Fusarium spp fungi are extremely common and often contaminate growing plants and stored feeds. Corn (maize), wheat, and barley, and forage (silages) are commonly contaminated. In moderate climates under humid weather conditions, F graminearum and several other Fusarium species can produce zearalenone, one of the resorcyclic acid lactones (RALs). Zearalenone (formerly called F2 toxin) is a potent nonsteroidal estrogen and is the only known mycotoxin with primarily estrogenic effects. Often, zearalenone is produced concurrently with deoxynivalenol. Depending on the ratio of these two mycotoxins, signs of reduced feed intake or reproductive dysfunction may predominate, but presence of deoxynivalenol may limit exposure to zearalenone, thus reducing its practical effect.
In the body, zearalenone binds to receptors for 17-beta-estradiol, and this complex binds to estradiol sites on DNA. Specific RNA synthesis leads to signs of estrogenism. Zearalenone is a weak estrogen with potency 2 to 4 times less than estradiol. Under controlled administration, zearalanol, a closely related RAL, is widely used in cattle as an anabolic agent.
Estrogenism due to zearalenone was first clinically recognized as vulvovaginitis in prepubertal gilts fed moldy corn (maize), but zearalenone is occasionally reported as a suspected disease-causing agent for sporadic outbreaks in dairy cattle, sheep, chickens, and turkeys. High dietary concentrations (>20–30 ppm) are required to produce infertility in cattle and sheep, and extremely high dosages are required to affect poultry.
Etiology of Estrogenism and Vulvovaginitis in Animals
Zearalenone has been detected in corn, oats, barley, wheat, and sorghum (both fresh and stored); in rations compounded for cattle and pigs; in corn ensiled at the green stage; and occasionally in hay that has been stored wet. It has been detected occasionally in samples from pastures in temperate climates at levels believed sufficient to cause reproductive failure of grazing herbivores. Additionally, significant concentrations of zearalenone and the trichothecene mycotoxins DON (deoxynivalenol) and T-2/HT-2 toxins can be produced within 7 to 14 days after hail storms in field corn maturing in late July through September in North America. Historically, the practice of storing ear corn in open wire corn cribs in North America often contributed to increased zearalenone concentrations in the corn that was produced during late winter.
Clinical Findings of Estrogenism and Vulvovaginitis in Animals
Clinical effects cannot be distinguished from excessive estrogen administration or from consumption of significant concentrations of phytoestrogens, particularly coumestrol in alfalfa and white clover and some of the isoflavones in red clover. Physical and behavioral signs of estrus are induced in young gilts by dietary zearalenone at a concentration as little as 1 ppm. In pigs, zearalenone primarily affects weaned and prepubertal gilts, causing hyperemia and enlargement of the vulva (known as vulvovaginitis). There is hypertrophy of the mammary glands and uterus, and abdominal straining results in prolapse of the uterus and rectum in severe cases. Removal of affected grain results in return to normal in ~1 week and up to 3 weeks.
Zearalenone causes reproductive toxicosis in sexually mature sows by inhibiting secretion and release of follicle-stimulating hormone (FSH), resulting in arrest of preovulatory ovarian follicle maturation. Reproductive effects in sexually mature sows depend on time of consumption. Zearalenone fed at 3–10 ppm on days 12–14 of the estrous cycle in open gilts results in retention of corpora lutea and prolonged anestrus (pseudopregnancy) for up to 40–60 days. Zearalenone fed at ≥30 ppm in early gestation (7–10 days after breeding) may prevent implantation and cause early embryonic death. Zearalenone metabolites can be excreted in milk of exposed sows, resulting in hyperestrogenic effects in their nursing piglets.
In cattle, dietary concentrations >10 ppm may cause reproductive dysfunction in dairy heifers, although mature cows may tolerate up to 20 ppm.
Young males, both swine and cattle, may become infertile, with atrophy of the testes. However, mature boars appear unaffected by as much as 200 ppm dietary zearalenone. Zearalenone in male animals can act as an anabolic agent.
Ewes may show reduced reproductive performance (reduced ovulation rates and numbers of fertilized ova, and markedly increased duration of estrus) and abortion or premature live births.
