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

Birth Defects Research Part B - Developmental and Reproductive Toxicology

Volumn 92, Issue 5, 2011, Pages 421-468

  McCarver, Gail ^a   Bhatia, Jatinder ^b   Chambers, Christina ^c   Clarke, Robert ^d   Etzel, Ruth ^e   Foster, Warren ^f   Hoyer, Patricia ^g   Leeder, J Steven ^h   Peters, Jeffrey M ⁱ   Rissman, Emilie ^j   Rybak, Michael ^k   Sherman, Claire ^l   Toppari, Jorma ^m   Turner, Katie ⁿ  

^a MEDICAL COLLEGE OF WISCONSIN   (United States)

^b MEDICAL COLLEGE OF GEORGIA   (United States)

^c UCSD MEDICAL CENTER   (United States)

^d GEORGETOWN UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e GEORGE WASHINGTON UNIVERSITY   (United States)

^f MCMASTER UNIVERSITY   (Canada)

^g UNIVERSITY OF ARIZONA   (United States)

^h CHILDREN'S MERCY HOSPITALS AND CLINICS   (United States)

ⁱ PENNSYLVANIA STATE UNIVERSITY   (United States)

^j UNIVERSITY OF VIRGINIA   (United States)

^k CENTERS FOR DISEASE CONTROL AND PREVENTION   (United States)

^l CERUS CORPORATION   (United States)

^m UNIVERSITY OF TURKU   (Finland)

ⁿ RTI INTERNATIONAL   (United States)

more..

Author keywords

Endocrine disrupters; Nutrition; Safety assessment

Indexed keywords

DAIDZEIN; EQUOL; GENISTEIN; GLYCITEIN; ISOFLAVONE; PHYTOESTROGEN; SOYBEAN PROTEIN;

ARTICLE; ARTIFICIAL MILK; CHILD DEVELOPMENT; HUMAN; INFANT NUTRITION; NONHUMAN; POLICY; PRIORITY JOURNAL; REPRODUCTIVE TOXICITY; SAFETY; SOYBEAN MILK; TOXICITY TESTING;

ANIMALS; FEMALE; HUMANS; INFANT; INFANT FORMULA; INFANT, NEWBORN; ISOFLAVONES; MALE; MICE; PHYTOESTROGENS; RATS; SOY FOODS; SOYBEAN PROTEINS;

ANIMALIA; GLYCINE MAX;

EID: 80054691595     PISSN: 15429733     EISSN: 15429741     Source Type: Journal    
DOI: 10.1002/bdrb.20314     Document Type: Article

References (181)

