gossypol-acetic-acid and Body-Weight

To evaluate the efficacy and feasibility of a new regimen of low-dose gossypol acetic acid (GA) combined with desogestrel/ethinylestradiol and testosterone undecanoate (DSG/E/TU) as a male contraceptive, adult male rats were fed orally with GA (12.5 mg/kg/day) and DSG (0.125 mg/kg)/E (0.025 mg/kg)/TU (100 mg/kg) daily for 8 weeks as loading dose until infertility, and a similar low dose of GA alone for infertility maintenance. Control animals were administered a single low dose of GA (12.5 mg/kg/day) or DSG (0.125 mg/kg)/E (0.025 mg/kg)/TU (100 mg/kg), and vehicle, respectively. Results demonstrated that the combined dosage regimen could damage epididymal sperm motility and density, and induce infertility within 8 weeks in rats; the infertility could be consistently sustained by giving single GA (12.5 mg/kg/day), and was reversible in about 8 weeks following withdrawal of gossypol. The regimen rendered treated male rats with spermiation failure within a period of 6-20 weeks of treatment. Also, the serum luteinizing hormone, follicle-stimulating hormone and testicular interstitial fluid testosterone levels showed a transient decrease at the end of 6 or 8 weeks, which returned to control levels after 8 weeks of recovery phase. No hypokalemia or other adverse effects in viscera were observed. These results provide a promising approach to using the new regimen for the development of an effective and reversible oral male contraceptive.

Topics: Animals; Body Weight; Contraceptive Agents, Male; Contraceptives, Oral, Synthetic; Desogestrel; Ethinyl Estradiol; Fertility; Gossypol; Male; Organ Size; Random Allocation; Rats; Rats, Wistar; Sexual Behavior, Animal; Sperm Motility; Spermatogenesis; Testis; Testosterone

The effects of Gossypol acetic acid (10 mg/kg b. wt. daily for 15 days), an experimental male antifertility agent and its subsequent withdrawal for another 15 days, on the structure and functions of the rat small intestinal tract have been investigated. Gossypol feeding causes a reduction in body weight and intestinal weight, length, protein, and nucleic acid contents. A 27%-50% reduction in the uptake of glucose, alanine, leucine, and calcium is observed after Gossypol feeding which is found to be reversible after 15 days of withdrawal of the drug. Gossypol also causes a significant reduction in the activities of sucrase, lactase, maltase and alkaline phosphatase in the intestinal homogenates as well as in the purified brush border membrane of the microvillus. A decrease in the maximum of apparent enzyme velocity and no change in the substrate affinity constant in these digestive hydrolases are observed on Gossypol treatment. It also causes a shift in the transition temperature in these enzymes and predictably changes the energy of activation both below and above the temperature of transition, although the Arrhenius expression of the temperature dependence still shows proximity, non-linearity, and is parallel to the control group. These changes are reversed on withdrawal of the drug and during the subsequent recovery period. Recovery experiments also show near identical values in kinetic parameters (Kt and Jmax) of 14C-glucose uptake in jejunal segments both in the presence and absence of Na+ ions. Also, no difference is observed between the control and recovery groups with respect to body and intestinal weight, intestinal length, and DNA, RNA, protein, lactate dehydrogenase and glucose-6-phosphate phosphohydrolase values in the intestinal homogenates. Phospholipid, cholesterol and sialic acid levels in both the groups also show nearly identical values. Molecular mechanism of the effects of Gossypol on brush border membrane-bound enzyme/carrier molecules operation is discussed in view of the kinetic and thermodynamic data obtained.

Topics: Amino Acids; Animals; Biological Transport; Body Weight; Glucose; Gossypol; Intestinal Absorption; Intestinal Mucosa; Intestines; Kinetics; Male; Rats; Spermatocidal Agents

Oral administration of Gossypol acetic acid (10 mg/kg body wt./day, daily for 15 days), an experimental antifertility agent to male rats, caused significant reduction in the uptake of glucose, alanine, leucine and calcium in the small intestinal segments. Gossypol also caused significant decrease in the intestinal brush border membrane--associated enzymes, sucrase, lactase, maltase and alkaline phosphatase. Kinetic analysis indicated that Gossypol decreased the apparent velocity of the disaccharidases while the Km was not altered. It also caused a shift in the transition temperature in these enzymes and predictably changed the energy of activation both below and above the transition temperature, although the Arrhenius expressions of the temperature dependence still showed proximity and were parallel to the control group.

Topics: Administration, Oral; Animals; Body Weight; Digestion; Gossypol; Intestinal Mucosa; Intestines; Kinetics; Male; Microvilli; Rats; Rats, Inbred Strains; Spermatocidal Agents; Thermodynamics

The toxicity of gossypol has been investigated in Sprague-Dawley rats at dosages of 0, 0.5, 5.0 and 25 mg/kg per day of (+/-)-gossypol acetic acid. The most significant toxicological finding was marked suppression of body weight gain in rats receiving 25 mg/kg per day. Terminal studies showed 6 out of 20 rats receiving 25 mg/kg per day to have varying degrees of testicular pathology. Five mg/kg per day was shown to be a "no effect" level. A study in cynomolgus monkeys at 25 mg/kg per day of (+/-)-gossypol acetic acid for 13 weeks induced death, a variety of clinical signs, extensive biochemical change and pathology in the heart, liver, kidney and testes. The toxicity of (-)-gossypol was investigated in male cynomolgus monkeys at dosages of 1.5, 4 or 5 mg/kg/day for 4 weeks. No animals died. Clinical signs involving the gastrointestinal tract, adverse effects on body weight gain, consistent biochemical changes in serum proteins, calcium, inorganic phosphorus and serum cholesterol were recorded at 4 mg/kg per day and above. Morphological change was not induced.