Lesions in pigs include ovarian atrophy and follicular atresia, uterine edema, cellular hypertrophy in all layers of the uterus, and a cystic appearance in degenerative endometrial glands. The mammary glands show ductal hyperplasia and epithelial proliferation. Squamous metaplasia occurs in the cervix and vagina. Sexually mature sows will have retained corpora lutea for 40–70 days after exposure, consistent with signs of pseudopregnancy.
Diagnosis of Estrogenism and Vulvovaginitis in Animals
History and clinical signs
Chemical analysis of suspect feed
Diagnosis is based on altered reproductive performance in the herd or flock, clinical signs, or hyperestrogenism such as swollen mammary glands and vulvae, prolapsing vulva, uterus, and rectum, history of diet-related occurrence, and excluding other known causes of infertility. Chemical analysis of suspect feed for zearalenone and careful examination of reproductive organs at postmortem examination are required. Differential diagnoses include reproductive tract infections and other causes of impaired fertility such as diethylstilbestrol in the diet of housed stock. In grazing herbivores, especially sheep, the plant estrogens (eg, isoflavones associated with some varieties of subterranean and red clovers, as well as coumestans in certain fodders [eg, alfalfa]) affecting cattle and horses should be considered.
Control of Estrogenism and Vulvovaginitis in Animals
Stop exposure to contaminated feed.
Switch to a clean feed.
Management of swine with hyperestrogenism should include changing the grain immediately. Signs should stop within 1 week. Animals should be treated symptomatically for vaginal or rectal prolapse and physical damage to external genitalia. For sexually mature sows with anestrus, one 10-mg dose of prostaglandin F2alpha, or two 5-mg doses on successive days, has corrected anestrus caused by retained corpora. Alfalfa and alfalfa meal fed to swine at 25% of the ration may reduce absorption and increase fecal excretion of zearalenone, but this is often not considered practical and alfalfa can contain phytoestrogens that can be an additive effect to zearalenone. Feeding activated charcoal, cholestyramine, or alfalfa meal may reduce zearalenone absorption and retention, but the high concentrations needed generally render this impractical.
The US FDA does not have guidelines for zearalenone levels in animal feeds; however, the EU has proposed zearalenone guidelines for complete feedstuffs for different species and all are <0.5 ppm (500 ppb).
Unless livestock are severely or chronically affected, usually reproductive functions recover and signs regress 1–4 weeks after intake of zearalenone ceases. However, multiparous sows may remain anestrous up to 8–10 weeks. If required, surgical intervention to replace prolapsed rectums and vaginas/uterus may be required.
Several Fusarium species, but particularly F graminearum, can produce the estrogenic mycotoxin zearalenone under conditions of warm days and cool nights during the late summer and fall in growing plants (corn or maize, wheat, barley) and stored feeds such as corn silages and wet hays.
Zearaelenone is a potent estrogen that binds to receptors for 17 beta-estradiol and causes hyperestrogenism.
Young pigs are the most susceptible and clinical signs can include swollen vulvae and mammary glands, abdominal straining and sometimes prolapse of the uterus and rectum; females can develop abnormal estrous cycles and at higher concentration male animals may be less fertile.
Treatment is to stop the exposure to contaminated feed and switch to clean feed (the European Community has proposed a guideline for zearalenone in animal feeds of <0.5 ppm [500 ppb]).
For More Information
European Food Safety Authority CONTAM Panel (EFSA panel on contaminants in the food chain), Knutsen HK, Alexander J, Barregard L, et al. Scientific opinion on the risks for animal health related to the presence of zearalenone and its modified forms in feed. EFSA Journal 2017:15(7):4851, 123 pp. https://doi.org/10.2903/j.efsa.2017.4851.
Commission of European Communities (EC). Commission recommendation on the presence of deoxynivalenol, zearalenone, ochratoxin A, T-2 and HT-2 and fumonisins in products intended for animal feeding. 17 August 2006. Official J European Union. 23.8.2006 2006/576/EC. Accessed 2010.
Meerdink GL. Zearalenone. In: Plumlee KH, ed. Clinical Veterinary Toxicology. St. Louis: Mosby, 2004:273-275
Minervini F, Dell’Aquilla ME. Zearalenone and reproductive function in farm animals. Int J Mol Sci 2008;12:2570-2584.