2007 Annual Report 1a.Objectives (from AD-416) Certain common dietary factors appear to be capable of:. 1)affecting growth and development;. 2)transiently and permanently altering metabolism;. 3)influencing body composition; and. 4)preventing some diseases. For example, fruits, vegetables, grains and milk contain natural compounds (phytochemicals, peptides and proteins) that can alter development, physiology and metabolism, which can ultimately lead to disease prevention and phenotypic changes. We will:. 1)document which foods and dietary factors can alter body composition either in children or in offspring born to mothers who consume those foods;. 2)determine how much of and in what context, these foods are needed to affect body composition;. 3)study dietary factors in foods commonly consumed by children, such as fruits, rice, milk, and soy to determine how they may affect calorie balance and diseases associated with energy utilization (such obesity-associated insulin resistance), cardiovascular disease, and breast cancer;. 4)identify the biologically active dietary factors and determine their bioavailability, the doses required for specific effects and their mechanisms of action;. 5)determine the direct and indirect effects of dietary factors and the interactions of these factors with endogenous signals in human subjects and animal models throughout early life stages and phenotypes. For example, the isoflavones (also called "phytoestrogens") are particularly concentrated in soybeans and can have many of the same actions as the major female hormones in women, the estrogens. Countries with regular consumption of large amounts of soy foods report lower incidence of cancer, cardiovascular disease, and obesity; and factors in soy (isoflavones and peptides) are postulated as being partially responsible. The soy connection to long-term health is important, because one million U.S. infants are fed infant formula containing soy protein each year and the phytoestrogen content in their blood is extremely high. Virtually nothing is known about the actions of these substances in children, nor on the long-term health consequences of this early exposure. Since this affects nearly 25% of America's youngest people, it is essential to ascertain the long-term health consequences, both positive and negative, of early consumption of these phytochemicals. This is just one example of several foods containing different phytochemicals that have potential health effects during development. 1b.Approach (from AD-416) Studies will focus on the various dietary factors found in foods such as fruits, rice, milk, sorghum, and soy to determine their long-term health effects in infants and children. Phytochemicals (such as the isoflavones) and peptides will be studied to determine the possible effects on risk of cancer, cardiovascular disease, obesity, and other chronic diseases. For example, evidence suggests that exposure to soy foods early in life will reduce the risk of cancer and cardiovascular disease later in life. Similarly, we suspect that there may be some as yet unrecognized effects related to hormonally sensitive systems that regulate energy metabolism and fat disposition that affect development of obesity and that affect drug efficacy. We will conduct laboratory, animal, and clinical studies to test these hypotheses, determine the positive and negative health consequences of various dietary factors such as soy phytoestrogens in maternal diet and infant formula, especially as it relates to safety and disease prevention; understand which phytochemicals have health consequences, how much and how often they should be consumed, and at what age they should be eaten; and, whether it is possible to affect cancer and cardiovascular diseases, and under what circumstances. This same approach will be utilized for dietary factors in other foods. 4.Accomplishments Maternal Overweight Identified as Programming Obesity in Offspring: Epidemiological data suggest a link between obesity in mothers and the risk of developing obesity in their children. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, used a rodent model to demonstrate that females who are obese prior to conception give birth to offspring of normal body weight, but these offspring are much more susceptible to becoming obese later in life than are offspring from lean mothers. This effect was shown to be the result of "fetal programming" of the offspring metabolism. These results have widespread potential significance, because they provide a potential explanation for the relatively rapid increase in obesity, an increase that can be exacerbated by generational programming. In addition, these scientists have developed a model to identify molecular mechanisms of obesity and to test dietary interventions. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project. 3) Long-term Health Consequences of Infant Feeding: The Beginnings Study: No comprehensive study of the three major infant diets (breast feeding, milk- and soy-based formulas) has been conducted. This study is extremely important in light of:. 1)continued rise in incidence of childhood obesity at younger ages each year;. 2)safety and efficacy issues of soy formula; and. 3)the seemingly ever changing composition of commercial formula (e.g., DHA) which have not been adequately studied. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, are conducting the world’s largest longitudinal study (birth to age 6 years) of breast- and formula-fed infants. This past year, they have reached their goal of increasing participant enrollment and have completed more than 500 study visits, including extensive assessments of diet, growth, body composition, and development. This landmark study is the first to comprehensively document the effects of formula feeding on development, and it is providing an enormous data base that will be used for years. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods] (ACNC Project 3) Establishment of New Model of Nonalcoholic Steatohepatitis (NASH): One consequence of childhood obesity is an inflamed fatty liver (termed non-alcoholic steatohepatitis, NASH), and NASH is the most rapidly increasing liver pathology in the U.S. There is no animal model that completely replicates human NASH, and there are no effective treatments. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, developed a new rodent model of NASH in which modest overfeeding of diets high in polyunsaturated fats to sedentary rats via intragastric infusion replicates many of the pathological, endocrine, and metabolic features of this clinical condition. This model provides the best scientific opportunity to replicate most or all the clinical features of human NASH and to learn about how this disease develops. It is anticipated that these results will lead to food-based prevention strategies and may also lead to treatment methods as well. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 3) Rice Protein Has Heart Healthy Properties: Blockage of coronary arteries (atherosclerosis) is the leading cause of death in Western societies, and it is strongly linked to dietary habits. Americans get most of the dietary starch by consuming potatoes; whereas, Asians who have low incidence of atherosclerosis consume rice. The role of rice in preventing disease is not well understood. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, studied mice with high risk of atherosclerosis and found that feeding a diet with rice protein isolate (RPI) lowered the number of coronary artery lesions. Analyses of proximal aorta showed reduced expression of chemokines as compared to controls. Many phytochemicals are bound to the RPI, and our findings raise the possibility that either RPI can be metabolized to heart-healthy bioactive peptides or there are heart-healthy phytochemicals in RPI. Either RPI could be used to develop a food-based strategy to prevent or treat CHD, or RPI peptides or phytochemicals could be used to develop drug-based strategies to prevent or treat CHD. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Chemoprotective Effects of Soy Feeding on Chemical Procarcinogen Activation: Extensive epidemiological studies have linked soy consumption in populations eating a traditional Asian diet with reduced cancer incidence; however, molecular mechanisms underlying these effects are as yet unclear. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, demonstrated that soy protein isolate (SPI) feeding impairs AhR-mediated procarcinogen activation to carcinogenic products by preventing the AhR binding to the CYP1A promoter and stimulating ubiquitination and degradation of AhR by the 26S proteosome. Furthermore, neither the phytochemical-free protein nor pure genistein or diadzein had these effects, suggesting that either another SPI factor is responsible for these effects or the interaction of more than one SPI factors is responsible. These data suggest that reductions in cancer risk associated with soy consumption may be the result of complex mixtures. This may also have significant implications for the rash of commercially available soy "neutraceuticals", since isolated phytochemicals sold in pill form may not replicate the health effects of whole foods. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 1) Aryl Hydrocarbon Receptor-Estrogen Receptor Crosstalk Identified as a Factor in Increased Cancer Risk: Female rodents have increased susceptibility to cancers produced by exposure to environmental and dietary procarcinogens such as polycyclic aromatic hydrocarbons, but the mechanism has not been examined. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, showed that signaling through a transcription factor, the AhR and procarcinogen activation by cytochrome P450 CYP1 enzymes is enhanced by estrogens as the result of recruitment of ER alpha to the AhR and CYP1A promoters. This discovery sheds light on molecular mechanisms underlying increased risk of some cancers such as those produced by consuming overcooked or charred red meats or cigarette smoking in premenopausal women. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 3) Milk Proteins Reduce Risk Mammary Cancer Risks in Young Female Rats: Breast cancer strikes over 200,000 American women annually and although the exact causes are unknown, it is widely believed that dietary factors can positively and negatively contribute to the risk. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, have previously shown that whey protein, a major class of milk proteins and a byproduct of cheese production, can reduce chemically induced rat mammary tumors, and are now studying the mechanism underlying the protective effects. Our lab found elevated serum levels of monocyte chemoattractant protein 1 [MCP-1]) in young adult rats fed a diet made with whey protein hydrolysate, but not in casein-fed rats where no breast cancer protection occurred. This finding is potentially important because this serum protein may serve as a tool (a biomarker) for measuring breast health status of children, and may be useful for developing new preventive or therapeutic strategies (involving either foods, dietary supplements or drugs) to combat breast cancer. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project. 1) In Utero Exposure to Dietary Factors May Prevent Breast Cancer: Human population studies have clearly demonstrated that adolescent girls who consume soy foods have significantly lower risk of breast cancer as they age. This may also be true for women whose mothers consumed soy foods during pregnancy, but solid proof for protection associated with fetal exposures is lacking. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, demonstrated that female rats born of dams (mothers) that consumed a soy diet only during pregnancy were largely protected against mammary cancer later in life. This important finding advances our understanding of the developmental window at which dietary exposure to soy-rich diets can have healthful benefits. Further, this finding will be useful for informing the general population, specifically pregnant mothers, in ways to plan dietary intake to improve the health status of their female offspring at later adult stage. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 1) Effects Epigenetic Effects: Differences in Soy Phytochemicals and Soy Protein: Concerns have been raised with regard to the safety of soy infant formula, particularly related to early developmental exposure to the isoflavones in soy (such as genistein), which are "phytoestrogens" said by some to have significant estrogenic actions. Previous studies with pure isoflavones have suggested the potential for permanent programming of gene expression associated with gestational and neonatal exposure, but children are not exposed to pure genistein, and these studies need to be conducted using soy protein. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, studied the effects of feeding soy protein isolate (SPI), the actual protein source used in soy-infant formulas, in the viable yellow mouse model in which epigenetic changes are revealed by changes in offspring coat color. No effects of SPI-feeding were observed. These studies are important because they demonstrate that whole diets have substantially different effects from dietary phytochemicals studied in isolation, and because they support other animal and human studies suggesting feeding soy infant formulas to infants is safe and is associated with no toxic effects. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 3) Is Infant Reproductive Organ Development Altered by Early Exposure to Soy?: Soy formula has been essentially banned from use in France and severely limited in the United Kingdom, primarily because of concerns about adverse effects on reproduction. One highly publicized study, conducted in marmoset monkeys, indicated increased testicular volume in male monkeys fed soy formula. Scientists at the Arkansas Children’s Nutrition Center in Little Rock, AR, established and standardized ultrasonography methods to image and quantitate volume of reproductive organs in infants and have obtained scans on 86 infants. Preliminary analysis suggests no difference in testicular volume of males on milk- versus soy-formula. Over the next year, additional images will be collected and complete analysis of breast buds, uterus, ovaries, and prostate will be completed. These results are distinctly different from the previous report in marmoset monkeys that suggested a detrimental effect of soy formula, and demonstrate the need for carefully controlled human studies, such as the Beginnings study. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 3) Reducing the Risk of Coronary Heart Disease (CHD) in High Risk Populations: CHD is the leading killer of Americans. Traditionally, some Asian populations have had lower CHD incidence, and this has been associated with lifestyle issues, especially diet and exercise. Increased consumption of soy foods has been linked to lower CHD in Asia, but the mechanisms have not been demonstrated. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, found that in mice at high risk for developing atherosclerosis (Apo-E mice), soy-containing diets partially blocked production of atherosclerotic lesions and reduced proinflammatory cytokines which are thought to mediate damaging effects to coronary arteries. These findings provide the basic foundation for future research that is expected to lead to:. 1)development of novel diet-related strategies to prevent CHD; and. 2)determination of whether fetal or neonatal programming from maternal soy consumption during pregnancy or feeding soy infant formula can reduce risk of CHD that occurs later in life. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Effects of Soy Protein on Breast Cancer Prevention: The signaling pathways that are both affected by dietary factors and act to reduce the risk of mammary gland (breast) cancer are not well known or understood, yet their identities are essential to understanding how to prevent this disease. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, used gene array technology to identify signaling pathways that are altered by consumption of soy-rich diets and showed that soy can regulate the expression of genes involved in metabolism, immune response, signal transduction, and ion transport. We further showed that a signaling cascade that is a major oncogenic pathway in mammary tumorigenesis (called the Wnt pathway) is down-regulated by dietary soy proteins in mammary epithelial cells (the cells that develop tumors). This discovery provides a solid scientific basis for dietary influence on reducing the risks of age-related diseases. New putative targets have been identified that further our understanding the dietary modulation of normal mammary development and that are highly relevant to dietary prevention of breast cancer [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 1) Determining Whether the Soy-Mediated Athero-Protection Occurs by Regulation of Endothelial Cell Specific Cell Adhesion Molecules: Increased consumption of soy foods has been linked to lower coronary heart disease in Asia, but the mechanisms have not been demonstrated. As endothelial cell adhesion molecules play a major role in the initiation of atherosclerosis, knowing whether expression of endothelial cell adhesion molecules is affected by soy consumption would be an important step in defining the mechanisms by which soy factors work. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, found that in soy isoflavones, inhibited pro-inflammatory cytokine induced expression of endothelial cell adhesion molecules. These findings provide evidence that soy-based diets may have anti-inflammatory functions and lay the foundation to understand the protective effect of soy-based diets on inflammation [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Micorarray to Determine Gene Expression Profiles of Aortic Endothelial Cells and Macrophages: Increased consumption of soy foods has been linked to lower coronary heart disease (CHD) in Asia, but the mechanisms have not been demonstrated. As a preliminary step to understand the mechanisms scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, carried out proteomics analysis using an atherosclerosis antibody array kit. Our lab has found that in Apo-E mice fed soy-containing diets, there is a partially blocked expression of cell adhesion molecules expressed on aorta and macrophages, which are key players in the inflammation. These findings provide the basic foundation to understand the protective effect of soy-based diets on inflammation, and for future research that is expected to lead to:. 1)development of novel diet-related strategies to prevent CHD; and. 2)determination of whether fetal or neonatal programming from maternal soy consumption during pregnancy or feeding soy infant formula can reduce risk of CHD that occurs later in life. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Effects of Soy Infant Formula Feeding on Drug Metabolism Identified: It has previously been reported that rats fed soy protein isolate (the same protein used in soy infant formula) have elevated CYP3A, the major enzyme that metabolizes most pediatric medications. If this is true for children fed soy formula, it would be extremely important, because drug efficacy in these infants may be reduced. This question is difficult to study in children, so a more clinically similar model between the rat and children was needed. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, studied neonatal piglets fed essentially the same soy formula fed to human infants and found increased expression and activity of CYP3A enzymes, an effect mirroring our previous findings in rats. These data are significant and suggest the same condition probably occurs in infants. This provides the basic foundation for further studies in both the pig model and in children, and demonstrates how important dietary factors could be in modulating different aspects of human health, especially early in life. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 3) Body Fat Assessment of Breast-Fed Infants during the First Year of Life The assessment of infant body fat has been difficult to obtain due to technical issues and because currently used state-of-the-art methodologies vary widely in technology, concepts, assumptions and results; thus the early development of body composition, in particular percent body fat, is relatively unknown. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, led a multi-site international project to develop normative body composition data of exclusively breast-fed (BF) infants (age of 0-6 months) using air displacement plethysmography (PeaPod). Preliminary findings demonstrate that there are differences between BF boys/girls in body mass and lean body mass at all time points, but there is no body fat percentage difference between boys/girls. However, some of our results were lower than results found in the on-going longitudinal cohort study, Beginnings, which samples both BF and forumula-fed infants. This suggests that body composition differs significantly between BF and FF infants in the first 6 months of life. This new body composition data for exclusively BF infants will add to the existing literature and may serve as a clinical and research reference for those interested in a prescriptive standard for how infants should grow when provided care that meets the current public health recommendations and may be important in understanding how to prevent childhood obesity. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods] (ACNC Project 3) Soy-based Diets Modulate the Function of Macrophages Isolated from the ApoE-/- Mouse: Uptake of oxLDL by macrophages leads to foam cell formations and this is the initial event in the atherosclerotic process. Effect of soy isoflavones on the expression of receptors for the uptake of oxLDL is not known. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, found that in soy isoflavones partially inhibited expression of oxLDL binding receptors. These findings provide evidence that soy-based diet may prevent atherosclerosis by inhibiting uptake of oxLDL. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Consumption of Soy-Based Diets on Reduces Antibodies Against Oxidized-LDL: Elevated levels of anti-oxLDL antibody have been implicated in the initiation and progression of atherosclerosis. The effects of feeding soy-based diets on the production of anti-oxLDL antibody in vivo have not been determined. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, found lower levels of circulating anti-oxLDL antibody response in apoE-/- mice fed soy-based diet. To further understand the anti-oxLDL antibody in atherosclerosis, a double knockout animal lacking IgG binding receptors in apoE-/- background was generated. These findings provide evidence that consumption of the soy-based diet may prevent atherosclerosis by inhibiting anti-oxLDL antibody. The double knockout mouse generated in these experiments will be used to determine the role for anti-oxLDL antibody in atherosclerosis and will be made available to other researchers. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Anti-inflammatory properties of soy isoflavones: Atherosclerosis is a chronic inflammatory disease, and cytokines play a major role in the progression of atherosclerosis. Since soy consumption has been associated with lower atherosclerosis risk, it would be important to know if the production of proinflammatory cytokines was altered by soy. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, found that in soy isoflavones inhibited oxLDL-induced pro-inflammatory cytokine responses. These findings suggest that soy-based diet may prevent atherosclerosis by attenuating the expression of pro-inflammatory cytokines. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Soy-based Diets Prevent Hyperhomocysteinemia-Induced Atherosclerosis: Homocysteine has been identified as an independent risk factor for atherosclerosis, but the effects of soy-isoflavones on homocysteine-induced atherosclerosis is unknown. As a preliminary step to understand the molecular mechanisms contributing to the homocysteine-mediated promotion of atherosclerosis, scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, developed a mouse model by feeding dietary homocysteine. ACNC researchers found that feeding homocysteine in atherosclerosis-prone apoE-/- mice promotes atherosclerosis, and furthermore that soy isoflavones inhibit:. 1)homocysteine-mediated activation of macrophages using a cell culture model; and. 2)homocysteine-induced pro-inflammatory cytokine responses by macrophages. These findings suggest that soy-based diets may prevent homocysteine-mediated promotion of atherosclerosis. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 2) Effects of Dietary Proteins on Gene Expression Profiles of Small Intestine: The gastrointestinal tract (GIT) is the only organ that is directly exposed to diet. The intestine is the largest and most important metabolic, endocrinologic, and immunologic GIT segment, and intestinal exposure to dietary factors plays a significant role in health. Although linking dietary proteins to modulations of specific intestinal genes and the eventual metabolic and immunologic effects has important ramifications for child growth, development, body composition, and disease prevention, this has not been well studied. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, used microarray technology to identify mRNAs/genes expressed in young adult rat small intestine (jejunum) that encode metabolic, transcriptional, or secreted proteins/peptides, and which are differentially regulated in their expression by lifetime consumption of dietary soy protein vs. casein (control protein). These data establish a basic scientific foundation for subsequent elucidation of molecular mechanisms by which soy proteins affect postnatal growth, nutrient utilization, and peripheral body composition (anti-obesity). [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 1) Prenatal Nutritional Proteins can Alter Rat Progeny’s Risk for Adult Colon Cancer: The concept that there are fetal origins of adult diseases that can be influenced by dietary factors requires much more study before researchers understand how to prevent or reduce disease. Colon cancer may be one of the diseases that could be reduced by dietary intervention. Scientists from the Arkansas Children’s Nutrition Center in Little Rock, AR, found that feeding soy protein isolate (the protein source in soy infant formula) or genistein (a soy isoflavone) to pregnant rats altered the numbers of adult colon tumors (multiplicity) and also altered the colon tissue gene expression, and serum IGF-I and testosterone levels in the offspring of these rats. This is some of the first published data to suggest that colon cancer risk may be affected by early developmental events/nutrition as opposed to being a disease solely of the aging. [NP 107; Component 5, Health Promoting Properties of Plant and Animal Foods](ACNC Project 1) 6.Technology Transfer Number of new CRADAs and MTAs 1 Number of non-peer reviewed presentations and proceedings 28 Review Publications Xiao, R., Carter, J.A., Linz, A.L., Ferguson, M., Badger, T.M., Simmen, F.A. 2006. Dietary whey protein lowers serum C-peptide concentration and duodenal SREBP-1c mRNA abundance, and reduces occurrence of duodenal tumors and colon aberrant crypt foci in azoxymethane-treated male rats. Journal of Nutritional Biochemistry. 17(9):626-634. Ronis, M.J., Little, J.M., Barone, G.W., Chen, G., Radominska-Pandya, A., Badger, T.M. 2006. Sulfation of the isoflavones genistein and daidzein in human and rat liver and gastrointestinal tract. Journal of Medicinal Foods. 9(3):384-355. Nagarajan, S. 2007. Anti-OxLDL IgG blocks OxLDL interaction with CD36, but promotes FcyR, CD32A-dependent inflammatory cell adhesion. Immunology Letters. 108(1):52-61. Shankar, K., Hidestrand, M., Liu, X., Xiao, R., Skinner, C.M., Simmen, F.A., Badger, T.M., Ronis, M.J. 2006. Physiologic and genomic analyses of nutrition-ethanol interactions during gestation: implications for fetal ethanol toxicity. Experimental Biology and Medicine. 231(8):1379-1397. Prior, R.L., Wu, X., Gu, L. 2006. Flavonoid metabolism and challenges to understanding mechanisms of health effects. Journal of the Science of Food and Agriculture. 86(15):2487-2491. Prior, R.L., Wu, X. 2006. Anthocyanins: structural characteristics that result in unique metabolic patterns and biological activities. Free Radical Research. 40(10):1014-1028. Chen, J., Haley, R.L., Hidestrand, M., Shankar, K., Liu, X., Lumplin, C.K., Simpson, P.M., Badger, T.M., Ronis, M.J. 2006. Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kB ligand in osteoblasts. Journal of Pharmacology and Experimental Therapeutics. 319(3):1182-1190. Eason, R., Till, R.S., Frank, J.A., Badger, T.M., Simmen, F.A., Simmen, R.C. 2006. Tumor-protective and Tumor-promoting actions of dietary whey proteins in an N-methyl-N-nitrosourea model of rat mammary carcinogenesis. Nutrition and Cancer. 55(2):171-177. Prior, R.L., Wu, X., Gu, L., Jacob, R.A., Cao, G., Cook, R.A. 2007. Plasma antioxidant capacity changes following a meal as a measure of the ability of a food to alter in vivo antioxidant status. Journal of American College of Nutrition. 26(2):170-171. Golden, C., McMahon, M., Thampi, P., Badger, T.M., Nagarajan, S., Helm, R.M. 2007. Diet regulates the development of gut-associated lymphoid tissues in neonatal piglets. Neonatology. 91(4):248-255. Su, Y., Eason, R.R., Till, R.S., Badger, T.M., Simmen, R.C. 2007. In utero exposure to maternal diets containing soy protein isolate, but not genistein alone, protects young adult rat offspring from NMU-induced mammary tumorigenesis. Carcinogenesis. 28(5):1046-1051. Simmen, F.A., Xiao, R., Velarde, M.C., Nicholson, R.D., Bowman, M., Fujii-Kuriyama, Y., Oh, P.S., Simmen, R. 2007. Dysregulation of crypt cell proliferation and lineage determination, and villus cell migration in the small intestines of mice lacking the intestinal smooth muscle-expressed transcription factor, Krüppel-like factor 9 (Klf9). Molecular and Cellular Biology. 292(6):1757-1769. Nagarajan, S., Stewart, B.W., Badger, T.M. 2006. Soy isoflavones attenuate human monocyte adhesion to endothelial cell¿specific CD54 by inhibiting monocyte CD11a1. Journal of Nutrition. 136(9):2384-2390. Gu, L., House, S.E., Prior, R.L., Rooney, L. 2007. Sorghum bran in the diet dose dependently increased excretion of catechins and microbial derived phenolic acids in female rats. Journal of Agricultural and Food Chemistry. 55(13):5326-5334. Su, Y., Simmen, F.A., Xiao, R., Simmen, R.C. 2007. Expression profiling of rat mammary epithelial cells reveals candidate signaling pathways in dietary protection from mammary tumors. Physiological Genomics. 30(1):8-16. Baumgardner, J., Shankar, K., Korourian, S., Badger, T.M., Ronis, M.J. 2007. Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition. American Journal of Physiology Gastrointestinal Liver Physiology. 38(1):355-364. Singhal, R., Badger, T.M., Ronis, M.J. 2007. Reduction in 7,12-dimethylbenz[a]anthracene-induced hepatic cytochrome-P450 1A1 expression following soy consumption in female rats is mediated by degradation of the aryl hydrocarbon receptor. Journal of Nutrition. 137(1):19-24. Rizki, G., Arnaboldi, L., Gabrielli, B., Yan, J., Lee, G., Ng, R., Turner, S., Badger, T.M., Pitas, R., Maher, J.J. 2006. Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1. Journal of Lipid Research. 47(10):2280-2290. Heneman, K.M., Chang, H.C., Prior, R.L., Steinberg, F.M. 2007. Soy protein with and without isoflavones fails to substantially increase postprandial antioxidant capacity. Journal of Nutritional Biochemistry. 18(1):46-53. Schauss, A.G., Wu, X., Prior, R.L., Ou, B., Huang, D., Owens, J., Agarwal, A., Jensen, G.S., Hart, A.N., Shanbrom, E. 2006. Antioxidant capacity and other bioactivities of the freeze-dried Amazonian palm berry, Euterpe oleraceae mart. (acai). Journal of Agriculture and Food Chemistry. 54(22):8604-8610. Schauss, A.G., Wu, X., Prior, R.L., Ou, B., Patel, D., Huang, D., Kababick, J.P. 2006. Phytochemical and nutrient composition of the freeze-dried amazonian palm berry, Euterpe oleraceae mart. (acai). Journal of Agriculture and Food Chemistry. 54(22):8598-8603. Wahl, E.C., Aronson, J., Liu, L., Liu, Z., Perrien, D.S., Skinner, R.A., Badger, T.M., Ronis, M.J., Lumpkin, C.K. 2007. Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis. Journal of Toxicology and Applied Pharmacology. 220(3):302-310. Shankar, K., Ronis, M.J., Badger, T.M. 2007. Effects of pregnancy and nutritional status on alcohol metabolism. Alcohol Research and Health. 30(1):55-59. Ronis, M.J., Badger, T.M., Wands, J., De La Monte, S., Lang, C.H., Calissendorff, J. 2007. Alcohol-induced disruption of endocrine signaling. Alcoholism: Clinical and Experimental Research. 31(8):1-17. Wang, T., Shankar, K., Ronis, M.J., Mehendale, H.M. 2007. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Critical Reviews in Toxicology. 37(5):413-459. Helm, R.M. 2006. Animal models for food allergy. In: Maleki, S., Burks, W., Helm, R., editors. Food Allergy. 1st Edition. Washington, D.C.: ASM Press. p. 171-177. Wahl, E.C., Liu, L., Perrien, D.S., Aronson, J., Hogue, W.R., Skinner, R.A., Hidestrand, M., Ronis, M.J., Badger, T.M., Lumpkin, C.K. 2006. A novel mouse model for the study of the inhibitory effects of chronic ethanol exposure on direct bone formation. Alcohol. 39(3):159-067.