1. Adachi T, Ono Y, Koh KB, et al. 2004. Long-term alteration of gene expression without morphological change in testis after neonatal exposure to genistein in mice: toxicogenomic analysis using cDNA microarray. Food Chem Toxicol 42:445-452.
2. Adlercreutz H, Fotsis T, Watanabe S, et al. 1994. Determination of lignans and isoflavonoids in plasma by isotope dilution gas chromatography-mass spectrometry. Cancer Detect Prev 18:259-271.
3. Agostoni C, Axelsson I, Goulet O, et al. 2006. Soy protein infant formulae and follow-on formulae: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 42:352-361.
4. Agostoni C, Fiocchi A, Riva E, et al. 2007. Growth of infants with IgE-mediated cow's milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol 18:599-606.
5. Akingbemi BT, Braden TD, Kemppainen BW, et al. 2007. Exposure to phytoestrogens in the perinatal period affects androgen secretion by testicular Leydig cells in the adult rat. Endocrinology 148:4475-4488.
6. Atanassova N, McKinnell C, Turner KJ, et al. 2000. Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: evidence for stimulatory effects of low estrogen levels. Endocrinology 141:3898-3907.
7. Awoniyi CA, Roberts D, Veeramachaneni DN, et al. 1998. Reproductive sequelae in female rats after in utero and neonatal exposure to the phytoestrogen genistein. Fertil Steril 70:440-447.
8. Badger TM, Ronis MJ, Hakkak R, et al. 2002. The health consequences of early soy consumption. J Nutr 132:559S-565S.
9. Bateman HL, Patisaul HB. 2009. Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus. Neurotoxicology 29(6):988-997.
10. Berger-Achituv S, Shohat T, Romano-Zelekha O, et al. 2005. Widespread use of soy-based formula without clinical indications. J Pediatr Gastroenterol Nutr 41:660-666.
11. Bhatia J, Greer F. 2008. Use of soy protein-based formulas in infant feeding. Pediatrics 121:1062-1068.
12. Bloedon LT, Jeffcoat AR, Lopaczynski W, et al. 2002. Safety and pharmacokinetics of purified soy isoflavones: single-dose administration to postmenopausal women. Am J Clin Nutr 76:1126-1137.
13. Boucher BA, Cotterchio M, Kreiger N, Thompson LU. 2008. Soy formula and breast cancer risk. Epidemiology 19:165-166.
14. Brown NM, Setchell KD. 2001. Animal models impacted by phytoestrogens in commercial chow: implications for pathways influenced by hormones. Lab Invest 81:735-747.
15. Busby MG, Jeffcoat AR, Bloedon LT, et al. 2002. Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men. Am J Clin Nutr 75:126-136.
16. Cabanes A, Wang M, Olivo S, et al. 2004. Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis 25:741-748.
17. Cao YA, Calafat AM, Doerge DR, et al. 2009. Isoflavones in urine, saliva, and blood of infants: data from a pilot study on the estrogenic activity of soy formula. J Expo Sci Environ Epidemiol 19:223-234.
18. Casanova M, You L, Gaido KW, et al. 1999. Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro. Toxicol Sci 51:236-244.
19. Cassidy A. 2006. Factors affecting the bioavailability of soy isoflavones in humans. J AOAC Int 89:1182-1188.
20. Cassidy A, Albertazzi P, Lise Nielsen I, et al. 2006. Critical review of health effects of soyabean phyto-oestrogens in post-menopausal women. Proc Nutr Soc 65:76-92.
21. Chan GM, Leeper L, Book LS. 1987. Effects of soy formulas on mineral metabolism in term infants. Am J Dis Child 141:527-530.
22. Chandra RK. 1997. Five-year follow-up of high-risk infants with family history of allergy who were exclusively breast-fed or fed partial whey hydrolysate, soy, and conventional cow's milk formulas. Journal of Pediatric Gastroenterology and Nutrition 24(4):380-388.
