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Zearalenone Toxicosis In Economic Animal Production

By Dr. Ko-Hua Tso, scientific expert at Dr. Bata Ltd.
Zearalenone Toxicosis In Economic Animal Production
  1. Introduction

Animal feed is an essential part of the food chain and shows an enormous role in the safety and quality of animal by-products in the food supply chain. However, natural contamination of feed raw materials with fungal pathogens, before and after harvest, is a continuing and growing problem worldwide, as many of these fungal species produce mycotoxins that can profoundly affect animal health [1]. Zearalenone (ZEN), previously known as F-2 toxin, is a non-steroidal estrogenic mycotoxin that causes various changes and disorders related to the reproductive systems of most animal species, generating considerable economic losses in animal husbandry, especially for swine production [2-4]. ZEN and its metabolites pose a potential risk to mammals, especially when exposed to high doses over prolonged periods. Grain and balanced feeds from East Asia, Sub-Saharan Africa, and South America have the highest positive ZEN rate compared to other regions [5]. Maize is the most contaminated cereal, although ZEN has also been found in soybean, rice, rye, sorghum, oats, barley, and wheat products [6]. Zearalenone also often co-occurs with other Fusarium mycotoxins, mainly deoxynivalenol (DON) [7]. Both ZEN and DON can be produced by F. graminearum or F. culmorum, which means the most suitable moisture and temperature for Fusarium spp. growth and production of ZEN are the same that favor DON production [8]. Many global surveys indicate that the mycotoxin combinations of DON and ZEN are the most commonly detected in raw materials and finished feeds [5,9].

  1. Toxicities on Animal Production

Zearalenone is a mycotoxin with strongly estrogenic and slightly hepatotoxic as well as immunotoxic effects [6,10,11]. The sensitivities of ZEN toxicities in farm animals depend on the metabolite distribution ratio of the animal and the situations of the reproductive system (e.g., male or female; adolescence or pregnancy stages) [12]. Prepubertal female piglets are more susceptible to ZEN exposure than mature sows [13]. Zearalenone is metabolized in the digestive system and has two primary metabolites: α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) [14,15]; they are formed via the reduction of ZEN. Zearalenone and its metabolites are structurally similar to endogenous estrogen hence, bind with estradiol receptors in the absence or low presence of estrogen resulting in morphological and biological alteration in reproductive organs [12]. Besides, ZEN cause reproductive changes due to higher estrogenic potential than other natural non-steroidal estrogenic compounds [16]. The α-ZEL has a greater affinity for estrogen receptors and is, therefore, more toxic than ZEN, while the β-ZEL has a lower affinity for these receptors, making it practically harmless [17]. The species of common economic animals most sensitive to the effects of ZEN is pigs, while the second most sensitive is ruminants, and the most resistant one is poultry [18]. The main reason for this phenomenon is that the main metabolite is α-ZEL in swine, while in ruminants and birds, it is β-ZEL [19,20]. The liver is the major organ of ZEN distribution, as ZEN induces histopathological changes and causes an increase in serum transaminases and bilirubin levels in animals at high concentrations in feed ingredients and animal feeds [6,21]. In general, ZEN does not negatively affect growth performances in farm animals unless it is present in extremely high levels in cereal and complete feeds [22]. Although ZEN is strongly estrogenic, fortunately, the amount of ZEN that carries over into final animal products (meat, eggs, and milk) is minimal under typical farming systems [2,23]; therefore, humans have less chance of indirect poisoning through the food chain system.

Table 1. The guidance values of the European Union (EU) Commission, United States Food and Drug Administration (FDA), and China for zearalenone concentrations (μg/kg) in complete feed [24-26].

Animal Species EU FDA China
Swine -
  Piglets and gilts 100 - Gilts :100 ; Piglets : 150
  Sows and fattening pigs 250 - 250
Poultry - - 500
Ruminants 500 - 500

