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The Scientific World Journal

Volume 2014 (2014), Article ID 231635, 11 pages

http://dx.doi.org/10.1155/2014/231635
Review Article

Gossypol Toxicity from Cottonseed Products

1Programa de Pós-graduação em Ciência Animal, Universidade Federal Rural do Semi-Árido, BR 110 Km 47, 59628-360 Mossoró, RN, Brazil

2Fundação Ezequiel Dias (FUNED), Rua Conde Pereira Carneiro 80, 30510-010 Belo Horizonte, MG, Brazil

3Departamento de Clínica e Cirurgia Veterinárias, Escola de Veterinária, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, 30123-970 Belo Horizonte, MG, Brazil

Received 29 January 2014; Revised 4 April 2014; Accepted 16 April 2014; Published 6 May 2014

Academic Editor: Chad C. Chase Jr.

Copyright © 2014 Ivana Cristina N. Gadelha et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Gossypol is a phenolic compound produced by pigment glands in cotton stems, leaves, seeds, and flower buds (Gossypium spp.). Cottonseed meal is a by-product of cotton that is used for animal feeding because it is rich in oil and proteins. However, gossypol toxicity limits cottonseed use in animal feed. High concentrations of free gossypol may be responsible for acute clinical signs of gossypol poisoning which include respiratory distress, impaired body weight gain, anorexia, weakness, apathy, and death after several days. However, the most common toxic effects is the impairment of male and female reproduction. Another important toxic effect of gossypol is its interference with immune function, reducing an animal’s resistance to infections and impairing the efficiency of vaccines. Preventive procedures to limit gossypol toxicity involve treatment of the cottonseed product to reduce the concentration of free gossypol with the most common treatment being exposure to heat. However, free gossypol can be released from the bound form during digestion. Agronomic selection has produced cotton varieties devoid of glands producing gossypol, but these varieties are not normally grown because they are less productive and are more vulnerable to attacks by insects.

1. Introduction

Cotton (Gossypium spp.) is an arborous plant from the Malvaceae family. It is one of the earliest plants that were cultivated by man and it has been used for over 4,000 years. It is primarily cultivated for fiber used in the textile industry and the oil from the cotton seed [1]. The genus Gossypium spp. includes many species distributed throughout the world, but only four species are grown for cotton fiber: Gossypium hirsutum L., Gossypium barbadense L., Gossypium arboreum L., and Gossypium herbaceum L. The most economically important cotton species is G. hirsutum, which is grown to produce 90% of the world’s cotton [2]. Cotton fiber and oil production generate byproducts rich in fat from oil and protein which are used for animal feeding. However, this plant contains a toxic compound, gossypol [1].

2. Chemistry of Gossypol

Gossypol is a phenolic compound that was first isolated in 1899. The name is derived from the plant genus scientific name (Gossypium) combined with the ending “ol” from phenol [1]. Gossypol has a 518.55 Dalton molecular weight, has a yellow pigment, is crystalline, is insoluble in water and hexane, is soluble in acetone, chloroform, ether, and methyl ethyl ketone (butanone), and is partly soluble in crude vegetable oils. The chemical formula is C30H30O8, and the chemical structural formula is 2,2′-bis(8-formyl-1,6,7-trihydroxy-5-isopropyl-3-methylnaphthalene) (Figure 1) [1, 3, 4].

231635.fig.001
Figure 1: Chemical structure, formula, and structural formula of gossypol.

Gossypol is produced by pigment glands in cotton stems, leaves, seeds, and flower buds. The pigment glands are small black spots distributed throughout the cotton plant but their greatest concentration is in the seeds [1, 46]. The seed of G. barbadense may contain up to 34 g of gossypol/kg [7]. Gossypol promotes several toxic effects in vertebrates but provides the cotton plant with resistance to pests [1, 46]. The pigment glands produce additional phenolic pigments (at least 14), but they are at concentrations well below the concentration of gossypol and thus have little toxicological significance [1].

Gossypol is a mixture of two enantiomers, (−) and (+) gossypol [1, 811]. The (−) gossypol enantiomer is more slowly eliminated [12], although it is the most biologically active form. Consequently, it is more toxic than the (+) gossypol [11, 13]. The Gossypium species produces both enantiomers in varying proportions, which is genetically determined [1, 9, 10, 14]. For example, the (−) gossypol proportion ranges from 33.8 to 47.0% in the seeds of upland variety (G. hirsutum) [15, 16] and from 24.9 to 68.9% in the seeds of G. barbadense [7].

Two gossypol forms have been observed, free and bound [6]. The bound form is produced via covalent bonds between gossypol and the free epsilon-amino groups from lysine and arginine [1, 17, 18] through the browning or Maillard reaction [1]. However, this reaction reduces the availability of amino acids for absorption by the animal with lysine being the most affected [18].

Total gossypol production is influenced by several factors, including weather conditions and cotton species. Considering weather conditions, gossypol production is positively correlated with the rainfall rate and negatively correlated with temperature [19]. Regarding variation among cotton species, G. barbadense has higher gossypol concentrations than G. hirsutum. On the other hand, cotton storage slightly decreases the free gossypol content [1].

3. Gossypol in Cotton Products

The free gossypol content in whole cotton seeds varies among the many cotton varieties [6, 20]; gossypol concentrations range from 0.02 to 6.64% [21]. Cottonseed may contain concentrations greater than 14,000 mg/kg of total gossypol and 7,000 mg/kg of free gossypol [6]. However, after oil extraction from the seeds, up to 0.6% is available following solvent extraction, but approximately 0.06% is available, if the extraction process involves mechanical pressure and heat treatment [22].

In addition to its harmful effects, gossypol and its derivatives have potential therapeutic use. These compounds showed in vitro action against some viruses such as human immunodeficiency virus [23, 24] and H5N1 influenza virus [24, 25] and several bacteria and yeasts [2629]. Gossypol is a promising treatment for leukemia [30], lymphoma [31], colon carcinoma [32], breast cancer [33, 34], myoma [35], prostate cancer [36], and other malignancies [3743]. Furthermore, it was used in China, in 1970, to treat uterine fibroids, endometriosis, and uterine bleeding in women [35].

4. Toxicokinetics

The gossypol absorption rate is inversely proportional to the amount of iron in the diet [71], and dietary supplementation with ferrous sulfate inactivates free gossypol [72]. In ruminants, microbial fermentation in the rumen binds dietary free gossypol with proteins [73], but it is not known whether the bound form can be absorbed by the intestines or the microorganisms can release free gossypol from the bound form. The absorbed gossypol accumulates in the liver [74] and kidneys [75]. The primary gossypol excretion route is through bile; it is then eliminated through feces after conjugation with glucuronides and sulfates [76]. In rats dosed orally with 5 mg of both racemic forms of gossypol, 70.4% of (+) and 80.2% of (−) gossypol were excreted in the feces within five days, whereas 2.30% of (+) and 2.79% of (−) gossypol were excreted in the urine [77]. Small amounts of gossypol are also excreted in expired air [1]. Little to no gossypol is excreted in the milk [74]. The half-lives ( ) of total (+) and (−) gossypol in rats following a single intravenous dose were estimated as 25.26 hours and 10.53 hours, respectively [77].

5. Gossypol Poisoning

Cottonseed includes sufficiently high gossypol concentrations to produce acute poisoning. However, there are cumulative effects of dietary gossypol and toxicity which can occur following an ingestion period of one to three months [1, 7881]. Gossypol poisoning has been reported in many species, including broiler chicks [82], pigs [71], dogs [83, 84], sheep [85], and goats [86]. Monogastric animals, such as pigs, birds, fish, and rodents, are more susceptible to gossypol toxicity than ruminants [5, 6, 20, 87]. Moreover, young ruminants are more sensitive to gossypol compared with adult ruminants [1] because gossypol is not bound during ruminal fermentation, as it occurs in animals with fully functional rumens. However, if the gossypol intake overwhelms the ruminal detoxification capacity, free gossypol may be absorbed at hazardous concentrations even in adult ruminant animals [88].

General signs of acute toxicity are similar among animal species and include respiratory distress, impaired body weight gain, anorexia, weakness, apathy, and death after several days [1, 6, 80, 85, 8993]. Heart failure was reported in calves [90, 94], lambs [85], and dogs [79].

The postmortem findings in ruminants include pulmonary edema, yellowish liquid in the chest and peritoneal cavities, gastroenteritis, centrilobular liver necrosis, and hypertrophic cardiac fiber degeneration. In calves, the major pathologic findings are ascites, visceral edema, acute centrilobular hepatocyte necrosis, kidney damage, and cardiovascular lesions. Increased pneumonia has also been observed, likely due to an increased sensitivity to secondary infections [85, 9092].