23. Chandra RK. 1998. Five-year follow up of high-risk infants with family history of allergy exclusively breast-fed or fed partial whey hydrolysate, soy and conventional cow's milk formulas. Nutrition Research 18(8):1395-1411.
24. Chandra RK, Hamed A. 1991. Cumulative incidence of atopic disorders in high risk infants fed whey hydrolysate, soy, and conventional cow milk formulas. Ann Allergy 67(2 Pt 1):129-132.
25. Chandra RK, Puri S, Hamed A. 1989. Influence of maternal diet during lactation and use of formula feeds on development of atopic eczema in high risk infants. BMJ 299(6693):228-230.
26. Chandra RK, Puri S, Suraiya C, Cheema PS. 1986. Influence of maternal food antigen avoidance during pregnancy and lactation on incidence of atopic eczema in infants. Clin Allergy 16(6):563-569.
27. Chandra RK, Singh G, Shridhara B. 1989. Effect of feeding whey hydrolysate, soy and conventional cow milk formulas on incidence of atopic disease in high risk infants. Ann Allergy 63(2):102-106.
28. Chang HC, Churchwell MI, Delclos KB, et al. 2000. Mass spectrometric determination of Genistein tissue distribution in diet-exposed Sprague-Dawley rats. J Nutr 130:1963-1970.
29. Chen A, Rogan WJ. 2004. Isoflavones in soy infant formula: a review of evidence for endocrine and other activity in infants. Annu Rev Nutr 24:33-54.
30. Chen Y, Huang C, Zhou T, Chen G. 2008. Genistein induction of human sulfotransferases in HepG2 and Caco-2 cells. Basic Clin Pharmacol Toxicol 103:553-559.
31. Choi SY, Ha TY, Ahn JY, et al. 2008. Estrogenic activities of isoflavones and flavones and their structure-activity relationships. Planta Med 74:25-32.
32. Chorazy PA, Himelhoch S, Hopwood NJ, et al. 1995. Persistent hypothyroidism in an infant receiving a soy formula case report and review of the literature. Pediatrics 96:148-150.
33. Coldham NG, Sauer MJ. 2000. Pharmacokinetics of [(14)C]Genistein in the rat: gender-related differences, potential mechanisms of biological action, and implications for human health. Toxicol Appl Pharmacol 164:206-215.
34. Conrad SC, Chiu H, Silverman BL. 2004. Soy formula complicates management of congenital hypothyroidism. Arch Dis Child 89:37-40.
35. Cotroneo MS, Wang J, Eltoum IA, Lamartiniere CA. 2001. Sex steroid receptor regulation by genistein in the prepubertal rat uterus. Mol Cell Endocrinol 173:135-145.
36. Cotroneo MS, Wang J, Fritz WA, et al. 2002. Genistein action in the prepubertal mammary gland in a chemoprevention model. Carcinogenesis 23:1467-1474.
37. Cruz MLA, Wong WW, Mimouni F, et al. 1994. Effects of infant nutrition on cholesterol synthesis rates. Pediatr Res 35:135-140.
38. Dalu A, Blaydes BS, Bryant CW, et al. 2002. Estrogen receptor expression in the prostate of rats treated with dietary genistein. J Chromatogr 777:249-260.
39. Delclos KB, Bucci TJ, Lomax LG, et al. 2001. Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reprod Toxicol (Elmsford, NY) 15:647-663.
40. Delclos KB, Weis CC, Bucci TJ, et al. 2009. Overlapping but distinct effects of genistein and ethinyl estradiol (EE(2)) in female Sprague-Dawley rats in multigenerational reproductive and chronic toxicity studies. Reprod Toxicol 27:117-132.
41. Doerge DR, Chang HC, Churchwell MI, Holder CL. 2000. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab Dispos 28:298-307.
42. Doerge DR, Churchwell MI, Chang HC, et al. 2001. Placental transfer of the soy isoflavone genistein following dietary and gavage administration to Sprague Dawley rats. Reprod Toxicol 15:105-110.
43. Doerge DR, Twaddle NC, Banks EP, et al. 2002. Pharmacokinetic analysis in serum of genistein administered subcutaneously to neonatal mice. Cancer Lett 184:21-27.
