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      Gossypol Toxicity from Cottonseed Products

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          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.

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          Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial.

          Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.
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            Gossypol: a contraceptive for men.

            Gossypol is a polyphenol isolated from the seed, roots, and stem of the cotton plant (Gossypium sp.). The substance, a yellow pigment similar to flavonoids, is present in cottonseed oil. In the plant, it acts as a natural defensive agent against predators, provoking infertility in insects. In most animals, gossypol provokes infertility, and in man it causes spermatogenesis arrest at relatively low doses. Studies carried out in China, Africa, and Brazil have shown that the substance is well tolerated, causing no side effects that lead to discontinuation. The reported hypokalemia of early studies has not been confirmed in the latest trials. The only concern at present appears to be lack of reversibility in over 20% of subjects. Gossypol should be prescribed preferably to men who have completed their families or for those who would accept permanent infertility after a few years of use.
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              Effects of gossypol and cottonseed products on reproduction of mammals.

              Gossypol is a toxic factor indigenous to the cotton plant genus Gossypium. Concentrations of free gossypol contained in feedstuffs such as whole cottonseed and cottonseed meals vary considerably. Nonruminant animals are particularly sensitive to the toxic effects of gossypol, whereas ruminants are somewhat more resistant. Signs of gossypol toxicosis in nonruminants, preruminants, and ruminants are similar and include labored breathing, dyspnea, decreased growth rate, and anorexia but are not pathognomonic. Postmortem findings include generalized edema and congestion of lungs and liver, fluid-filled thoracic and peritoneal cavities, and degeneration of heart fibers. The antifertility effect observed in many nonruminant species is overshadowed by toxic effects, particularly in females. Gossypol seems to disrupt estrous cycles, pregnancy, and early embryo development in females of all nonruminant species studied. Probable mechanisms include an endocrine effect on the ovary as well as a cytotoxic effect on the uterus or embryo. The female ruminant seems to be relatively insensitive to the antifertility effect of gossypol; however, in vitro data indicate some inhibition of embryonic development and ovarian steroidogenesis. The antifertility effect of gossypol has been studied most in males of nonruminant species. The effects of gossypol in the male are both dose- and time-dependent. At effective doses, gossypol causes males to be infertile because of sperm immotility and depressed sperm counts. Specific mitochondrial damage in the tails of spermatozoa seems to render them immotile, and extensive damage to germinal epithelium may be responsible for depressions in spermatogenesis. In ruminant males fed diets containing gossypol, ejaculated sperm appears normal under light microscopy. The integrity of the membrane of sperm cells may be damaged. Extensive damage to the germinal epithelium has been shown in both rams and bulls fed diets containing gossypol and is of major concern.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                Hindawi Publishing Corporation
                2356-6140
                1537-744X
                2014
                6 May 2014
                : 2014
                : 231635
                Affiliations
                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
                Author notes

                Academic Editor: Chad C. Chase Jr.

                Author information
                http://orcid.org/0000-0003-3861-1838
                Article
                10.1155/2014/231635
                4033412
                1e87fdc8-2c28-4c6c-8b15-e9c3ab54ac9e
                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.

                History
                : 29 January 2014
                : 4 April 2014
                : 16 April 2014
                Funding
                Funded by: Universidade Federal de Minas Gerais
                Award ID: PRP-UFMG 03/2013
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                Review Article

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