Relative toxicity of gossypol enantiomers in broilers

Use of cottonseed meal in poultry diets has been avoided in large part because of fear of gossypol toxicity. Gossypol exists naturally as a mixture of 2 enantiomers that exhibit different biological activities. Two experiments were conducted to determine the relative toxicity of gossypol enantiomers on broilers. In the first experiment, 3-d-old broilers were fed a standard diet containing 0, 100, 200, 300, or 400 mg of gossypol from gossypol acetic acid per kilogram of diet from 3 to 42 d of age. This form of gossypol contains both enantiomers in an equimolar ratio. Each dietary treatment consisted of 6 replicate pens of 4 birds. In the second experiment, 3-dold broilers were divided into 15 pens of 4 birds each and fed a standard diet supplemented with either no gossypol or one of the gossypol enantiomers at 200 or 400 mg/kg of diet from 3 to 21 d of age. In both experiments, feed intake and BW gain were measured. In addi- (Key words: cottonseed meal, gossypol, gossypol enantiomer, broiler) 2005 Poultry Science 84:1376–1382 INTRODUCTION Cottonseed meal (CSM) could be an attractive alternative protein source for poultry diets, but concern over the presence of the potentially toxic agent, gossypol, has limited its use. Gossypol [1,1′,6,6′,7,7′-hexahydroxy-5,5′- diisopropyl-3, 3′-dimethyl-(2, 2′- binaphthalene)-8, 8′-dicarboxaldehyde] is a polyphenolic compound located in pigment glands that are distributed throughout the cotton plant. Gossypol is composed of 2 naphthalene rings with restricted rotation around the bond connecting the rings. As a result of this restricted rotation, gossypol occurs naturally as a mixture of 2 enantiomers [(+)- and (−)- 2005 Poultry Science Association, Inc. Received for publication February 7, 2005. Accepted for publication May 5, 2005. 1This research was supported in part by grant 2631RE683-118 from the Georgia Cotton Commission, Perry, GA. 2Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. 3To whom correspondence should be addressed: [email protected]. 1376 tion, several organ and tissue samples were collected at 21 d (experiments 1 and 2) and 42 d (experiment 1) of age and analyzed for gossypol. In experiment 1, feed consumption and BW gain were reduced (P < 0.05) at 21 and 42 d for the birds fed the highest level of gossypol. The concentration of gossypol in the heart, kidney, and plasma were equivalent at 21 and 42 d of age. In experiment 2, total feed consumption was reduced only in birds consuming (−)-gossypol, but BW gains were lower for birds fed either enantiomer. However, (−)-gossypol was more detrimental to growth than (+)-gossypol. The liver had the highest tissue concentration of both enantiomers, and accumulation of (+)-gossypol was higher than (−)- gossypol in all tissues examined. No racemization of the enantiomers was apparent in the tissues analyzed. Our results indicated that both gossypol enantiomers were toxic to broilers but that (−)-gossypol was more harmful to efficient broiler production than (+)-gossypol

Relative toxicity of gossypol enantiomers in laying and broiler breeder hens

Gossypol, a natural component of cottonseed meal, exists in positive (+) or negative (−) enantiomeric forms, and their levels and ratio could be altered by developing new genetic strains of cotton. Two experiments were conducted to determine the relative toxicity of the individual gossypol enantiomers in laying and broiler breeder hens. In the first experiment, 25 individually caged Hy-Line W-36 forty-three-week-old laying hens were fed a standard corn-soy diet supplemented with either no gossypol or the individual enantiomers at 200 and 400 mg/kg of diet for 20 d (5 hens/treatment). In the second experiment, 15 individually caged Cobb 500 fast-feathering 44-wk-old broiler breeder hens were fed a standard corn-soy-wheat middlings diet supplemented with either no gossypol or the individual enantiomers at 400 mg/kg of diet for 18 d (5 hens/treatment). In both experiments, feed intake, egg production, and egg weight were determined daily. All eggs were individually opened and scored for yolk discoloration. At the end of both experiments, several organ and tissue samples were collected for gossypol analyses. In both experiments, the addition of (+)-gossypol to the diet reduced egg production. Only laying and broiler breeder hens fed (+)-gossypol produced eggs with severe yolk discoloration (score ≥ 4). Total feed intake was lower (P < 0.05) in laying hens fed the 400 mg/kg level of (+)-gossypol compared with laying hens fed the other dietary treatments. In contrast, broiler breeder hens consumed less of the diet supplemented with (−)-gossypol. In both experiments, tissue accumulation of (+)-gossypol was higher than (−)-gossypol, with the exception of bile and excreta. The results suggest that in hens the ingestion of (+)-gossypol has a greater effect on egg yolk discoloration than the consumption of (−)-gossypol

Near infrared reflectance spectroscopy for the determination of free gossypol in cottonseed meal

Gossypol is a toxic polyphenolic compound produced by the pigment glands of the cotton plant. The free gossypol content of cottonseed meal (CSM) is commonly determined by the American Oil Chemists’ Society (AOCS) wet chemistry method. The AOCS method, however, laboratory-intensive, time-consuming, and therefore, not practical for quick field analyses. To determine if the free gossypol content of CSM could be predicted by near infrared reflectance spectroscopy (NIRS), CSM samples were collected from all over the world. All CSM samples were ground and a portion of each analyzed for free gossypol by the AOCS procedure (reference data) and by NIRS (reflectance data). Both reflectance and reference data were combined in calibration. The coefficient of determination (r2) and standard error of prediction (SEP) were used to assess the calibration accuracy. The r2 was 0.728, and the SEP was 0.034 for the initial calibration that included samples from all over the world. However, the r2 and SEP improved to 0.921 and 0.014, respectively, if the calibration was made using CSM samples only from the United States. These results indicate that a general prediction equation can be developed to predict the free gossypol content of CSM by NIRS. From a practical standpoint, NIRS technology provides a method for quickly assessing whether a particular batch of CSM has a free gossypol content low enough to be suitable for use in poultry diets.This research was supported in part by grant 05-635GA from the Georgian Cotton Commission, Perry, G

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Effect of Whole Cottonseed, Gossypol, and Ruminally Protected Lysine Supplementation on Milk Yield and Composition

To determine whether the gossypol content of the diet affected availability of dietary Lys, 4 cows with ruminal and duodenal cannulas and 16 intact cows in early lactation were assigned to diets containing either glanded cottonseed, glanded cottonseed plus 15 g/d of ruminally protected Lys, glandless cottonseed, or glandless cottonseed plus 15 g/d of ruminally protected Lys. The experimental design was a 4 × 4 Latin square design with 3-wk experimental periods. Gossypol concentrations in plasma were lower when cows were fed glandless cottonseed. Lysine supplementation increased the flow and percentage of Lys in duodenal digesta and increased the concentration of Lys in plasma. Neither type of cottonseed nor Lys supplementation affected dry matter intake. Yields of milk and fat-corrected milk from cannulated cows were not affected by diet, but yields from intact cows were increased by Lys supplementation. For both cannulated and intact cows, Lys supplementation increased the percentage of milk protein, and milk protein yield was increased by Lys in intact cows. Dietary gossypol did not affect the response to Lys, indicating that dietary gossypol had little or no effect on the availability of Lys for dairy cows