44. Drugstore.com. 2009. Formulation information for soy protein-based infant formulas. Available at (see "Baby & Mom"). Accessed March 10, 2009.
45. Essex C. 1996. Phytoestrogens and soy based infant formula: risks remain theoretical. Br Med J 313:507-508.
46. Faber KA, Hughes Jr CL. 1991. The effect of neonatal exposure to diethylstilbestrol, genistein, and zearalenone on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat. Biol Reprod 45:649-653.
47. Faber KA, Hughes Jr CL. 1993. Dose-response characteristics of neonatal exposure to genistein on pituitary responsiveness to gonadotropin releasing hormone and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in postpubertal castrated female rats. Reprod Toxicol 7:35-39.
48. FDA. 2000a. Infant formula. 21 CFR 107.
49. FDA. 2000b. Soy: Health claims for soy protein, questions about other components. Available at. Food and Drug Administration.
50. Fielden MR, Fong CJ, Haslam SZ, Zacharewski TR. 2002. Normal mammary gland morphology in pubertal female mice following in utero and lactational exposure to genistein at levels comparable to human dietary exposure. Toxicol Lett 133:181-191.
51. Fielden MR, Samy SM, Chou KC, Zacharewski TR. 2003. Effect of human dietary exposure levels of genistein during gestation and lactation on long-term reproductive development and sperm quality in mice. Food Chem Toxicol 41:447-454.
52. Flynn KM, Ferguson SA, Delclos KB, Newbold RR. 2000. Effects of genistein exposure on sexually dimorphic behaviors in rats. Toxicol Sci 55:311-319.
53. Forsyth BW, McCarthy PL, Leventhal JM. 1985. Problems of early infancy formula changes and mothers beliefs about their infants. J Pediatr 106:1012-1017.
54. Fort P, Lanes R, Dahlem S, et al. 1986. Breast feeding and insulin-dependent diabetes mellitus in children. J Am Coll Nutr 5:439-441.
55. Foster WG, Younglai EV, Boutross-Tadross O, et al. 2004. Mammary gland morphology in sprague-dawley rats following treatment with an organochlorine mixture in utero and neonatal genistein. Toxicol Sci 77:91-100.
56. Franke AA, Custer LJ, Tanaka Y. 1998. Isoflavones in human breast milk and other biological fluids. Am J Clin Nutr 68:1466S-1473S.
57. Franke AA, Halm BM, Custer LJ, et al. 2006. Isoflavones in breastfed infants after mothers consume soy. Am J Clin Nutr 84:406-413.
58. Franke AA, Halm BM, Ashburn LA. 2008a. Isoflavones in children and adults consuming soy. Arch Biochem Biophys 476:161-170.
59. Franke AA, Halm BM, Ashburn LA. 2008b. Urinary isoflavones are increased in adults, but decreased in children, consuming soy when on oral antibiotic therapy. Nutr Cancer 60:627-635.
60. Freni-Titulaer LW, Cordero JF, Haddock L, et al. 1986. Premature thelarche in Puerto Rico. A search for environmental factors. Am J Dis Child 140:1263-1267.
61. Fritz WA, Coward L, Wang J, Lamartiniere CA. 1998. Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 19:2151-2158.
62. Genovese MI, Lajolo FM. 2002. Isoflavones in soy-based foods consumed in Brazil: levels, distribution, and estimated intake. J Agric Food Chem 50:5987-5993.
63. Gorski K, Taciak M, Romanowicz K, Misztal T. 2006. Differential effects of soy-containing diets on the reproductive tissues growth and reproductive hormone secretion in male rats. Reprod Biol 6:275-290.
64. Gruskay FL. 1982. Comparison of breast, cow, and soy feedings in the prevention of onset of allergic disease: a 15-year prospective study. Clin Pediatr (Phila) 21:486-491.
65. Guerrero-Bosagna CM, Sabat P, Valdovinos FS, et al. 2008. Epigenetic and phenotypic changes result from a continuous pre and post natal dietary exposure to phytoestrogens in an experimental population of mice. BMC Physiol 8:17.
