Overview of Gossypol Poisoning
Gossypol poisoning, usually chronic, cumulative, and sometimes insidious, follows consumption of cottonseed or cottonseed products that contain excess free gossypol. It is of most concern in domestic livestock, especially preruminants or immature ruminants and pigs; mature ruminants are more resistant to gossypol’s toxic effects. However, gossypol toxicosis can affect high-producing dairy cows with high feed intake, dairy goats, and other mature ruminants fed excess gossypol for long periods. It has also been reported in dogs fed cottonseed meal in diets or housed on cottonseed bedding.
Gossypol, the predominant pigment and probably the major toxic ingredient in the cotton plant (Gossypium spp), and other polyphenolic pigments are contained within small, discrete structures called pigment glands found in various parts of the cotton plant. Gossypol is found in cottonseed as both protein-bound and free forms; only the free form is toxic. Gossypol content of cottonseeds varies from a trace to >6% and is affected by plant species and variety and by environmental factors such as climate, soil type, and fertilization. Gossypol is a natural component of all but the rarely produced “glandless” variety of cotton.
Cottonseed is processed into edible oil, meal, linters (short fibers), and hulls. Cottonseed meal is marketed with 50%–90% protein, depending on intended use. Cottonseed and cottonseed meal are widely used as protein supplements in animal feed. Cottonseed oil soapstock (foots) is the principal by-product of cottonseed oil refining. Cottonseed soapstocks are being increasingly used as animal feed additives; cottonseed hulls are used as a source of additional fiber in animal feeds and contain much lower gossypol concentrations than do whole cottonseeds.
Lipid-soluble gossypol is readily absorbed from the GI tract. It is highly protein-bound to amino acids, especially lysine, and to dietary iron. The precise mechanism of action is not known, but gossypol renders many amino acids unavailable by the formation of a Schiff’s base-type derivative as well as additional protein/gossypol interactions. Gossypol also affects enzymatic reactions critical for many biologic processes, including the ability of cells to respond to oxidative stress and inhibition of oxygen release from hemoglobin. Conjugation, metabolism, and urinary excretion of gossypol is limited; most is eliminated in the feces.
All animals are susceptible, but monogastrics, preruminants, immature ruminants, and poultry appear to be affected most frequently. Adult ruminants are able to detoxify gossypol by formation of stable complexes with soluble proteins in the rumen, thus preventing absorption, something lacking in swine, preruminants, and young ruminants with only a partially functioning rumen. Pigs, guinea pigs, and rabbits are reported to be sensitive. Dogs and cats appear to have intermediate sensitivity. Goats may be more sensitive to gossypol than are cattle. Horses appear relatively resistant but caution is still advised. Toxic effects usually occur only after longterm exposure to gossypol, often weeks to months.
Signs may relate to effects on the cardiac, hepatic, renal, reproductive, or other systems. Prolonged exposure can cause acute heart failure resulting from cardiac necrosis. Also, a form of cardiac conduction failure similar to hyperkalemic heart failure can result in sudden death. Pulmonary effects, labored breathing, and chronic dyspnea are most likely secondary to cardiotoxicity from congestive heart failure.
Hepatotoxicity can be a primary effect from direct damage to hepatocytes or metabolism of phenolic compounds to reactive intermediates, or liver necrosis may be secondary to congestive heart failure. Gossypol inhibits glutathione-S-transferase, impairing the liver’s ability to metabolize xenobiotic compounds. Hematologic effects include anemia with reduced numbers of RBCs and increased RBC fragility, decreased oxygen release from oxyhemoglobin, and reduced oxygen-carrying capacity of blood with lowered Hgb and PCV values due to complexing of iron by gossypol.
Reproductive effects include reduced libido with decreased spermatogenesis and sperm motility, as well as sperm abnormalities (which are reversible) resulting from enzyme inhibition of steroid synthesis in testicular Leydig cells. Specific mitochondrial damage in spermatozoa appears to cause immobility and depressed sperm counts. Extensive damage to germinal epithelium in both rams and bulls fed excessive gossypol may be responsible for depressed spermatogenesis. Effects in females may include irregular cycling, luteolytic disruption of pregnancy, and direct embryotoxicity; probable mechanisms include an endocrine effect on the ovary as well as a direct cytotoxic effect on the uterus or embryo. Green discoloration of egg yolks and decreased egg hatchability have been reported in poultry. However, antifertility and reproductive effects in many nonruminant species are secondary to the more toxic effects, particularly in females.
Signs of prolonged excess gossypol exposure in many animals are reduced growth rate, weight loss, weakness, anorexia, and increased susceptibility to stress. Young lambs, goats, and calves may suffer cardiomyopathy and sudden death; if the course is more chronic, they may be depressed, anorectic, and have pronounced dyspnea. Adult dairy cattle may show weakness, depression, anorexia, edema of the brisket, and dyspnea, and also have gastroenteritis, hemoglobinuria, and reproductive problems. In monogastric animals, acute exposure may result in sudden circulatory failure, whereas subacute exposure may result in pulmonary edema secondary to congestive heart failure; anemia may be another common sequela. Violent dyspnea (“thumping”) is the outstanding clinical sign in pigs. In dogs, gossypol poisoning is primarily reflected by cardiotoxic effects; condition deteriorates progressively, and ascites may be marked. Affected dogs may show polydipsia and have serum electrolyte imbalances, most notably hyperkalemia, with pronounced ECG abnormalities.
