|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: 9/10/2005
Publication Date: 12/12/2005
Citation: Ronis, M.J., Gilchrist, J.M., Nagarajan, S., Simmen, F.A., Simmen, R.C., Badger, T.M. 2005. Developmental exposure to soy protein isolate: potential health effects associated with feeding soy-based infant formulas [abstract]. In: Proceedings of the Society of Toxicology of Canada, December 13-15, 2005, Montreal, Canada. 2005 CDROM
Interpretive Summary: One million babies a year are fed soy formula. Soy protein isolate (SPI) is the sole protein source in soy infant formulas sold in the USA. No reports of significant adverse health effects associated with soy formula feeding have appeared in the more than 23 million infants fed soy formula over the past 50 years. However, safety concerns have been raised as the result of the presence of some plant-derived chemicals (the phytochemicals called isoflavones) bound to SPI. They have been shown to stimulate or inhibit of estrogenic pathways depending on dose, interactions with normal circulating hormones, and the cell type examined. Our laboratory has studied SPI effects for a decade. We find that feeding diets containing SPI as the sole protein source to Sprague-Dawley rats over several generations has no effects on classical indicators of estrogen action or changes in normal sex hormone concentrations in SPI-fed female rats. However, we have observed significant increases in breast development and function. This is associated with protection against chemically induced breast cancer since the functional changes in the breast tissue reduce cancer-causing agents. 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. Furthermore, we have data from animal models and soy-fed infants showing improved body composition associated with reduced fat mass and protection against development of heart disease. All these effects are health beneficial rather than indications of toxicity.
Technical Abstract: Soy protein isolate (SPI) is the sole protein source in soy infant formulas, approximately 25% of all formula sold in the USA. No reports of significant adverse health effects associated with soy formula have appeared in the more than 23 million infants fed soy formula over the past 50 years. However, health concerns have been raised as the result of the presence of isoflavone phytoestrogens bound to SPI. The major isoflavones in SPI are genistein and daidzein. These compounds and the daidzein metabolite equol are structurally similar to 17 alpha-estradiol. They have been shown to be weakly estrogenic with SERM-like activity and have higher affinity for ER. Isoflavones also have antiandrogen activities. There has been extensive discussion regarding possible safety issues associated with neonatal soy consumption, and several governments have issued restrictions against soy-based formulas. The toxicity issues raised relate to possible reproductive impairment, endocrine disruption, increased cancer risk, and immune dysfunction. Concerns 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 studies and animal studies in which SPI has been administered following gonadectomy to remove endogenous sex steroids. These studies ignore important dose-response issues; the role of metabolism by gut microflora; first pass conjugation of isoflavones crossing the intestinal mucosa; species differences in isoflavone metabolism; the complexity of SPI which contains many phytochemicals other than isoflavones and additional bioactive peptides or proteins and interactions between isoflavones and endogenous steroids. In studies in our laboratory, feeding diets containing SPI as the sole protein source to Sprague Dawley rats over several generations has been shown to result in no significant effects on fertility, reproductive or endocrine development relative to rats fed casein-based diets. We have observed no increases in uterine weight, a classical indicator of estrogenicity, in SPI fed female rats. However, we have observed significant increases in mammary differentiation and impaired Ah receptor signaling in SPI-fed rats associated with protection against chemically induced mammary tumorigenesis and increased apoptosis in mammary tumor cells exposed to serum from SPI-fed rats. These data are consistent with epidemiological studies indicating that soy consumption is cancer protective. In addition, we have data from animal models and soy-fed infants showing improved body composition associated with reduced fat mass and protection against development of atherosclerotic plaque formation in apoE knockout mice models. We have also demonstrated reduced hepatic steatosis, cholesterol and triglyceride content associated with activation of PPAR alpha and gamma and LXR-mediated signaling. All these effects would be health beneficial rather than indications of toxicity. The only potential safety issue we have observed is increased expression of hepatic CYP3A enzymes in prepubertal rats fed SPI compared to casein which might be associated with increased clearance of some pediatric medications.