  1. Swine

Pigs are generally regarded as susceptible species to ZEN, the most sensitive being prepubertal female piglets, the second sensitive being mature sows, and the more tolerant being male swine compared to the former two [27,28]. The preliminary estrogenic effects of ZEN induce fertility disorders (infertility or reduced fertility) in swine [29]. Zearalenone inhibits the secretion of steroid hormones, interferes with the estrogen response in the pre-ovulatory phase, and inhibits mammal follicle maturation [30,31]. In female pigs, redness and swelling of the vulva, enlargement of the uterus and mammary glands, and cyst formation on the ovaries have been observed [32,33]. Zearalenone causes permanent estrus, pseudo-pregnancy, infertility, lower libido, stillbirths, and small litter in female swine upon extended exposure to higher concentrations of mycotoxin [12,34]. The European Commission stipulated limitations of 100 and 500 μg/kg for ZEN levels in the complete feed of piglets and gilts as well as sows and fattening pigs, respectively [25]. However, previous research reported that prepubertal female pigs fed 50 μg/kg of ZEN saw an increased number of vesicula follicles, while those fed 250 μg/kg of ZEN exhibited not only numerous vesicular follicles but also redness and swelling of the vulva, mammary glands swelling, and some cystic follicles on the ovaries [35]. On the other hand, ZEN induces feminization and testicular atrophy as well as reducing spermatogenesis, libido, and testosterone levels in male swine [32].

In addition to causing reproductive disorders, feeding female pigs 1.3 mg/kg of ZEN can reduce platelets, hemoglobin, globulin, triglycerides, and high-density lipoproteins in serum; increase enzyme activities; and lead to the degeneration of the liver and kidney [36]. Zearalenone is also a potential hepatotoxin and spleen toxin which induce oxidative stress and inflammation [37,38]. Besides, swine exposed to feed containing high doses of ZEN induced poor growth performances [39]. Previous meta-analysis research pointed out that feed containing an average of 3.8 mg/kg of ZEN resulted to 15.8% in feed intake and 28.8% in body weight gain reductions [40]. 

In terms of effects on future generations, in general, piglets can be exposed to ZEN in utero or by ingesting contaminated sow milk [38]. There are numerous cases of ZEN causing low reproductive performances in pigs in the field [13]. In Serbia and Germany, some swine farms observed such symptoms as increased rates of rebreeding, infertility, and anestrus in sows and a large number of stillborn and farrowed piglets with vulvovaginitis [13]. 

Fig. 1 Two-day old piglet of exposed sows with a swollen vulva. [13]

Table 1. Zearalenone (ZEN) toxicities on reproductive abilities and growth performances in swine

Stage ZEN level Effects Reference
Reproductive ability
Postweaning female piglets >100 μg/kg Inhibited follicles maturation and ovarian development; increased length, width, height, and area of vulval (vulvar malformation); reproductive related hormonal imbalance (e.g., luteinizing hormone) [33,36,41]
prepubertal female piglets >50 μg/kg Increased vesicular follicles, redness and swelling of the vulva, mammary glands swelling, and some cystic follicles on the ovaries; reproductive related hormonal imbalance (e.g., luteinizing hormone) [27,35,37]
Sow and gilts >200 μg/kg Disturbances of development and maturation of ovarian follicles; reproductive system disorders and abnormal estrous cycle; reproductive related hormonal imbalance (e.g., luteinizing hormone) [42,43]
Pregnant sow >250 μg/kg Increased rates of rebreeding, infertility, and anestrus in sows and a large number of stillborn and farrowed piglets with vulvovaginitis [44,45]
Mature male swine >200 mg/kg Feminization and testicular atrophy as well as reducing spermatogenesis, libido, and testosterone levels [29,46]
Growth performance
Growing pig >3 mg/kg Decreased feed intake and body weight gain; damages of liver and spleen [15,33,47]

2.2 Poultry

Poultry responds to the presence of ZEN in the feed only at relatively high dietary concentrations and can generally be regarded as resistant [48]. There are two main conclusions regarding this phenomenon: The leading opinion to the naturally high concentration of estrogen in poultry blood, seeing as natural estrogens are considered to higher receptor affinity compare to ZEN [23]; the other opinion suggested that most research indicated ZEN was more extensively metabolized to less toxic α-ZEL than β-ZEL [49]. Zearalenone toxicities are observed only at exposure levels, hardly to occur under experimental poultry feeding conditions or continuous feeding for an exceedingly long period [48]. Furthermore, the EU has not imposed maximum ZEN limits because poultry has a high tolerance towards the substance as well [25]. Exposing adult laying hens to feed containing 0.75 mg/kg of ZEN for 35 days resulted in significant reduction in egg production compared with control group [3]. Besides, male turkeys fed 400 and 800 mg/kg of ZEN had a reduced sperm percentage and fertilization rate, and it promoted precocity [50]. Therefore, ZEN has low reproductive toxicity to poultry. Zearalenone almost did not affect growth performances (e.g., feed intake, body weight, and feed conversion ratio) unless chicks were fed a diet of over 2 mg/kg for 42 days [51]. In contrast, feeding ZEN-contaminated diets to turkeys leads to strutting behavior, increased size and coloration of caruncles and dewlaps, and swollen vent tissue [52]. An additional study indicated that purified ZEN increases oviduct development in growing female chickens and delays the growth of the testes in young male chickens [50]. In commercial feeding conditions, there are no detected ZEN residues in eggs from commercial production. However, previous research indicated that for feed containing high dose exposure of ZEN (10 mg/kg) in laying hens, significant levels of ZEN lipophilic metabolites might accumulate in the egg yolk if the exposure time was prolonged [53].