Topics: Animals; Body Weight; Contraceptive Agents, Male; Gossypol; Macaca fascicularis; Male; Rats; Rats, Inbred Strains; Spermatocidal Agents

Gossypol-acetic acid (GAA) has been shown to be a powerful chelator of iron. To determine how subchronic administration of GAA affects the distribution and utilization of radioiron, male Holtzman rats, which had received a daily oral dose of GAA (20 mg/kg body weight) for 16 weeks, were injected i.p. with [59Fe]citrate (activity = 16.5 muCi/kg body weight) and [59Fe] incorporation into circulating erythrocytes, bone marrow, liver, spleen, skeletal muscle, and urine was measured 6, 12, or 24 h after [59Fe] administration. Iron [59Fe] incorporation was enhanced in the spleens, livers, bone marrow, and blood of the GAA-treated rats, and increased as the time post-[59Fe] injection increased. Hematological parameters remained within normal limits throughout the 16-week treatment period, suggesting an erythropoietic compensation in the GAA-treated rats. Iron status was markedly different in the GAA-treated rats at the end of the 16 week treatment period, suggesting altered iron utilization. The data suggest that [59Fe] is preferentially distributed to the erythroid tissues of GAA-treated rats for utilization in erythropoiesis.

Topics: Administration, Oral; Animals; Body Weight; Bone Marrow; Erythrocytes; Gossypol; Iron; Iron Radioisotopes; Liver; Male; Rats; Spermatocidal Agents; Spleen

To determine the effects of gossypol, a male antifertility drug, on the eyefluke, P. gralli, this chemical was administered orally to chickens in long-term and short-term regimens. Gossypol acetic acid (GAA), fed to juvenile chickens from 1 to 35 days, caused a decreased weight gain when compared to controls on untreated feed. An FeSO4 supplement to the GAA-fed chickens provided partial protection from the toxic effects of GAA. Worms from GAA-fed chickens were significantly larger than controls, while those from chickens fed GAA + FeSO4 were intermediate in size. Sperm development in these worms was unaffected by GAA. In a second experiment, GAA was administered either in the feed of the hosts from days 35 to 70 or by capsule from days 63 to 77. Worms were exposed to [3H] thymidine, transplanted to the host's eyes, removed on a timed schedule, and processed for autoradiography to determine the rate of spermatogenesis in both GAA-feed and GAA-capsule groups. Early stages of spermatogenesis in both groups were unaffected by GAA and later stages developed at a slightly faster rate than reported for worms from chickens on untreated feed. Higher frequencies of testicular anomalies were observed in both groups including 3 testes, 1 testis, no testes, fused testes, degenerating testes, ovarian tissue in the testes, deformed sperm, and encapsulated sperm. Testes from chickens in both groups showed a significantly lower weight and no signs of spermatogenesis when compared to control chickens.

Topics: Animal Feed; Animals; Body Weight; Chickens; Ferric Compounds; Gossypol; Male; Organ Size; Poultry Diseases; Spermatogenesis; Testis; Trematoda; Trematode Infections

The 24-h incorporation of 59Fe into circulating red blood cells, bone marrow, urine, liver, spleen, and skeletal muscle was measured in splenectomized and sham-splenectomized rats which had received a daily, oral dose of gossypol acetic acid (20 mg GAA/kg body wt) for 91 days. A significant decrease in total body weight gain was observed in all GAA treated animals. Splenectomized rats dosed with GAA exhibited a significant decrease in hemoglobin concentration, hematocrit and erythrocyte count. A significant increase in 59Fe incorporation by red blood cells and a decrease in hepatic incorporation of 59Fe indicate a preferential utilization of iron in erythropoiesis among GAA treated animals.

Topics: Animals; Body Weight; Erythrocytes; Erythropoiesis; Gossypol; Iron; Iron Radioisotopes; Male; Rats; Spermatocidal Agents; Splenectomy

The effects of gossypol acetic acid (GAA) on various aspects of female rat reproduction were evaluated. Forty sexually mature, nulliparous female Holtzman rats received a daily, oral dose of GAA (20 mg GAA/Kg body wt) for 60 days. Nineteen control animals were utilized. Throughout the treatment period, GAA treated rats had significantly more irregular estrous cycles than did controls, and the mean duration of an estrous cycle in the GAA rats was significantly longer than that of controls. A significantly lower body weight gain was observed in all GAA treated animals. A prolonged time for mating, a decrease in incidence of pregnancy, and a reduction in number of viable embryos at Day 13 of gestation were noted among GAA treated animals. Weaning weights of offspring from GAA dams were significantly less than weaning weights of offspring from control dams.

Topics: Animals; Body Weight; Estrus; Female; Gossypol; Rats; Reproduction