66. Guo TL, Zhang XL, Bartolucci E, et al. 2002. Genistein and methoxychlor modulate the activity of natural killer cells and the expression of phenotypic markers by thymocytes and splenocytes in F0 and F1 generations of Sprague-Dawley rats. Toxicology 172:205-215.
67. Hakkak R, Korourian S, Shelnutt SR, et al. 2000. Diets containing whey proteins or soy protein isolate protect against 7, 12-dimethylbenz(a)anthracene-induced mammary tumors in female rats. Cancer Epidemiol Biomarkers Prev 9:113-117.
68. Halm BM, Ashburn LA, Franke AA. 2007. Isoflavones from soya foods are more bioavailable in children than adults. Br J Nutr 98:998-1005.
69. Halm BM, Franke AA, Ashburn LA, et al. 2008. Oral antibiotics decrease urinary isoflavonoid excretion in children after soy consumption. Nutr Cancer 60:14-22.
70. Hilakivi-Clarke L, Cho E, Clarke R. 1998. Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring. Oncol Rep 5:609-616.
71. Hilakivi-Clarke L, Cho E, Onojafe I, et al. 1999a. Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring. Oncol Rep 6:1089-1095.
72. Hilakivi-Clarke L, Onojafe I, Raygada M, et al. 1999b. Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis. Br J Cancer 80:1682-1688.
73. Hilakivi-Clarke L, Cho E, Cabanes A, et al. 2002. Dietary modulation of pregnancy estrogen levels and breast cancer risk among female rat offspring. Clin Cancer Res 8:3601-3610.
74. Hillman LS. 1988. Bone mineral content in term infants fed human milk, cow milk-based formula, or soy-based formula. J Pediatr 113:208-212.
75. Hillman LS, Chow W, Salmons SS, et al. 1988. Vitamin D metabolism, mineral homeostasis, and bone mineralization in term infants fed human milk, cow milk-based formula, or soy-based formula. J Pediatr 112:864-874.
76. Hines RN. 2008. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther 118:250-267.
77. Hoey L, Rowland IR, Lloyd AS, et al. 2004. Influence of soya-based infant formula consumption on isoflavone and gut microflora metabolite concentrations in urine and on faecal microflora composition and metabolic activity in infants and children. Br J Nutr 91:607-616.
78. ILSI. 1999. Safety assessment and potential health benefits of food components based on selected scientific criteria. ILSI North America Technical Committee on Food Components for Health Promotion. Crit Rev Food Sci Nutr 39:203-316.
79. Irvine CH, Shand N, Fitzpatrick MG, Alexander SL. 1998. Daily intake and urinary excretion of genistein and daidzein by infants fed soy- or dairy-based infant formulas. Am J Clin Nutr 68:1462S-1465S.
80. Jabbar MA, Larrea J, Shaw RA. 1997. Abnormal thyroid function tests in infants with congenital hypothyroidism: the influence of soy-based formula. J Am Coll Nutr 16:280-282.
81. Jefferson WN, Couse JF, Padilla-Banks E, et al. 2002. Neonatal exposure to genistein induces estrogen receptor (ER)alpha expression and multioocyte follicles in the maturing mouse ovary: evidence for ERbeta-mediated and nonestrogenic actions. Biol Reprod 67:1285-1296.
82. Jefferson WN, Padilla-Banks E, Newbold R. 2005. Adverse effects on female development and reproduction in CD-1 mice following neonatal exposure to the phytoestrogen genistein at environmentally relevant doses. Biol Reprod 73:798-806.
83. Jefferson W, Newbold R, Padilla-Banks E, Pepling M. 2006. Neonatal genistein treatment alters ovarian differentiation in the mouse: inhibition of oocyte nest breakdown and increased oocyte survival. Biol Reprod 74:161-168.
84. Jefferson WN, Doerge D, Padilla-Banks E, et al. 2009a. Oral exposure to genistin, the glycosylated form of genistein, during neonatal life adversely affects the female reproductive system. Environ Health Perspect 117:1883-1889.