Pigs may present reduced weight gain, anorexia, respiratory distress, cardiac insufficiency, coughing, and exercise intolerance. Necropsy findings include fluid accumulation in the body cavities; edema and congestion in the liver, lung, and spleen; and cardiac hypertrophy with degenerated muscle fiber [71].

Anemia is often observed in animals fed cottonseed. In fact, gossypol is a highly reactive compound that readily binds to minerals and amino acids. Binding with iron forms a gossypol-iron complex, which inhibits the absorption of this metal. The consequent iron deficiency affects erythropoiesis. Furthermore, gossypol promotes increased erythrocyte fragility [57, 74, 87, 95]. Gossypol also stimulates the eryptosis (apoptosis-like erythrocyte death) by increasing cytosolic Ca2+ activity resulting in cell membrane scrambling and contraction, which contributes to anemia [96].

Gossypol also affects thyroidal metabolism [68, 97100]. Some studies with male [98] and female [99] rats showed decreased blood concentrations of T4 and T3 after dosing with gossypol. On the other hand, gossypol dosing resulted in increased T3 serum concentrations without affecting T4 in rats [97] and sheep [68]. The histopathological evaluation of thyroid glands from male rats dosed with gossypol revealed follicular degeneration and atrophy [98]. The thyrotropic cells in the pituitary gland, which are specialized for TSH synthesis and secretion, showed hypertrophy, hyperplasia, and degranulation after gossypol dosing in rats [100].

Certain clinical signs of gossypol poisoning have been attributed to reduced antioxidants in tissues and increased reactive oxygen species formation, which produces lipid peroxidation [101104]. At high concentrations, gossypol also impairs energy generation from oxidative metabolism by interfering with enzymatic activity in the mitochondrial electron transport chain and oxidative phosphorylation [105107]. Furthermore, gossypol decreases the contraction force of the heart and the extent of contraction of cardiac fibers [108].

6. Liver Damage

In addition to such effects, gossypol is hepatotoxic (Table 1) [11, 4447, 71, 109, 110]. Ascites and hepatocyte degeneration (strong cytoplasmic eosinophilia and nuclear pyknosis) were observed in rats that received a single intraperitoneal gossypol dose of 25 mg/kg BW [45] or 30 mg/kg BW [46]. Rats that received lower gossypol doses (15 mg/kg/day for four weeks or 30 mg/kg/day for two weeks) showed morphological changes in the liver, as observed through electron microscopy, which were characterized by mitochondrial vacuolation, an enlarged endoplasmatic reticulum, an expanded perinuclear space, and collagen fiber proliferation in the perisinusoidal space [109]. Chickens fed a diet with 0.1% free gossypol for 21 days had increased plasma gamma glutamyltransferase activity and liver lipidosis [44]. Broilers that received a diet with 0.4% total gossypol for 20 days had greater liver weights [11].

tab1
Table 1: Experimental studies showing liver damage induced by gossypol.

7. Reproductive Effects

Gossypol affects male and female gametogenesis and promotes embryo lesions [81]. In the 1950s, China underwent a sharp drop in the birthrate in many rural areas where humans were consuming cottonseed oil containing gossypol. This observation was initially associated with male infertility caused by gossypol in the cottonseed oil that they were consuming. Gossypol has been investigated for use as a male contraceptive in a number of experimental studies [1, 81, 111115].

The gossypol toxicity for male reproduction (Table 2) was reported in several studies showing that it inhibits spermatogenesis, which decreases the sperm count and spermatozoid motility and viability [20, 4751, 53, 55, 102, 116120]. The male antifertility effect is dose and time dependent; in effective doses, gossypol causes infertility by inhibiting sperm motility, decreasing sperm concentrations, inducing specific mitochondrial injury to the sperm tail, and damaging the germinal epithelium [20]. However, such effects are reversible when gossypol is no longer ingested [52]. Furthermore, gossypol administration to male rats did not interfere in the embryonic and fetal development of untreated dam offspring [121].

tab2
Table 2: Selected experimental studies describing effects of gossypol on male reproduction.

The deleterious effects on male reproduction have not been observed for all animals fed cottonseed meal. In adult male goats [122] and sheep [123] fed a diet with 0.5 kg/animal/day cottonseed meal for 120 consecutive days, no detrimental effects on semen volume, sperm concentration, motility, and morphology.

The gossypol-mediated spermatozoid disturbance mechanism includes the inhibition of release and utilization of ATP by the sperm cells [124]. Another effect of gossypol is the reduction of cellular and microtubular -tubular content in spermatocytes and spermatids [125]. Furthermore, gossypol inhibits calcium influx [126, 127] and Mg-ATPase and Ca-Mg-ATPase activity in spermatozoid plasmatic membranes [126]. Abnormal spermatozoids are produced because gossypol produces ultrastructural alterations in the nuclear membrane, endoplasmic reticulum, and mitochondria [119, 128130]. In cultivated Sertoli cells from piglets, gossypol also decreases cellular oxidase activity and damages the DNA [131]. Reduced nuclear expression of androgen receptors was observed in Leydig cells, Sertoli cells, and myoid cells from rats fed gossypol-rich cottonseed flour [132].

Gossypol also affects female reproduction (Table 3), and ruminant females tolerate higher dietary gossypol concentrations than nonruminant females [20, 54, 118, 133], probably due to the ruminal detoxification. Female exposure to gossypol has been associated with interference with the estrous cycle, pregnancy, and early embryonic development [20, 57, 81]. Gossypol interfered with rodent estrous cycles [54, 134] and pig granulosa cell function [135]. Furthermore, ovaries from heifers fed cottonseed meal had fewer large follicles (>5 mm) than heifers fed soybean meal [57]. Gossypol affected in vitro ovarian steroidogenesis [136, 137] as well as bovine oocyte cumulus expansion and nuclear maturation [137].

tab3
Table 3: Selected experimental studies describing effects of gossypol on female reproduction.

Previous studies have shown that gossypol interferes with embryonic development [118, 138141]. In fact, gossypol may reach the uterine fluids through the maternal circulation [141]. A gossypol-mediated embryotoxic effect has been observed in in vitro [118, 138, 140142] and in vivo [57, 139, 141, 143] studies. The early pregnancy loss promoted by gossypol is not due exclusively to direct damage to embryos but also to interference with implantation of the embryo [139]. However, this compound significantly reduced the fetal body weight in pregnant mice, but no fetal abnormalities were observed [144].

The probable mechanism for gossypol embryotoxicity is through direct embryonic cytotoxicity [20, 143]. This cytotoxic effect might be promoted by (1) generation of reactive oxygen species inducing oxidative stress [102, 104, 145], (2) intercellular communication disruption [146], (3) apoptosis induction [32, 147152], or (4) interference with ionic transport in membranes, which increases intracellular calcium [153].

8. Immunotoxicity

Gossypol may cause a reduced number of leukocytes and primarily lymphocytes, which affects the immunocompetence of the organism [154]. In vivo and in vitro mouse experiments also demonstrated that gossypol has immunosuppressive activity [155], which operates by affecting lymphocytes through inhibiting proliferation and inducing apoptosis [155, 156]. Mice that received gossypol had significantly decreased numbers of lymphocytes in the thymus and mesenteric lymph nodes [157], in the total spleen cell population [144], and in the capacity of blood and lymphatic cells to produce antibodies after sheep erythrocyte immunization [144, 157]. Furthermore, the spleen and lymph nodes from mice receiving gossypol had decreased CD4+ thymocyte populations and increased CD8+ lymphocyte populations [157].

The interference of gossypol with lymphocytes influence immune function as observed in a number of studies [157160]. After inoculation with Brucella abortus smooth strain 99 (S99), specific anti-Brucella antibody production was impaired in lambs [159] and calves [160] fed cottonseed meal. Mice treated with gossypol had decreased IgM and IgG production after sheep erythrocyte immunization [157]. Men treated with gossypol as a male contraceptive showed reduced IgG titers which could be associated with altered lymphocytes [158].

In vitro murine macrophage proliferation was inhibited by gossypol [157]. Furthermore, rat peritoneal macrophages incubated with gossypol inhibited arachidonic acid metabolism and prostaglandin E2 production [161]. On the other hand, macrophage chemotaxis induced by Edwardsiella ictaluri challenge was increased in channel catfish (Ictalurus punctatus) fed cottonseed [162] or receiving gossypol [163], but catfish were unaffected by gossypol in another study [27]. Gossypol also increased serum lysozyme activity in channel catfish following an E. ictaluri challenge [27, 163].

