi-
and cattle are more susceptible than adult ruminants due
to the lack of rumen presystemic detoxification. dromes, apart from negative effects on growth and pro-
Critically, poisoning can still occur among adult rumi- duction, include: (1) gossypol poisoning (acute/subacute/
nants if the intake is sufficiently high. Goats appear to be subchronic); (2) anemia; (3) hepatotoxicity; (4) disruption
more sensitive than sheep and cattle. Among monogastric of reproduction; (5) immunotoxicity; and (6) effects on
animals, guinea pigs and rabbits appear to be the most eggs.
sensitive species. Horses are relatively resistant to toxic-
ity, but caution is still required. TOXICITY
It should be noted that ammoniation of cottonseed
meals (a procedure used to reduced aflatoxin content) The gossypol dose-response has been poorly explored in
may increase the risk of gossypol toxicity (Smalley and most species. Much of the available information derives
Bicknell, 1982). from small research studies utilizing a limited dose range
and anecdotal clinical information (Table 68.2). Notably,
gossypol toxicity has been associated with the use of cot-
MECHANISM OF ACTION
tonseed bedding for dogs (Uzal et al., 2005).
The mechanisms of action of gossypol are complex and
incompletely understood: (1) gossypol has six phenolic Acute Gossypol Poisoning
hydroxyl groups and two aldehyde groups that allow
covalent binding to epsilon-amino acids via Schiff’s base Acute poisoning is rare, but may occur if free gossypol
condensation reactions (Fig. 68.3); this mechanism may intake levels are sufficiently high. Gossypol has only
explain the disruptive effects of gossypol on a large range moderate acute lethality in most species (oral LD 50 sof
of enzymes and proteins; (2) it uncouples mitochondrial 2400 3340 mg/kg for rats, 500 950 mg/kg for mice,
oxidative phosphorylation; (3) it chelates iron, copper, 350 600 mg/kg for rabbits, 550 mg/kg for pigs and
aluminum and zinc resulting in mineral deficiencies 280 300 mg/kg for guinea pigs) with monogastric spe-
(commonly iron deficiency); (4) it has complex oxidant cies being more susceptible than ruminants. The clinical
and antioxidant activities; (5) it alters biological mem- signs of acute toxicity are similar across species and are
brane potential, fluidity and permeability; (6) it binds to relatively nonspecific: respiratory distress, impaired body
tubulin and inhibits microtubule assembly; (7) it disrupts weight gain, anorexia, weakness, apathy, and death after
gap junctions and cell to cell communication; (8) it several days (Alexander et al., 2008; Kerr, 1989; Morgan
induces renal leakage of potassium (most likely due to a et al., 1988; Rogers et al., 1975; Holmberg et al., 1988;
direct effect on renal tubular epithelia) resulting in hypo- Risco et al., 1992; Zelski et al., 1995; Fombad and
kalemia; (9) it increases erythrocyte osmotic fragility; Bryant, 2004). Heart failure is a feature of acute toxicity
(10) it stimulates eryptosis by increasing erythrocyte in calves, lambs, and dogs (Holmberg et al., 1988; East
21
cytolsolic Ca ; (11) it decreases myocardial contractility et al., 1994; Patton et al., 1985). Necropsy findings in
resulting in congestive heart failure; (12) it disrupts car- ruminants include cardiogenic pulmonary edema, yellow-
diac conduction; and (13) it alters DNA synthesis and cell ish pleural effusions and ascites, gastroenteritis, centrilo-
cycle progression. Gossypol poisoning can (rarely) occur bular liver necrosis, and hypertrophic cardiac fiber
acutely, but more typically the toxidrome develops slowly degenerations, sometimes with evidence of acute conges-
after weeks to months of exposure. Critically, because of tive heart failure and cardiac dilation. An increased

FIGURE 68.3 Covalent binding of gossypol via epsilon-amino acids via Schiff’s base condensation reactions (particularly with lysine residues).