85. Jefferson WN, Padilla-Banks E, Goulding EH, et al. 2009b. Neonatal exposure to genistein disrupts ability of female mouse reproductive tract to support preimplantation embryo development and implantation. Biol Reprod 80:425-431.
86. Jing H, Pivik RT, Gilchrist JM, Badger TM. 2008. No difference indicated in electroencephalographic power spectral analysis in 3- and 6-month-old infants fed soy- or milk-based formula. Matern Child Nutr 4:136-145.
87. Joannou GE, Kelly GE, Reeder AY, et al. 1995. A urinary profile study of dietary phytoestrogens. The identification and mode of metabolism of new isoflavonoids. J Steroid Biochem Mol Biol 54:167-184.
88. Jung AL, Carr SL. 1977. A soy protein formula and a milk-based formula. A comparative evaluation in milk-tolerant infants showed no significant nutritional differences. Clin Pediatr (Phila) 16:982-985.
89. King RA, Mano MM, Head RJ. 1998. Assessment of isoflavonoid concentrations in Australian bovine milk samples. J Dairy Res 65:479-489.
90. Klein SL, Wisniewski AB, Marson AL, et al. 2002. Early exposure to genistein exerts long-lasting effects on the endocrine and immune systems in rats. Mol Med 8:742-749.
91. Klemola T, Vanto T, Juntunen-Backman K, et al. 2002. Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow's milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr 140:219-224.
92. Köhler L, Meeuwisse G, Mortensson W. 1984. Food intake and growth of infants between six and twenty-six weeks of age on breast milk, cow's milk formula, or soy formula. Acta Paediatr Scand 73:40-48.
93. Kouki T, Kishitake M, Okamoto M, et al. 2003. Effects of neonatal treatment with phytoestrogens, genistein and daidzein, on sex difference in female rat brain function: estrous cycle and lordosis. Horm Behav 44:140-145.
94. Kulkarni PB, Dorand RD, Bridger WM, et al. 1984. Rickets in premature infants fed different formulas. South Med J 77:13-16, 20.
95. Kurzer MS, Xu X. 1997. Dietary phytoestrogens. Annu Rev Nutr 17:353-381.
96. Lamartiniere CA. 2000. Protection against breast cancer with genistein: a component of soy. Am J Clin Nutr 71:1705S-1707S; discussion 1708S-1709S.
97. Lamartiniere CA, Moore J, Holland M, Barnes S. 1995a. Neonatal genistein chemoprevents mammary cancer. Proc Soc Exp Biol Med 208:120-123.
98. Lamartiniere CA, Moore JB, Brown NM, et al. 1995b. Genistein suppresses mammary cancer in rats. Carcinogenesis 16:2833-2840.
99. Larkin T, Price WE, Astheimer L. 2008. The key importance of soy isoflavone bioavailability to understanding health benefits. Crit Rev Food Sci Nutr 48:538-552.
100. Lasekan JB, Ostrom KM, Jacobs JR, et al. 1999. Growth of newborn, term infants fed soy formulas for 1 year. Clin Pediatr (Phila) 38:563-571.
101. Latendresse JR, Bucci TJ, Olson G, et al. 2009. Genistein and ethinyl estradiol dietary exposure in multigenerational and chronic studies induce similar proliferative lesions in mammary gland of male Sprague-Dawley rats. Reprod Toxicol 28:342-353.
102. Lephart ED, Adlercreutz H, Lund TD. 2001. Dietary soy phytoestrogen effects on brain structure and aromatase in Long-Evans rats. Neuroreport 12:3451-3455.
103. Levy JR, Faber KA, Ayyash L, Hughes Jr CL. 1995. The effect of prenatal exposure to the phytoestrogen genistein on sexual differentiation in rats. Proc Soc Exp Biol Med 208:60-66.
104. Lewis RW, Brooks N, Milburn GM, et al. 2003. The effects of the phytoestrogen genistein on the postnatal development of the rat. Toxicol Sci 71:74-83.
105. Liu Z, Zhang X, Li L, et al. 2008. Effects of lactational exposure to soy isoflavones on reproductive system in neonatal female rats. Basic Clin Pharmacol Toxicol 102:317-324.