9. Preventive Procedures

The preventive procedures at this time involve the treatment of cottonseed products to decrease the concentrations of free gossypol through the use of heat and pressure in the processing of these products (Table 4). Agronomic selection has produced cotton varieties devoid of glands producing gossypol [164], but these varieties are less grown because they are not as productive and are more vulnerable to attacks by insects [1]. One alternative is the selection and use of cotton varieties containing a relatively high (+) to (−) gossypol enantiomer ratio [13]. The directive 2002/32 of the European Union (2002L0032 - EN - 26.02.2013 - 017.001) states that the maximum free gossypol concentrations for cottonseed are 5,000 ppm and 1,200 ppm for cottonseed meal or cake and, for complete feeding stuffs, are 20 ppm for laying hens and piglets, 60 ppm for rabbits and pigs, 100 ppm for poultry and calves, and 500 ppm for cattle, sheep, and goats.

tab4
Table 4: Preventive procedures for reducing gossypol toxicity.

Processing including heat treatment [58, 165] and extrusion process [59] can reduce free gossypol concentrations in cottonseed. However, it is possible that the conjugate formed can release free gossypol during digestion. In fact, cows fed diets containing whole cottonseed with similar total gossypol concentrations but different free gossypol concentrations had similar total plasma gossypol [59]. Furthermore, even though the extrusion process reduced free gossypol concentration but not the total gossypol concentration; broiler chicks fed extruded cottonseed meal or feed-grade cottonseed meal showed decreased body weight gain, increased feed intake, and inefficient feed conversion rate [166].

Radiation treatment using gamma [60, 167, 168] or electron beam irradiation [60, 61] may reduce free gossypol concentrations. In fact, gossypol irradiation reduced in vitro prooxidative activity and embryotoxicity in mice [168]. The mechanism for gossypol destruction through radiation is unknown, but it has been speculated that gossypol molecule aggregation, gossypol cross-linking with other molecules, and gossypol molecule fragmentation or breakdown may produce such destruction [61]. On the other hand, ammoniation, which is a procedure that is used to reduce aflatoxin content of food, increased cottonseed meal toxicity in dairy cattle [169].

Some fungus may reduce free gossypol concentrations in cottonseed meal by fermentation, including Aspergillus niger [63, 64, 170], Aspergillus oryzae [62], Candida tropicalis [6366], Saccharomyces cerevisiae [63, 64], and Geotrichum candidum [67]. The use of fermented cottonseed meal to feed animals seems to be safe [62, 171]. However, while these microorganisms could be used to reduce free gossypol concentration in cottonseed meal, they are not currently commercially available.

Supplementation with ferric sulfate reduces free gossypol concentrations in food due to ferric sulfate binding with reactive groups from gossypol, which forms a conjugate. The recommendation for supplementation is 1 mol of gossypol for each mol of iron, which could increase the maximum concentration of gossypol from 50 to 150 ppm for laying birds and from 100 ppm to 400 ppm for pigs and poultry [1]. Additional nutrients may be used for dietary supplementation to reduce gossypol availability. Supplementing the diet with 1 mg of sodium selenite per day in adult sheep reduced the gossypol toxicity affecting semen quality [68]. Dietary vitamin E supplementation at 4000 IU/bull/day also reversed the negative effects of gossypol on sperm production and semen quality of bulls [69] and reversed the increased erythrocyte osmotic fragility in heifers [70] promoted by feeding cottonseed meal.

Gossypol was produced as a conjugate with bovine serum albumin for vaccines. This conjugate induces antibody production against gossypol in rats, but the immunized animals were more sensitive to the acute hepatotoxic effect of gossypol [46].

10. Conclusions and Future Research Directions

The ingestion of gossypol present in cottonseed and its products (cakes and meal) may promote clinical poisoning, liver damage, male and female reproductive toxicity, and immunological impairment. The acute poisoning is not currently a significant problem but the reproductive damage causes serious economic losses to the livestock industry. Even though the male reproductive toxicity is well known, there is a need for more studies to understand the female reproductive damage promoted by gossypol. The immunotoxicity of gossypol is far from being completely elucidated, but it impacts animals by reducing their resistance to infections and by impairing the efficiency of vaccines. Extensive research is needed to develop more efficient and inexpensive technologies to reduce gossypol toxicity.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

This work received support for language editing by the Pró-Reitoria de Pesquisa of the Universidade Federal de Minas Gerais (Edital PRP-UFMG 03/2013).

