|Ronis, Martin - ACNC/UAMS|
|Nagarajan, Shanmugam - ACNC/UAMS|
|Simmen, Frank - ACNC/UAMS|
|Simmen, Rosalia - ACNC/UAMS|
|Badger, Thomas - ACNC/UAMS|
Submitted to: Meeting Proceedings
Publication Type: Abstract Only
Publication Acceptance Date: March 1, 2006
Publication Date: April 1, 2006
Citation: Ronis, M.J., Gilchrist, J.M., Nagarajan, S., Simmen, F.A., Simmen, R.C., Badger, T.M. 2006. Developmental exposure to soy protein isolate: Potential health effects [abstract]. International Life Sciences Institute Food, Nutrition, and Safety Program. Available: http://www.ilsina.org/programs/food_components_health_promotion.html. Interpretive Summary: Recently, concerns have been raised about the safety of soy-based baby formula. Soy formulas make up about 25% of the U.S. market and are fed to over 1 million babies each year. Soy protein isolate (SPI) is the sole protein source in these formulas and is made by processing and extracting soy beans. Arguments about health effects have centered around plant chemicals called isoflavones that are naturally found in soy and are structurally related to the female sex hormone estradiol. The major soy isoflavones are called genistein and daidzein, and they weakly bind to estrogen and androgen receptors in the test tube. However, most of the studies have used cells exposed to pure chemicals, or experimental animals injected with genistein or daidzein, and ignore many issues related to feeding soy protein isolate to babies. In particular, the chemical form of isoflavones is different in SPI. In SPI the isoflavones exist as sugar conjugates that have to be digested by gut bacteria before genistein or daidzein can be absorbed into the body. In addition, during absorption these chemicals are re-conjugated to sugars and sulfate. As a result, the tissue levels of isoflavones are 10-fold lower after dietary consumption of SPI, compared to injecting the pure chemicals i.v. In addition, effects of mixtures are often very different from those of pure components and experimental animals including monkeys break down isoflavones significantly differently from babies. We have observed no harmful effects of feeding SPI to rats throughout development including no effects on fertility, reproductive development, or endocrine disruption. The only potentially important health effect we have observed is increases of liver enzymes (CYP3A) that may speed up the break down of some pediatric drugs. In contrast to toxic effects, we have observed health benefical anti-cancer effects and reduced body fat in SPI-fed rats and soy formula fed infants associated with increased fat breakdown.
Technical Abstract: Soy protein isolate (SPI) is the sole protein source in soy infant formulas, which constitute approximately 25% of all formula sold in America. No reports of significant health problems associated with soy formula feeding have appeared in the more than 20 million infants fed soy formulas since they came on the market. However, health concerns have been raised as the result of the presence of some plant-derived chemicals (the phytochemicals called isoflavones) found in SPI. The major isoflavones in SPI are genistein and daidzein. These compounds and the daidzein metabolite equol, which is made by gut bacteria during the digestion of soy products, are structurally similar to the female hormone 17 beta-estradiol and have been called phytoestrogens. They have been shown to have weak binding to estrogen receptors with activity similar to selective estrogen-receptor modulators (SERMS) such as the breast cancer drug tamoxifen. They have been shown to stimulate or inhibit estrogen signaling depending on dose, levels of endogenous estrogens, and relative expression of estrogen receptor alpha or beta in the target cells. In some studies, isoflavones also appear to have anti-androgenic activities such as the ability to reduce testosterone concentrations. There is controversy regarding possible safety issues associated with soy formula consumption based on early exposure to high concentrations of these isoflavones (4-7 mg/kg/d), and as a result, several governments have issued restrictions against soy-based formulas. The toxicity issues raised relate to possible endocrine disruption, including effects on fertility, increased cancer risk, and immune dysfunction. Safety fears have been based largely on studies in which pure isoflavones have been administered to laboratory animals at high doses, often by routes other than the diet: in vitro cell culture studies and animal studies in which SPI has been administered following castration to remove normal sex steroids. These studies have largely ignored important dose-response issues, the role of metabolism by gut microflora and metabolism during first pass intestinal absorption, species differences in isoflavone metabolism, the complexity of SPI which contains many different phytochemicals and bioactive peptides or proteins, and interactions between isoflavones and normal steroids. In studies in our laboratory, feeding diets containing SPI as the sole protein source to Sprague Dawley rats results in no significant effects on fertility, reproductive or endocrine development relative to rats fed casein-based diets. We have observed no changes in weight of testis, ovary or secondary sex organs, and no changes in normal sex hormone concentrations during development. The only potential safety issue we have observed is increased expression of CYP3A enzymes in the livers of rats fed SPI compared to casein which might be associated with faster breakdown of some pediatric medications. In contrast, we have observed protection against chemically induced breast and colon cancer in rats fed SPI. Breast cancer protection was associated with significant increases in mammary gland differentiation and impaired signaling through a transcription factor in SPI-fed rats called the Ah receptor which normally stimulates metabolic activation of chemical pro-carcinogens. In addition we have seen increased cell death in breast tumor cells exposed to serum from SPI-fed rats in the test tube. These data are consistent with population studies indicating that soy consumption is cancer protective. In addition, we have data from animal models and soy-fed infants showing reduced body fat and protection against development of coronary artery disease in apoE knockout mice models. We have also demonstrated reduced fatty liver, and cholesterol content associated with activation of a number of liver nuclear receptors including PPAR alpha and gamma and LXR which stimulate fat and cholesterol breakdown and excretion. All these effects would be health beneficial rather than indications of toxicity.