Table 2. Zearalenone (ZEN) toxicities on growth performances and reproductive abilities in poultry

Stage ZEN level  Effects Reference
Laying hens  >0.4 mg/kg for more than seven weeks Increased relative weight of oviduct and ovary, degeneration, and atrophy of the ovarian tissues [54,55]
Laying hens  >0.75 mg/kg diet for more than 5 weeks Increased feed conversion ratio (g feed/g egg), decreased egg production, albumen height, and Haugh unit [3]
Broiler  > 2 mg/kg diet for more than 3 weeks Decreased body weight gain, increased feed conversion ratio (g feed/g body weight), relative weight of liver, and liver damage [4,51]

2.3 Ruminants

The European Commission stipulated limitations of 500 μg/kg for ZEN levels in the complete feed of ruminants [25]. Zearalenone is produced in trace amounts in concentrates and forage (the average level of which being 25 to 100 μg/kg) occurring naturally [5], and rumen microbes extensively metabolize ZEN to generate less toxic metabolites (i.e., β-ZEL) [56]. Therefore, ruminants usually do not show symptoms of ZEN poisoning [2] unless highly superior levels of ZEN or other mycotoxins (e.g., DON) are both present in concentrates and forage [7]. Previous studies found that dairy herds receiving a diet contaminated with both DON and ZEN at levels of about 500 and 750 μg/kg, respectively, showed unsynchronized ovarian cycles, vaginitis, and early development of mammary glands in heifers [57]. However, heifers fed a diet containing only 1.25 mg/kg of ZEN did not show reproductive issues [58]. Zearalenone is toxic to ruminants at extremely high levels (at high doses rarely seen in nature) in naturally occurring concentrates and forages. Britain's research showed decreasing fertility in the dairy cows fed hay and grass silage containing ZEN at 14 mg/kg [59]. Another study indicated that dairy cows fed with ZEN-contaminated grain (25 mg/kg) show vaginitis, extended estrus, and decreased feed intake, and milk yield [59]. 

Currently, the only known field case is grazing sheep in New Zealand that were poisoned by ZEN, which caused infertility [60]. Most field or case reports in which a direct relationship between ZEN exposition levels and symptoms of estrogenic effects was not found were reported, suggesting this might reflect the variability in rumen degradation of ZEN. Previous research orally administered virgin heifers with an extremely high ZEN dose (250 mg) for 66 days, resulting in a slightly decreased conception rate (62%) compared to 87% found in the untreated control group) [48]. In general, ZEN and its metabolites can be detectable in the liver and bile, but most studies are not detected in milk because of their endogenous ruminal detoxification [61]. However, when dairy cows ingest exceptionally high levels of concentrates, that typically induces ZEN to carry over into milk. For instance, previous researchers found that 0.7% of ZEN could carry over into milk when 200 mg of ZEN/day is detected in the concentrate for 7 days [2].  

Table 3. Zearalenone (ZEN) toxicities on growth performances and reproductive abilities in ruminants

Animal/Stage ZEN level  Duration Effects Reference
Beef heifer 0.3 mg/kg 98 day Only decreased oocyte quality [31]
Breeding cow 1 mg/kg diet 30 day Increased ovarian antral follicle population; increased synthesis of AMH by granulosa cells; no effect of fertility [62]
Dry cow 5.9 mg/kg TMR 2 day Altered rumen microflora; decreased rumen pH; increased fiber breakdown; increased feed intake [56]
Ewe >3 mg/ewe/day 10 day Reproductive disorders, lower lambing percentages and infertility [63]

AMH: anti-müllerian hormone; TMR: total mixed ration. 

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