References

  1. B. Soto-Blanco, “Gossipol e fatores antinutricionais da soja,” in Toxicologia Aplicada à MedicIna VeterInária, H. S. Spinosa, S. L. Górniak, and J. P. Neto, Eds., pp. 531–545, Manole, Barueri, Brazil, 2008.
  2. A. Borém, E. C. Freire, J. Cesar, V. Penna, and P. A. Vianna, “Considerations about cotton gene escape in Brazil: a review,” Crop Breeding and Applied Biotechnology, vol. 3, no. 4, pp. 315–332, 2003. View at Publisher · View at Google Scholar
  3. M. B. Abou-Donia, “Physiological effects and metabolism of gossypol,” Residue Reviews, vol. 61, pp. 125–160, 1976. View at Scopus
  4. G. M. Rogers, M. H. Poore, and J. C. Paschal, “Feeding cotton products to cattle,” Veterinary Clinics of North America: Food Animal Practice, vol. 18, no. 2, pp. 267–294, 2002. View at Publisher · View at Google Scholar · View at Scopus
  5. J. A. Kenar, “Reaction chemistry of gossypol and its derivatives,” Journal of the American Oil Chemists' Society, vol. 83, no. 4, pp. 269–302, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. J. Alexander, D. Benford, A. Cockburn et al., “Gossypol as undesirable substance in animal feed,” EFSA Journal, vol. 908, pp. 1–55, 2008.
  7. R. G. Percy, M. C. Calhoun, and H. L. Kim, “Seed gossypol variation within Gossypium barbadense L. cotton,” Crop Science, vol. 36, no. 1, pp. 193–197, 1996. View at Scopus
  8. R. J. Hron Sr., H. L. Kim, M. C. Calhoun, and G. S. Fisher, “Determination of (+)-, (−)-, and total gossypol in cottonseed by high-performance liquid chromatography,” Journal of the American Oil Chemists' Society, vol. 76, no. 11, pp. 1351–1355, 1999. View at Scopus
  9. M. M. Lordelo, A. J. Davis, M. C. Calhoun, M. K. Dowd, and N. M. Dale, “Relative toxicity of gossypol enantiomers in broilers,” Poultry Science, vol. 84, no. 9, pp. 1376–1382, 2005. View at Scopus
  10. M. M. Lordelo, M. C. Calhoun, N. M. Dale, M. K. Dowd, and A. J. Davis, “Relative toxicity of gossypol enantiomers in laying and broiler breeder hens,” Poultry Science, vol. 86, no. 3, pp. 582–590, 2007. View at Scopus
  11. R. Kakani, D. A. Gamboa, M. C. Calhoun, A. U. Haq, and C. A. Bailey, “Relative toxicity of cottonseed gossypol enantiomers in broilers,” Open Toxicology Journal, vol. 4, pp. 26–31, 2010. View at Scopus
  12. D.-F. Wu, Y.-W. Yu, Z.-M. Tang, and M.-Z. Wang, “Pharmacokinetic of (±)-, (+)-, and (−)-gossypol in humans and dogs,” Clinical Pharmacology and Therapeutics, vol. 39, no. 6, pp. 613–618, 1986. View at Scopus
  13. C. A. Bailey, R. D. Stipanovic, M. S. Ziehr et al., “Cottonseed with a high (+)- to (−)-gossypol enantiomer ratio favorable to broiler production,” Journal of Agricultural and Food Chemistry, vol. 48, no. 11, pp. 5692–5695, 2000. View at Publisher · View at Google Scholar · View at Scopus
  14. J. A. Scheffler and G. B. Romano, “Breeding and genetics: modifying gossypol in cotton (Gossypium hirsutum L.): a cost effective method for small seed samples,” Journal of Cotton Science, vol. 12, no. 3, pp. 202–209, 2008. View at Scopus
  15. M. C. Calhoun, S. K. Kuhlmann, and B. C. Balwin, “Assessing the gossypol status of cattle fed cotton feed products,” pp. 147A–158A, Proceedings of the Pacific Northwest Animal Nutrition Conference, 1995.
  16. R. D. Stipanovic, L. S. Puckhaber, J. Liu, and A. A. Bell, “Total and percent atropisomers of Gossypol and Gossypol-6-methyl ether in seeds from Pima cottons and accessions of Gossypium barbadense L,” Journal of Agricultural and Food Chemistry, vol. 57, no. 2, pp. 566–571, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. R. Bressani, R. Jarquín, and L. G. Elías, “Free and total gossypol, epsilon-amino lysine, and biological evaluation of cottonseed meals and flours in Central America,” Journal of Agricultural and Food Chemistry, vol. 12, no. 3, pp. 278–282, 1964. View at Scopus
  18. S. R. Fernandez, Y. Zhang, and C. M. Parsons, “Dietary formulation with cottonseed meal on a total amino acid versus a digestible amino acid basis,” Poultry Science, vol. 74, no. 7, pp. 1168–1179, 1995. View at Scopus
  19. W. A. Pons Jr., C. L. Hoffpauir, and T. H. Hopper, “Gossypol in cottonseed: influence of variety of cottonseed and environment,” Journal of Agricultural and Food Chemistry, vol. 1, no. 18, pp. 1115–1118, 1953. View at Scopus
  20. R. D. Randel, C. C. Chase Jr., and S. J. Wyse, “Effects of gossypol and cottonseed products on reproduction of mammals,” Journal of Animal Science, vol. 70, no. 5, pp. 1628–1638, 1992. View at Scopus
  21. W. D. Price, R. A. Lovell, and D. G. McChesney, “Naturally occurring toxins in feedstuffs: center for veterinary medicine perspective,” Journal of Animal Science, vol. 71, no. 9, pp. 2556–2562, 1993. View at Scopus
  22. S. S. Nicholson, “Cottonseed toxicity,” in VeterInary Toxicology: Basic and Clinical Principles, R. C. Gupta, Ed., pp. 1161–1165, Academic Press, London, UK, 2nd edition, 2012.
  23. B. Polsky, S. J. Segal, P. A. Baron, J. W. M. Gold, H. Ueno, and D. Armstrong, “Inactivation of human immunodeficiency virus in vitro by gossypol,” Contraception, vol. 39, no. 6, pp. 579–587, 1989. View at Scopus
  24. J. Yang, F. Zhang, J. Li et al., “Synthesis and antiviral activities of novel gossypol derivatives,” Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 3, pp. 1415–1420, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Yang, G. Chen, L. L. Li et al., “Synthesis and anti-H5N1 activity of chiral gossypol derivatives and its analogs implicated by a viral entry blocking mechanism,” Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 9, pp. 2619–2623, 2013. View at Publisher · View at Google Scholar
  26. P. Margalith, “Inhibitory effect of gossypol on microorganisms,” Applied Microbiology, vol. 15, no. 4, pp. 952–953, 1967. View at Scopus
  27. P. Yildirim-Aksoy, C. Lim, M. K. Dowd, P. J. Wan, P. H. Klesius, and C. Shoemaker, “In vitro inhibitory effect of gossypol from gossypol-acetic acid, and (+)- and (−)-isomers of gossypol on the growth of Edwardsiella ictaluri,” Journal of Applied Microbiology, vol. 97, no. 1, pp. 87–92, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. E. Turco, C. Vizzuso, S. Franceschini, A. Ragazzi, and F. M. Stefanini, “The in vitro effect of gossypol and its interaction with salts on conidial germination and viability of Fusarium oxysporum sp. vasinfectum isolates,” Journal of Applied Microbiology, vol. 103, no. 6, pp. 2370–2381, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. Y. Anna, A. G. Medentsev, and V. I. Krupyanko, “Gossypol inhibits electron transport and stimulates ROS generation in yarrowia lipolytica mitochondria,” Open Biochemistry Journal, vol. 6, pp. 11–15, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Balakrishnan, W. G. Wierda, M. J. Keating, and V. Gandhi, “Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells,” Blood, vol. 112, no. 5, pp. 1971–1980, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. P. W. M. Johnson, “New targets for lymphoma treatment,” Annals of Oncology, vol. 19, no. 4, pp. iv56–iv59, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. X. Wang, J. Wang, S. C. H. Wong et al., “Cytotoxic effect of gossypol on colon carcinoma cells,” Life Sciences, vol. 67, no. 22, pp. 2663–2671, 2000. View at Scopus
  33. C. van Poznak, A. D. Seidman, M. M. Reidenberg et al., “Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial,” Breast Cancer Research and Treatment, vol. 66, no. 3, pp. 239–248, 2001. View at Publisher · View at Google Scholar · View at Scopus
  34. W. Ye, H.-L. Chang, L.-S. Wang et al., “Modulation of multidrug resistance gene expression in human breast cancer cells by (−)-gossypol-enriched cottonseed oil,” Anticancer Research, vol. 27, no. 1, pp. 107–116, 2007. View at Scopus
  35. M.-L. Han, Y.-F. Wang, M.-Y. Tang et al., “Gossypol in the treatment of endometriosis and uterine myoma,” Contributions to Gynecology and Obstetrics, vol. 16, pp. 268–270, 1987. View at Scopus
