NTP‐CERHR expert panel report on the developmental toxicity of soy infant formula

Abstract

Soy infant formula contains soy protein isolates and is fed to infants as a supplement to or replacement for human milk or cow milk. Soy protein isolates contains estrogenic isoflavones (phytoestrogens) that occur naturally in some legumes, especially soybeans. Phytoestrogens are nonsteroidal, estrogenic compounds. In plants, nearly all phytoestrogens are bound to sugar molecules and these phytoestrogen-sugar complexes are not generally considered hormonally active. Phytoestrogens are found in many food products in addition to soy infant formula, especially soy-based foods such as tofu, soy milk, and in some over-the-counter dietary supplements. Soy infant formula was selected for National Toxicology Program (NTP) evaluation because of (1) the availability of large number of developmental toxicity studies in laboratory animals exposed to the isoflavones found in soy infant formula (namely, genistein) or other soy products, as well as few studies on human infants fed soy infant formula, (2) the availability of information on exposures in infants fed soy infant formula, and (3) public concern for effects on infant or child development. On October 2, 2008 (73 FR 57360), the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) announced its intention to conduct an updated review of soy infant formula to complete a previous evaluation that was initiated in 2005. Both the current and previous evaluations relied on expert panels to assist the NTP in developing its conclusions on the potential developmental effects associated with the use of soy infant formula, presented in the NTP Brief on Soy Infant Formula. The initial expert panel met on March 15 to 17, 2006, to reach conclusions on the potential developmental and reproductive toxicities of soy infant formula and its predominant isoflavone constituent genistein. The expert panel reports were released for public comment on May 5, 2006 (71 FR 28368). On November 8, 2006 (71 FR 65537), CERHR staff released draft NTP Briefs on Genistein and Soy Formula that provided the NTP's interpretation of the potential for genistein and soy infant formula to cause adverse reproductive and/or developmental effects in exposed humans. However, CERHR did not complete these evaluations, finalize the briefs, or issue NTP Monographs on these substances based on this initial evaluation. Between 2006 and 2009, a substantial number of new publications related to human exposure or reproductive and/or developmental toxicity were published for these substances. Thus, CERHR determined that updated evaluations of genistein and soy infant formula were needed. However, the current evaluation focuses only on soy infant formula and the potential developmental toxicity of its major isoflavone components, e.g. genistein, daidzein (and estrogenic metabolite, equol), and glycitein. This updated evaluation does not include an assessment on the potential reproductive toxicity of genistein following exposures during adulthood as was carried out in the 2006 evaluation. CERHR narrowed the scope...

Prenatal Exposure to the Phytoestrogen Daidzein Resulted in Persistent Changes in Ovarian Surface Epithelial Cell Height, Folliculogenesis, and Estrus Phase Length in Adult Sprague-Dawley Rat Offspring

“…Studies evaluating these possible favorable effects have led to conflicting results (Andres et al, 2011;Kwack et al, 2009;Sacks, 2005). Nevertheless, an increased demand for soy and soy-based supplements by consumers has led to a significant rise in the use of soy-derived protein in an array of food products (Kwack et al, 2009;McCarver et al, 2011). This may be of concern as the ingestion of isoflavones has been associated with impaired reproductive function in sheep (Ch'Áng, 1958), mouse (Kaludjerovic et al, 2012), cheetahs in captivity (Setchell et al, 1987), and three women presenting with reproductive pathology (Chandrareddy et al, 2008).…”

Feeding soy protein isolate and treatment with estradiol have different effects on mammary gland morphology and gene expression in weanling male and female rats

“…Despite these apparent health benefits, the National Toxicology Program recently raised its level of concern about the potential reproductive toxicity of soy infant formula from negligible to minimal (31). This re-evaluation of soy infant formula, which has been in use in the US for over 50 yr and which is consumed by nearly 1 million infants/year, was motivated by a series of in vitro and in vivo results evaluating the estrogenic properties of the soy isoflavone genistein (31).…”

“…This re-evaluation of soy infant formula, which has been in use in the US for over 50 yr and which is consumed by nearly 1 million infants/year, was motivated by a series of in vitro and in vivo results evaluating the estrogenic properties of the soy isoflavone genistein (31). Although epidemiological studies in human infants consuming soy formula revealed normal growth and development (13,55), there is a concern that infants consuming soy formula are exposed to dangerously high levels of genistein and are at increased risk for reproductive tract malformations and for estrogen-sensitive cancers such as breast and uterine cancer, similarly to children of women exposed to diethylstilbestrol in utero (49).…”

“…Genistein and other soy-associated isoflavone phytochemicals, such as daidzein, and the daidzein metabolite equol have a structural similarity with estrogens and are able to bind weakly to the estrogen receptors alpha and beta (ER␣ and ER␤), with a preference for ER␤ (24,30). Genistein has been shown to have estrogen-like properties: stimulating growth in the MCF7 breast cancer cell line, inducing an increase in uterus weight, and inducing reproductive toxicity in rodents (18,20,31). However, genistein is only one of the hundreds of phytochemicals associated with soy.…”

Effects of Post-Weaning Consumption of Soy Isoflavones on Prepubertal and Postpubertal Serum Levels of Some Reproductive Hormones of Male Wistar Rats

“…Exposing female neonatal mice to the synthetic estrogen, ethinylestradiol, caused alteration in Cyst breakdown, oocyte survival and follicle development [13]. A combination of lignan, genistein and daidzein containing diet showed reduced serum estradiol levels in the pregnant rats as well as reduced anogenital distance in the newborn males [14]. While most of the researches focused on assessing the effects of isoflavones on postpubertal parameters, the researches which assess the effects of isoflavones on prepubertal parameters have not been fully demonstrated [15].…”