An enlarged, flabby, pale, streaked, and mottled heart with pale myocardial streaking, enlarged and dilated ventricles, and valvular edema may be evident. Skeletal muscles may also be pale. A froth-filled trachea and edematous, congested lungs are common, with interstitial pulmonary edema and markedly edematous interlobular septa. Generalized icterus and an enlarged, congested, mottled or golden, friable “nutmeg” liver with distinct lobular patterns may be seen. The kidneys, spleen, and other splanchnic organs may be congested, possibly with petechiae; mild renal tubular nephrosis may be present. Hemoglobinuria and edema and hyperemia of the visceral mucosa may develop. Cardiomyopathy in affected dogs has been characterized as focal or general, granular myocardial degeneration with edema between and within myofibers; severe abnormalities in contractility have resulted in right-side congestive heart failure without pronounced dilatation, and pulmonary or hepatic changes can be minimal.
Diagnosis is based on the following: 1) a history of dietary exposure to cottonseed meal or cottonseed products over a relatively long period; 2) signs, especially sudden death or chronic dyspnea, affecting multiple animals within a group; 3) lesions consistent with the reported syndrome and associated cardiomyopathy and hepatopathy, with increased amounts of fluids in various body cavities; 4) no response to antibiotic therapy; and 5) the presence of significant concentrations of free gossypol in the diet. Analyses of dietary components for free gossypol must be correlated with history, clinical signs, and postmortem findings. However, as with many feed-induced toxicoses, the responsible feed may be already completely consumed and not available for analysis. Free gossypol at >100 mg/kg (100 ppm) of feed in the diet of pigs or young ruminants <4 mo old supports a presumptive diagnosis. Adult ruminants can detoxify higher concentrations of gossypol, but intake should still be <1,000 ppm in the diet. Gossypol toxicosis developed in mature dairy goats each fed an estimated 350–400 mg gossypol/day for 3 mo in a diet containing ~400 ppm free gossypol. Adverse effects on semen quality (decreased sperm motility and morphologic abnormalities) occurred in young bulls fed a concentrate containing 1,500 ppm free gossypol (providing 8.2 g free gossypol/head/day). Cottonseed meal containing 26.6% (266,000 ppm) total gossypol and 0.175% (1,750 ppm) free gossypol was toxic when fed to adult dogs for an unspecified length of time; however, the equivalent oral dosage of free gossypol fed was <6 mg/kg/day.
Gossypol can gradually accumulate in the kidneys and liver, which are additional specimens for postmortem analyses. In sheep, gossypol concentrations (free or bound) >10 ppm in the kidneys and >20 ppm in the liver suggest excess gossypol exposure. However, background and significantly increased tissue gossypol concentrations have not been determined in all animal species, so tissue analyses may be of limited diagnostic value.
Differential diagnoses include poisonings by cardiotoxic ionophoric antibiotics (eg, monensin, lasalocid, salinomycin, narasin) and ammonia, nutritional or metabolic disorders (eg, selenium, vitamin E, or copper deficiency), infectious diseases, noninfectious diseases (eg, pulmonary adenomatosis, emphysema), mycotoxicoses caused by Fusarium-contaminated grain, and toxicoses caused by plants with cardiotoxic and other effects. Cardiotoxic plants (see Poisonous Plants), which may cause confusing or similar clinical signs and postmortem lesions, include English yew (Taxus baccata), Japanese yew (T cuspidata), laurel (Kalmia spp), azalea (Rhododendron spp), oleander (Nerium oleander), yellow oleander or yellow-be-still tree (Thevetia peruviana), purple foxglove (Digitalis purpurea), lily-of-the-valley (Convallaria majalis), dogbane (Apocynum spp), coffee senna (Senna occidentalis), bracken fern (Pteridium aquilinum), white snakeroot (Eupatorium rugosum), death camas (Zygadenus spp), lantana (Lantana camara), monkshood (Aconitum napellum), and milkweed (Asclepias spp).
There is no effective treatment for gossypol poisoning. Adsorbents such as activated charcoal and saline cathartics are of little value because of the chronic exposure and cumulative nature of gossypol. If gossypol toxicity is suspected, all cottonseed products should be removed from the diet immediately. However, severely affected animals may still die up to 4 wk after withdrawal of gossypol from the diet. Recovery depends primarily on the extent of toxic cardiopathy. Because exposure is usually chronic, and life-threatening lesions may be advanced before a diagnosis is made, a favorable prognosis for complete recovery may be unrealistic. Mild to moderate myocardial lesions may be reversible with time if stress is minimized and animals are carefully handled. However, poor weight gains in affected livestock and increased susceptibility to stress may persist for several weeks after cottonseed products are removed from the diet. A high-quality diet supplemented with lysine, methionine, and fat-soluble vitamins should be included in supportive therapy. Selenium or copper deficiencies may potentiate gossypol toxicosis.
A high intake of protein, calcium hydroxide, or iron salts appears to be protective in cattle. Mature cattle should also be given ≥40% of dry-matter intake from a forage source, and dietary gossypol concentrations should be limited to ≤1,000 ppm, because 1,500 ppm may cause anemia, poor growth, or decreased milk production. Swine and young ruminants are affected by dietary gossypol concentrations >100 ppm. Added iron of up to 400 ppm in swine diets and up to 600 ppm in poultry diets was reported to be effective in preventing signs and tissue residues of dietary gossypol exposure when used in ratios of 1:1 to 4:1 of iron to free gossypol. Poultry are affected by dietary gossypol concentrations >200 ppm.