  36. J. Jiang, V. Slivova, A. Jedinak, and D. Sliva, “Gossypol inhibits growth, invasiveness, and angiogenesis in human prostate cancer cells by modulating NF-κB/AP-1 dependent- and independent-signaling,” Clinical and Experimental Metastasis, vol. 29, no. 2, pp. 165–178, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. G. P. Tuszynski and G. Cossu, “Differential cytotoxic effect of gossypol on human melanoma, colon carcinoma, and other tissue culture cell lines,” Cancer Research, vol. 44, no. 2, pp. 768–771, 1984. View at Scopus
  38. Y.-W. Wu, C. L. Chik, and R. A. Knazek, “An in vitro and in vivo study of antitumor effects of gossypol on human SW-13 adrenocortical carcinoma,” Cancer Research, vol. 49, no. 14, pp. 3754–3758, 1989. View at Scopus
  39. S. Z. A. Badawy, A.-K. Souid, V. Cuenca, N. Montalto, and F. Shue, “Gossypol inhibits proliferation of endometrioma cells in culture,” Asian Journal of Andrology, vol. 9, no. 3, pp. 388–393, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. C.-H. Ko, S.-C. Shen, L.-Y. Yang, C.-W. Lin, and Y.-C. Chen, “Gossypol reduction of tumor growth through ROS-dependent mitochondria pathway in human colorectal carcinoma cells,” International Journal of Cancer, vol. 121, no. 8, pp. 1670–1679, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. C.-C. Chien, C.-H. Ko, S.-C. Shen, L.-Y. Yang, and Y.-C. Chen, “The role of COX-2/PGE2 in gossypol-induced apoptosis of colorectal carcinoma cells,” Journal of Cellular Physiology, vol. 227, no. 8, pp. 3128–3137, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. W.-T. Hsiao, M.-D. Tsai, G.-M. Jow, L.-T. Tien, and Y.J. Lee, “Involvement of Smac, p53, and caspase pathways in induction of apoptosis by gossypol in human retinoblastoma cells,” Molecular Vision, vol. 18, pp. 2033–2042, 2012.
  43. F. Y. Wong, N. Liem, C. Xie et al., “Combination therapy with gossypol reveals synergism against gemcitabine resistance in cancer cells with high BCL-2 expression,” PLoS ONE, vol. 7, no. 12, Article ID e50786, 2012. View at Publisher · View at Google Scholar
  44. S. Blevins, P. B. Siegel, D. J. Blodgett, M. Ehrich, G. K. Saunders, and R. M. Lewis, “Effects of silymarin on gossypol toxicosis in divergent lines of chickens,” Poultry Science, vol. 89, no. 9, pp. 1878–1886, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. D. P. Deoras, P. Young-Curtis, R. R. Dalvi, and F. E. Tippett, “Effect of gossypol on hepatic and serum γ-glutamyltransferase activity in rats,” Veterinary Research Communications, vol. 21, no. 5, pp. 317–323, 1997. View at Publisher · View at Google Scholar · View at Scopus
  46. N. B. S. Fonseca, I. C. N. Gadelha, S. C. S. Oloris, and B. Soto-Blanco, “Effectiveness of albumin-conjugated gossypol as an immunogen to prevent gossypol-associated acute hepatotoxicity in rats,” Food and Chemical Toxicology, vol. 56, pp. 149–153, 2013. View at Publisher · View at Google Scholar
  47. A. S. El-Sharaky, A. A. Newairy, N. M. Elguindy, and A. A. Elwafa, “Spermatotoxicity, biochemical changes and histological alteration induced by gossypol in testicular and hepatic tissues of male rats,” Food and Chemical Toxicology, vol. 48, no. 12, pp. 3354–3361, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. D. W. Hahn, C. Rusticus, and A. Probst, “Antifertility and endocrine activities of gossypol in rodents,” Contraception, vol. 24, no. 1, pp. 97–105, 1981. View at Scopus
  49. R. Heywood, G. K. Lloyd, S. K. Majeed, and C. Gopinath, “The toxicity of gossypol to the male rat,” Toxicology, vol. 40, no. 3, pp. 279–284, 1986. View at Scopus
  50. M. Gåfvels, J. Wang, A. Bergh, J. E. Damber, and G. Selstam, “Toxic effects of the antifertility agent gossypol in male rats,” Toxicology, vol. 32, no. 4, pp. 325–333, 1984. View at Publisher · View at Google Scholar · View at Scopus
  51. P. J. Chenoweth, C. A. Risco, R. E. Larsen, J. Velez, T. Tran, and C. C. Chase Jr., “Effects of dietary gossypol on aspects of semen quality, sperm morphology and sperm production in young Brahman bulls,” Theriogenology, vol. 42, no. 1, pp. 1–13, 1994. View at Scopus
  52. M. E. Hassan, G. W. Smith, R. S. Ott et al., “Reversibility of the reproductive toxicity of gossypol in peripubertal bulls,” Theriogenology, vol. 61, no. 6, pp. 1171–1179, 2004. View at Publisher · View at Google Scholar · View at Scopus
  53. Y. Gu and N. O. Anderson, “Effects of gossypol on the estrous cycle and ovarian weight in the rat,” Contraception, vol. 32, no. 5, pp. 491–496, 1985. View at Scopus
  54. Y. C. Lin, T. Fukaya, Y. Rikihisa, and A. Walton, “Gossypol in female fertility control: ovum implantation and early pregnancy inhibited in rats,” Life Sciences, vol. 37, no. 1, pp. 39–47, 1985. View at Publisher · View at Google Scholar · View at Scopus
  55. R. K. Lagerlöf and J. N. Tone, “The effect of gossypol acetic acid on female reproduction,” Drug and Chemical Toxicology, vol. 8, no. 6, pp. 469–482, 1985. View at Scopus
  56. M. D. Gambill and W. D. Humphrey, “Effects of diets containing gossypol on ovarian histology, function and fertility in prepubertal beef heifers,” Theriogenology, vol. 40, no. 3, pp. 585–593, 1993. View at Scopus
  57. R. D. Randel, S. T. Willard, S. J. Wyse, and L. N. French, “Effects of diets containing free gossypol on follicular development, embryo recovery and corpus luteum function in brangus heifers treated with bFSH,” Theriogenology, vol. 45, no. 5, pp. 911–922, 1996. View at Scopus
  58. A. Arieli, “Whole cottonseed in dairy cattle feeding: a review,” Animal Feed Science and Technology, vol. 72, no. 1-2, pp. 97–110, 1998. View at Scopus
  59. S. M. Noftsger, B. A. Hopkins, D. E. Diaz, C. Brownie, and L. W. Whitlow, “Effect of whole and expanded-expelled cottonseed on milk yield and blood gossypol,” Journal of Dairy Science, vol. 83, no. 11, pp. 2539–2547, 2000. View at Scopus
  60. P. Shawrang, M. H. Mansouri, A. A. Sadeghi, and F. Ziaie, “Evaluation and comparison of gamma- and electron beam irradiation effects on total and free gossypol of cottonseed meal,” Radiation Physics and Chemistry, vol. 80, no. 6, pp. 761–762, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. S. R. Ebrahimi-Mahmoudabad and M. Taghinejad-Roudbaneh, “Investigation of electron beam irradiation effects on anti-nutritional factors, chemical composition and digestion kinetics of whole cottonseed, soybean and canola seeds,” Radiation Physics and Chemistry, vol. 80, no. 12, pp. 1441–1447, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. S.-J. Lim and K.-J. Lee, “A microbial fermentation of soybean and cottonseed meal increases antioxidant activity and gossypol detoxification in diets for nile tilapia, oreochromis niloticus,” Journal of the World Aquaculture Society, vol. 42, no. 4, pp. 494–503, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. W.-J. Zhang, Z.-R. Xu, J.-Y. Sun, and X. Yang, “Effect of selected fungi on the reduction of gossypol levels and nutritional value during solid substrate fermentation of cottonseed meal,” Journal of Zhejiang University B: Science, vol. 7, no. 9, pp. 690–695, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. W.-J. Zhang, Z.-R. Xu, S.-H. Zhao, J.-Y. Sun, and X. Yang, “Development of a microbial fermentation process for detoxification of gossypol in cottonseed meal,” Animal Feed Science and Technology, vol. 135, no. 1-2, pp. 176–186, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. X.-Y. Weng and J.-Y. Sun, “Kinetics of biodegradation of free gossypol by Candida tropicalis in solid-state fermentation,” Biochemical Engineering Journal, vol. 32, no. 3, pp. 226–232, 2006. View at Publisher · View at Google Scholar · View at Scopus
  66. W.-J. Zhang, Z.-R. Xu, S.-H. Zhao, J.-F. Jiang, Y.-B. Wang, and X.-H. Yan, “Optimization of process parameters for reduction of gossypol levels in cottonseed meal by Candida tropicalis ZD-3 during solid substrate fermentation,” Toxicon, vol. 48, no. 2, pp. 221–226, 2006. View at Publisher · View at Google Scholar · View at Scopus
  67. Z.-T. Sun, C. Liu, and J.-H. Du, “Optimisation of fermentation medium for the detoxification of free gossypol in cottonseed powder by Geotrichum candidum G07 in solid-state fermentation with response surface methodology,” Annals of Microbiology, vol. 58, no. 4, pp. 683–690, 2008. View at Scopus
  68. M. Y. EL-Mokadem, T. A. Taha, M. A. Samak, and A. M. Yassen, “Alleviation of reproductive toxicity of gossypol using selenium supplementation in rams,” Journal of Animal Science, vol. 90, no. 9, pp. 3274–3285, 2012. View at Publisher · View at Google Scholar
  69. J. Velasquez-Pereira, P. J. Chenoweth, L. R. McDowell et al., “Reproductive effects of feeding gossypol and vitamin E to bulls,” Journal of Animal Science, vol. 76, no. 11, pp. 2894–2904, 1998. View at Scopus
  70. J. Velasquez-Pereira, C. F. Aréchiga, L. R. McDowell et al., “Effects of gossypol from cottonseed meal and dietary vitamin E on the reproductive characteristics of superovulated beef heifers,” Journal of Animal Science, vol. 80, no. 9, pp. 2485–2492, 2002. View at Scopus
  71. W. M. Haschek, V. R. Beasley, W. B. Buck, and J. H. Finnell, “Cottonseed meal (gossypol) toxicosis in a swine herd,” Journal of the American Veterinary Medical Association, vol. 195, no. 5, pp. 613–615, 1989. View at Scopus
  72. M. L. Barraza, C. E. Coppock, K. N. Brooks, D. L. Wilks, R. G. Saunders, and G. W. Latimer Jr., “Iron sulfate and feed pelleting to detoxify free gossypol in cottonseed diets for dairy cattle,” Journal of Dairy Science, vol. 74, no. 10, pp. 3457–3467, 1991. View at Scopus
  73. I. C. Schneider, M. L. Ames, M. A. Rasmussen, and P. J. Reilly, “Fermentation of cottonseed and other feedstuffs in cattle rumen fluid,” Journal of Agricultural and Food Chemistry, vol. 50, no. 8, pp. 2267–2273, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. T. O. Lindsey, G. E. Hawkins, and L. D. Guthrie, “Physiological responses of lactating cows to gossypol from cottonseed meal rations,” Journal of Dairy Science, vol. 63, no. 4, pp. 562–573, 1980. View at Scopus
  75. H. L. Kim, M. C. Calhoun, and R. D. Stipanovic, “Accumulation of gossypol enantiomers in ovine tissues,” Comparative Biochemistry and Physiology B: Biochemistry and Molecular Biology, vol. 113, no. 2, pp. 417–420, 1996. View at Publisher · View at Google Scholar · View at Scopus
  76. M. B. Abou-Donia, M. A. Othman, and P. Obih, “Interspecies comparison of pharmacokinetic profile and bioavailability of (±)-gossypol in male Fischer-344 rats and male B6C3F mice,” Toxicology, vol. 55, no. 1-2, pp. 37–51, 1989. View at Scopus
  77. Q. Q. Chen, H. Chen, and H. P. Lei, “Comparative study on the metabolism of optical gossypol in rats,” Journal of Ethnopharmacology, vol. 20, no. 1, pp. 31–37, 1987. View at Scopus
  78. E. Eagle, “Effect of repeated doses of gossypol on the dog,” Archives of Biochemistry, vol. 26, no. 1, pp. 68–71, 1950.
  79. C. S. Patton, A. M. Legendre, R. E. Gompf, and M. A. Walker, “Heart failure caused by gossypol poisoning in two dogs,” Journal of the American Veterinary Medical Association, vol. 187, no. 6, pp. 625–627, 1985. View at Scopus
  80. L. A. Kerr, “Gossypol toxicosis in cattle,” Compendium on Continuing Education for the Practising Veterinarian, vol. 11, no. 9, pp. 1139–1146, 1989.
  81. I. C. N. Gadelha, A. H. do Nascimento Rangel, A. R. Silva, and B. Soto-Blanco, “Efeitos do gossipol na reprodução animal,” Acta Veterinaria Brasilica, vol. 5, no. 2, pp. 129–135, 2011.
  82. M. H. Henry, G. M. Pesti, and T. P. Brown, “Pathology and histopathology of gossypol toxicity in broiler chicks,” Avian Diseases, vol. 45, no. 3, pp. 598–604, 2001. View at Scopus
  83. J. L. West, “Lesions of gossypol poisoning in the dog,” Journal of the American Veterinary Medical Association, vol. 96, pp. 74–76, 1940.
  84. F. A. Uzal, B. Puschner, J. M. Tahara, and R. W. Nordhausen, “Gossypol toxicosis in a dog consequent to ingestion of cottonseed bedding,” Journal of Veterinary Diagnostic Investigation, vol. 17, no. 6, pp. 626–629, 2005. View at Scopus
  85. S. Morgan, E. L. Stair, T. Martin, W. C. Edwards, and G. L. Morgan, “Clinical, clinicopathologic, pathologic, and toxicologic alterations associated with gossypol toxicosis in feeder lambs,” American Journal of Veterinary Research, vol. 49, no. 4, pp. 493–499, 1988. View at Scopus
  86. N. E. East, M. Anderson, and L. J. Lowenstine, “Apparent gossypol-induced toxicosis in adult dairy goats,” Journal of the American Veterinary Medical Association, vol. 204, no. 4, pp. 642–643, 1994. View at Scopus
  87. W.-J. Zhang, Z.-R. Xu, X.-L. Pan, X.-H. Yan, and Y.-B. Wang, “Advances in gossypol toxicity and processing effects of whole cottonseed in dairy cows feeding,” Livestock Science, vol. 111, no. 1-2, pp. 1–9, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. S. T. Willard, D. A. Neuendorff, A. W. Lewis, and R. D. Randel, “Effects of free gossypol in the diet of pregnant and postpartum Brahman cows on calf development and cow performance,” Journal of Animal Science, vol. 73, no. 2, pp. 496–507, 1995. View at Scopus
  89. P. A. M. Rogers, T. P. Henaghan, and B. Wheeler, “Gossypol poisoning in young calves,” Irish Veterinary Journal, vol. 29, no. 1, pp. 9–13, 1975. View at Scopus
  90. C. A. Holmberg, L. D. Weaver, W. M. Gutterbock, J. Genes, and P. Montgomery, “Pathological and toxicological studies of calves fed a high concentration cotton seed meal diet,” Veterinary Pathology, vol. 25, no. 2, pp. 147–153, 1988. View at Scopus
  91. C. A. Risco, C. A. Holmberg, and A. Kutches, “Effect of graded concentrations of gossypol on calf performance: toxicological and pathological considerations,” Journal of Dairy Science, vol. 75, no. 10, pp. 2787–2798, 1992. View at Scopus
  92. R. Z. Zelski, J. T. Rothwell, R. E. Moore, and D. J. Kennedy, “Gossypol toxicity in preruminant calves,” Australian Veterinary Journal, vol. 72, no. 10, pp. 394–398, 1995. View at Scopus
  93. R. B. Fombad and M. J. Bryant, “An evaluation of the use of cottonseed cake in the diet of growing pigs,” Tropical Animal Health and Production, vol. 36, no. 3, pp. 295–305, 2004. View at Publisher · View at Google Scholar · View at Scopus
  94. L. M. Hudson, L. A. Kerr, and W. R. Maslin, “Gossypol toxicosis in a herd of beef calves,” Journal of the American Veterinary Medical Association, vol. 192, no. 9, pp. 1303–1305, 1988. View at Scopus
  95. H. Mena, J. E. P. Santos, J. T. Huber, M. Tarazon, and M. C. Calhoun, “The effects of varying gossypol intake from whole cottonseed and cottonseed meal on lactation and blood parameters in lactating dairy cows,” Journal of Dairy Science, vol. 87, no. 8, pp. 2506–2518, 2004. View at Scopus
  96. M. Zbidah, A. Lupescu, N. Shaik, and F. Lang, “Gossypol-induced suicidal erythrocyte death,” Toxicology, vol. 302, no. 2-3, pp. 101–105, 2012. View at Publisher · View at Google Scholar
  97. F. Tang and P. Y. D. Wong, “Serum potassium and aldosterone levels in gossypol-treated rats,” International Journal of Andrology, vol. 7, no. 2, pp. 149–153, 1984. View at Scopus
  98. Y. Rikihisa and Y. C. Lin, “Effect of gossypol on the thyroid in young rats,” Journal of Comparative Pathology, vol. 100, no. 4, pp. 411–417, 1989. View at Scopus
  99. Y. C. Lin, M. Chitcharoenthum, and Y. Rikihisa, “Effect of gossypol on thyroid hormones in young female rats,” Contraception, vol. 41, no. 4, pp. 431–440, 1990. View at Publisher · View at Google Scholar · View at Scopus
  100. P. Udoh, D. R. Patil, and M. K. Deshpande, “Histopathological and biochemical effects of gossypol acetate on pituitary-gonadal axis of male albino rats,” Contraception, vol. 45, no. 5, pp. 493–509, 1992. View at Publisher · View at Google Scholar · View at Scopus
  101. D. R. Janero and B. Burghardt, “Protection of rat myocardial phospholipid against peroxidative injury through superoxide-(xanthine oxidase)-dependent, iron-promoted fenton chemistry by the male contraceptive gossypol,” Biochemical Pharmacology, vol. 37, no. 17, pp. 3335–3342, 1988. View at Publisher · View at Google Scholar · View at Scopus
  102. M. W. Fornes, A. M. Barbieri, and M. H. Burgos, “Sperm motility loss induced by gossypol: relation with OH. scavengers, motile stimulators and malondialdehyde production,” Biochemical and Biophysical Research Communications, vol. 195, no. 3, pp. 1289–1293, 1993. View at Publisher · View at Google Scholar · View at Scopus
  103. A. de Peyster, A. Quintanilha, L. Packer, and M. T. Smith, “Oxygen radical formation induced by gossypol in rat liver microsomes and human sperm,” Biochemical and Biophysical Research Communications, vol. 118, no. 2, pp. 573–579, 1984. View at Scopus
  104. P. Kovaci, “Mechanism of drug and toxic actions of gossypol: focus on reactive oxygen species and electron transfer,” Current Medicinal Chemistry, vol. 10, no. 24, pp. 2711–2718, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. L. A. Meksongsee, A. J. Clawson, and F. H. Smith, “The in vivo effect of gossypol on cytochrome oxidase, succinoxidase, and succinic dehydrogenase in animal tissues,” Journal of Agricultural and Food Chemistry, vol. 18, no. 5, pp. 917–920, 1970. View at Scopus
  106. M. B. Abou Donia and J. W. Dieckert, “Gossypol: uncoupling of respiratory chain and oxidative phosphorylation,” Life Sciences, vol. 14, no. 10, pp. 1955–1963, 1974. View at Scopus
  107. W. W. Tso and C. S. Lee, “Gossypol uncoupling of respiratory chain and oxidative phosphorylation in ejaculated boar spermatozoa,” Contraception, vol. 25, no. 6, pp. 649–655, 1982. View at Scopus
  108. W. M. Huang and F. Urthaler, “The direct negative inotropic effect of gossypol,” Journal of Ethnopharmacology, vol. 17, no. 1, pp. 31–36, 1986. View at Scopus
  109. Y. Wang and H.-P. Lei, “Hepatotoxicity of gossypol in rats,” Journal of Ethnopharmacology, vol. 20, no. 1, pp. 53–64, 1987. View at Scopus
  110. S. Manabe, D. C. Nuber, and Y. C. Lin, “Zone-specific hepatotoxicity of gossypol in perfused rat liver,” Toxicon, vol. 29, no. 6, pp. 787–790, 1991. View at Publisher · View at Google Scholar · View at Scopus
  111. S. Z. Qian and Z. G. Wang, “Gossypol: a potential antifertility agent for males,” Annual Review of Pharmacology and Toxicology, vol. 24, pp. 329–360, 1984. View at Scopus
  112. Z.-H. Yu and H. C. Chan, “Gossypol as a male antifertility agent—why studies should have been continued,” International Journal of Andrology, vol. 21, no. 1, pp. 2–7, 1998. View at Publisher · View at Google Scholar · View at Scopus
  113. E. M. Coutinho, “Gossypol: a contraceptive for men,” Contraception, vol. 65, no. 4, pp. 259–263, 2002. View at Publisher · View at Google Scholar · View at Scopus
  114. K. Dodou, “Investigations on gossypol: past and present developments,” Expert Opinion on Investigational Drugs, vol. 14, no. 11, pp. 1419–1434, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. Q. Chang, Z. Liu, W.-Z. Ma et al., “Drug synergistic antifertility effect of combined administration of low-dose gossypol with steroid hormones in rats,” Chinese Medical Journal, vol. 124, no. 11, pp. 1678–1682, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. S. Chongthammakun, C. Ekavipat, B. Sanitwongse, and K. Pavasuthipaisit, “Effects of gossypol on human and monkey sperm motility in vitro,” Contraception, vol. 34, no. 3, pp. 323–331, 1986. View at Scopus
  117. C. Y. Hong, J. J. Huang, and P. Wu, “The inhibitory effect of gossypol on human sperm motility: relationship with time, temperature and concentration,” Human Toxicology, vol. 8, no. 1, pp. 49–51, 1989. View at Scopus
  118. C. Brocas, R. M. Rivera, F. F. Paula-Lopes et al., “Deleterious actions of gossypol on bovine spermatozoa, oocytes, and embryos,” Biology of Reproduction, vol. 57, no. 4, pp. 901–907, 1997. View at Publisher · View at Google Scholar · View at Scopus
  119. P. J. Chenoweth, C. C. Chase Jr., C. A. Risco, and R. E. Larsen, “Characterization of gossypol-induced sperm abnormalities in bulls,” Theriogenology, vol. 53, no. 5, pp. 1193–1203, 2000. View at Publisher · View at Google Scholar · View at Scopus
  120. Y. Y. Yuan and Q. X. Shi, “Inhibition of hamster sperm acrosomal enzyme by gossypol is closely associated with the decrease in fertilization capacity,” Contraception, vol. 62, no. 4, pp. 203–209, 2000. View at Publisher · View at Google Scholar · View at Scopus
  121. A. R. Beaudoin, “A developmental toxicity evaluation of gossypol,” Contraception, vol. 37, no. 2, pp. 197–219, 1988. View at Scopus
  122. F. D. C. R. Nunes, D. A. F. V. de Araujo, M. B. Bezerra, and B. Soto-Blanco, “Effects of gossypol present in cottonseed cake on the spermatogenesis of goats,” Journal of Animal and Veterinary Advances, vol. 9, no. 1, pp. 75–78, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. F. C. B. Guedes and B. Soto-Blanco, “Sperm quality of sheep fed cottonseed cake,” Acta Scientiae Veterinariae, vol. 38, no. 4, pp. 415–418, 2010. View at Scopus
  124. H. Ueno, M. K. Sahni, S. J. Segal, and S. S. Koide, “Interaction of gossypol with sperm macromolecules and enzymes,” Contraception, vol. 37, no. 3, pp. 333–341, 1988. View at Scopus
  125. C. S. Teng, “Reversible changes in the content of cellular and microtubular tubulin in spermatogenic cells after gossypol treatment,” Contraception, vol. 55, no. 1, pp. 41–46, 1997. View at Publisher · View at Google Scholar · View at Scopus
  126. H. Breitbart, S. Rubinstein, and L. Nass-Arden, “Effect of gossypol-acetic acid on calcium transport and ATPase activity in plasma membranes from ram and bull spermatozoa,” International Journal of Andrology, vol. 7, no. 5, pp. 439–447, 1984. View at Scopus
  127. H. Breitbart, A. Mayevsky, and L. Nass-Arden, “Molecular mechanisms of gossypol action on sperm motility,” International Journal of Biochemistry, vol. 21, no. 10, pp. 1097–1102, 1989. View at Scopus
  128. A. P. Hoffer, “Effects of gossypol on the seminiferous epithelium in the rat: a light and electron microscope study,” Biology of Reproduction, vol. 28, no. 4, pp. 1007–1020, 1983. View at Scopus
  129. J. Arshami and J. L. Ruttle, “Effects of diets containing gossypol on spermatogenic tissues of young bulls,” Theriogenology, vol. 30, no. 3, pp. 507–516, 1988. View at Scopus
  130. G. S. Romualdo, G. R. Klinefelter, and W. de Grava Kempinas, “Postweaning exposure to gossypol results in epididymis-specific effects throughout puberty and adulthood in rats,” Journal of Andrology, vol. 23, no. 2, pp. 220–228, 2002. View at Scopus
  131. M. Zhang, H. Yuan, Z. He et al., “DNA damage and decrease of cellular oxidase activity in piglet sertoli cells exposed to gossypol,” African Journal of Biotechnology, vol. 10, no. 14, pp. 2797–2802, 2011. View at Scopus
  132. N. Timurkaan, F. Yilmaz, and S. Timurkaan, “Effects of cottonseed flour on immunohistochemical localization of androgen receptors (AR) in rat testes,” Revue de Medecine Veterinaire, vol. 162, no. 1, pp. 13–17, 2011. View at Scopus
  133. M. L. Gray, L. W. Greene, and G. L. Williams, “Effects of dietary gossypol consumption on metabolic homeostasis and reproductive endocrine function in beef heifers and cows,” Journal of Animal Science, vol. 71, no. 11, pp. 3052–3059, 1993. View at Scopus
  134. G. O. Adeyemo, O. G. Longe, and D. O. Adejumo, “The reproductive performance of breeder cocks fed cottonseed cake-based diets,” International Journal of Poultry Science, vol. 6, no. 2, pp. 140–144, 2007. View at Scopus
  135. G. Basini, S. Bussolati, L. Baioni, and F. Grasselli, “Gossypol, a polyphenolic aldehyde from cotton plant, interferes with swine granulosa cell function,” Domestic Animal Endocrinology, vol. 37, no. 1, pp. 30–36, 2009. View at Publisher · View at Google Scholar · View at Scopus
  136. Y. Gu, Y. C. Lin, and Y. Rikihisa, “Inhibitory effect of gossypol on steroidogenic pathways in cultured bovine luteal cells,” Biochemical and Biophysical Research Communications, vol. 169, no. 2, pp. 455–461, 1990. View at Publisher · View at Google Scholar · View at Scopus
  137. Y. C. Lin, S. Coskun, and A. Sanbuissho, “Effects of gossypol on in vitro bovine oocyte maturation and steroidogenesis in bovine granulosa cells,” Theriogenology, vol. 41, no. 8, pp. 1601–1611, 1994. View at Scopus
  138. S. M. Zirkle, Y. C. Lin, F. C. Gwazdauskas, and R. S. Canseco, “Effect of gossypol on bovine embryo development during the preimplantation period,” Theriogenology, vol. 30, no. 3, pp. 575–582, 1988. View at Scopus
  139. Y. C. Lin, P. Rajamahendran, and Y. Rikihisa, “Inhibition of rat embryo implantation in the gossypol-treated uterine horn,” Theriogenology, vol. 35, no. 4, pp. 769–777, 1991. View at Scopus
  140. J. Hernández-Cerón, F. D. Jousan, P. Soto, and P. J. Hansen, “Timing of inhibitory actions of gossypol on cultured bovine embryos,” Journal of Dairy Science, vol. 88, no. 3, pp. 922–928, 2005. View at Scopus
  141. M. Villaseñor, A. C. Coscioni, K. N. Galvão, R. C. Chebel, and J. E. P. Santos, “Gossypol disrupts embryo development in heifers,” Journal of Dairy Science, vol. 91, no. 8, pp. 3015–3024, 2008. View at Publisher · View at Google Scholar · View at Scopus
  142. Y. C. Lin, A. Sanbuissho, S. Coskun, and Y. Rikihisa, “Inhibition of in vitro fertilization and early embryonic development in hamsters by gossypol,” Life Sciences, vol. 55, no. 14, pp. 1139–1145, 1994. View at Publisher · View at Google Scholar · View at Scopus
  143. Y. F. Li, G. M. Booth, and R. E. Seegmiller, “Evidence for embryotoxicity of gossypol in mice and chicks with no evidence of mutagenic activity in the ames test,” Reproductive Toxicology, vol. 3, no. 1, pp. 59–62, 1989. View at Scopus
  144. G. M. Sein, “The embryotoxic and immunodepressive effects of gossypol,” American Journal of Chinese Medicine, vol. 14, no. 3-4, pp. 110–115, 1986. View at Scopus
  145. H. Morales, P. Tilquin, J. F. Rees, A. Massip, F. Dessy, and A. van Langendonckt, “Pyruvate prevents peroxide-induced injury of in vitro preimplantation bovine embryos,” Molecular Reproduction and Development, vol. 52, no. 2, pp. 149–157, 1999.
  146. J.-C. Hervé, F. Pluciennik, B. Bastide et al., “Contraceptive gossypol blocks cell-to-cell communication in human and rat cells,” European Journal of Pharmacology, vol. 313, no. 3, pp. 243–255, 1996. View at Publisher · View at Google Scholar · View at Scopus
  147. E. Yurtcu, M. A. Ergun, and A. Menevse, “Apoptotic effect of gossypol on human lymphocytes,” Cell Biology International, vol. 27, no. 9, pp. 791–794, 2003. View at Publisher · View at Google Scholar · View at Scopus
  148. G.-H. Cui, Z.-L. Xu, Z.-J. Yang, Y.-Y. Xu, and S.-P. Xue, “A combined regimen of gossypol plus methyltestosterone and ethinylestradiol as a contraceptive induces germ cell apoptosis and expression of its related genes in rats,” Contraception, vol. 70, no. 4, pp. 335–342, 2004. View at Publisher · View at Google Scholar · View at Scopus
  149. M. A. Ergun, E. Konac, D. Erbas, and A. Ekmekci, “Apoptosis and nitric oxide release induced by thalidomide, gossypol and dexamethasone in cultured human chronic myelogenous leukemic K-562 cells,” Cell Biology International, vol. 28, no. 3, pp. 237–242, 2004. View at Publisher · View at Google Scholar · View at Scopus
  150. D.-O. Moon, M.-O. Kim, J.-D. Lee, and G.-Y. Kim, “Gossypol suppresses NF-κB activity and NF-κB-related gene expression in human leukemia U937 cells,” Cancer Letters, vol. 264, no. 2, pp. 192–200, 2008. View at Publisher · View at Google Scholar · View at Scopus
  151. E. Cengiz, B. Karaca, Y. Kucukzeybek et al., “Overcoming drug resistance in hormone-and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination,” Molecular Biology Reports, vol. 37, no. 3, pp. 1269–1277, 2010. View at Publisher · View at Google Scholar · View at Scopus
  152. D.-O. Moon, Y. H. Choi, S.-K. Moon, W.-J. Kim, and G.-Y. Kim, “Gossypol decreases tumor necrosis factor-α-induced intercellular adhesion molecule-1 expression via suppression of NF-κB activity,” Food and Chemical Toxicology, vol. 49, no. 4, pp. 999–1005, 2011. View at Publisher · View at Google Scholar · View at Scopus
  153. J.-S. Cheng, Y.-K. Lo, J.-H. Yeh et al., “Effect of gossypol on intracellular Ca2+ regulation in human hepatoma cells,” Chinese Journal of Physiology, vol. 46, no. 3, pp. 117–122, 2003. View at Scopus
  154. A. P. Braga, M. V. MacIel, D. G. F. Guerra, I. S. A. S. Maia, S. C. S. Oloris, and B. Soto-Blanco, “Extruded-expelled cottonseed meal decreases lymphocyte counts in male sheep,” Revue de Medecine Veterinaire, vol. 163, no. 3, pp. 147–152, 2012. View at Scopus
  155. W.-B. Xu, L.-H. Xu, H.-S. Lu et al., “The immunosuppressive effect of gossypol in mice is mediated by inhibition of lymphocyte proliferation and by induction of cell apoptosis,” Acta Pharmacologica Sinica, vol. 30, no. 5, pp. 597–604, 2009. View at Publisher · View at Google Scholar · View at Scopus
  156. P. J. E. Quintana, A. de Peyster, S. Klatzke, and H. J. Park, “Gossypol-induced DNA breaks in rat lymphocytes are secondary to cytotoxicity,” Toxicology Letters, vol. 117, no. 1-2, pp. 85–94, 2000. View at Publisher · View at Google Scholar · View at Scopus
  157. D. Sijun, A. Pawlak, B. Poźniak et al., “Effects of gossypol acetic acid on cellular and humoral immune response in non-immunized and SRBC-immunized mice,” Central-European Journal of Immunology, vol. 37, no. 1, pp. 11–19, 2012. View at Scopus
  158. D. Xu, W.-J. Cai, B.-H. Zhu, C.-J. Dong, Z.-C. Zheng, and Z.-Q. Gao, “Clinical safety of long-term administration of gossypol in 32 cases,” Contraception, vol. 37, no. 2, pp. 129–135, 1988. View at Scopus
  159. D. Nagalakshmi, V. R. B. Sastry, D. K. Agrawal, and R. C. Katiyar, “Haematological and immunological response in lambs fed on raw and variously processed cottonseed meal,” Asian-Australasian Journal of Animal Sciences, vol. 14, no. 1, pp. 21–29, 2001. View at Scopus
  160. A. K. Pattanaik, V. R. B. Sastry, D. K. Singh, T. K. Goswami, and D. N. Mohanty, “Effect of gossypol from cottonseed meal diets on some clinico-biochemical parameters and humoral immune response of crossbred calves fed barley or sorghum,” Asian-Australasian Journal of Animal Sciences, vol. 16, no. 9, pp. 1291–1296, 2003. View at Scopus
  161. K. Ohuchi, M. Watanabe, N. Hirasawa, S. Tsurufuji, T. Ozeki, and H. Fujiki, “Inhibition by gossypol of tumor promoter-induced arachidonic acid metabolism in rat peritoneal macrophages,” Biochimica et Biophysica Acta: Molecular Cell Research, vol. 971, no. 1, pp. 85–91, 1988. View at Scopus
  162. M. M. Barros, C. Lim, and P. H. Klesius, “Effect of soybean meal replacement by cottonseed meal and iron supplementation on growth, immune response and resistance of channel catfish (Ictalurus puctatus) to Edwardsiella ictaluri challenge,” Aquaculture, vol. 207, no. 3-4, pp. 263–279, 2002. View at Publisher · View at Google Scholar · View at Scopus
  163. M. Yildirim, C. Lim, P. J. Wan, and P. H. Klesius, “Growth performance and immune response of channel catfish (Ictalurus puctatus) fed diets containing graded levels of gossypol-acetic acid,” Aquaculture, vol. 219, no. 1–4, pp. 751–768, 2003. View at Publisher · View at Google Scholar · View at Scopus
  164. G. S. Fisher, A. W. Frank, and J. P. Cherry, “Total gossypol content of glandless cottonseed,” Journal of Agricultural and Food Chemistry, vol. 36, no. 1, pp. 42–44, 1988. View at Scopus
  165. G. A. Broderick and W. M. Craig, “Effect of heat treatment on ruminal degradation and escape, and intestinal digestibility of cottonseed meal protein,” Journal of Nutrition, vol. 110, no. 12, pp. 2381–2389, 1980. View at Scopus
  166. M. H. Henry, G. M. Pesti, R. Bakalli et al., “The performance of broiler chicks fed diets containing extruded cottonseed meal supplemented with lysine,” Poultry Science, vol. 80, no. 6, pp. 762–768, 2001. View at Scopus
  167. H. Jaddou, M. Al Hakim, L. Z. Al Adamy, and M. T. Mhaisen, “Effect of gamma-radiation on gossypol in cottonseed meal,” Journal of Food Science, vol. 48, no. 3, pp. 988–989, 1983. View at Scopus
  168. C. Jo, H. S. Yook, M. S. Lee et al., “Irradiation effects on embryotoxicity and oxidative properties of gossypol dissolved in methanol,” Food and Chemical Toxicology, vol. 41, no. 10, pp. 1329–1336, 2003. View at Publisher · View at Google Scholar · View at Scopus
  169. S. A. Smalley and E. J. Bicknell, “Gossypol toxicity in dairy cattle,” Compendium on Continuing Education for the Practising Veterinarian, vol. 4, no. 9, pp. S378–S381, 1982.
  170. X. Yang, J.-Y. Sun, J.-L. Guo, and X.-Y. Weng, “Identification and proteomic analysis of a novel gossypol-degrading fungal strain,” Journal of the Science of Food and Agriculture, vol. 92, no. 4, pp. 943–951, 2012. View at Publisher · View at Google Scholar · View at Scopus
  171. H. Sun, J. W. Tang, C. L. Fang et al., “Molecular analysis of intestinal bacterial microbiota of broiler chickens fed diets containing fermented cottonseed meal,” Poultry Science, vol. 92, no. 2, pp. 392–401, 2013. View at Publisher · View at Google Scholar