106. Lu LJ, Anderson KE. 1998. Sex and long-term soy diets affect the metabolism and excretion of soy isoflavones in humans. Am J Clin Nutr 68:1500S-1504S.
107. Lu LJ, Grady JJ, Marshall MV, et al. 1995. Altered time course of urinary daidzein and genistein excretion during chronic soya diet in healthy male subjects. Nutr Cancer 24:311-323.
108. Lund TD, Lephart ED. 2001. Dietary soy phytoestrogens produce anxiolytic effects in the elevated plus-maze. Brain Res 913:180-184.
109. Lund TD, Rhees RW, Setchell KD, Lephart ED. 2001. Altered sexually dimorphic nucleus of the preoptic area (SDN-POA) volume in adult Long-Evans rats by dietary soy phytoestrogens. Brain Res 914:92-99.
110. MAFF. 1998. Plant oestrogens in soya-based infant formulae. Report nr 167. London, UK: Ministry of Agriculture, Fisheries, and Food. Available at:.
111. Mäkelä SI, Pylkkanen LH, Santti RS, Adlercreutz H. 1995. Dietary soybean may be antiestrogenic in male mice. J Nutr 125:437-445.
112. Malloy MH, Berendes H. 1998. Does breast-feeding influence intelligence quotients at 9 and 10 years of age? Early Hum Dev 50:209-217.
113. Mardon J, Mathey J, Kati-Coulibaly S, et al. 2008. Influence of lifelong soy isoflavones consumption on bone mass in the rat. Exp Biol Med (Maywood) 233:229-237.
114. Masutomi N, Shibutani M, Takagi H, et al. 2003. Impact of dietary exposure to methoxychlor, genistein, or diisononyl phthalate during the perinatal period on the development of the rat endocrine/reproductive systems in later life. Toxicology 192:149-170.
115. Masutomi N, Shibutani M, Takagi H, et al. 2004a. Dietary influence on the impact of ethinylestradiol-induced alterations in the endocrine/reproductive system with perinatal maternal exposure. Reprod Toxicol 18:23-33.
116. Masutomi N, Shibutani M, Takagi H, et al. 2004b. Alteration of pituitary hormone-immunoreactive cell populations in rat offspring after maternal dietary exposure to endocrine-active chemicals. Arch Toxicol 78:232-240.
117. McClain RM, Wolz E, Davidovich A, et al. 2007. Reproductive safety studies with genistein in rats. Food Chem Toxicol 45:1319-1332.
118. McVey MJ, Cooke GM, Curran IH. 2004a. Altered testicular microsomal steroidogenic enzyme activities in rats with lifetime exposure to soy isoflavones. J Steroid Biochem Mol Biol 92:435-446.
119. McVey MJ, Cooke GM, Curran IH. 2004b. Increased serum and testicular androgen levels in F1 rats with lifetime exposure to soy isoflavones. Reprod Toxicol 18:677-685.
120. Mimouni F, Campaigne B, Neylan M, Tsang RC. 1993. Bone mineralization in the first year of life in infants fed human milk, cow-milk formula, or soy-based formula. J Pediatr 122:348-354.
121. Moller FJ, Zierau O, Hertrampf T, et al. 2009. Long-term effects of dietary isoflavones on uterine gene expression profiles. J Steroid Biochem Mol Biol 113:296-303.
122. Montani C, Penza M, Jeremic M, et al. 2008. Genistein is an efficient estrogen in the whole-body throughout mouse development. Toxicol Sci 103:57-67.
123. Montani C, Penza M, Jeremic M, et al. 2009. Estrogen receptor-mediated transcriptional activity of genistein in the mouse testis. Ann N Y Acad Sci 1163:475-477.
124. Murrill WB, Brown NM, Zhang JX, et al. 1996. Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis 17:1451-1457.
125. Naciff JM, Jump ML, Torontali SM, et al. 2002. Gene expression profile induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat. Toxicol Sci 68:184-199.
126. Nagao T, Yoshimura S, Saito Y, et al. 2001. Reproductive effects in male and female rats of neonatal exposure to genistein. Reprod Toxicol 15:399-411.
127. National Toxicology Program (NTP). 2008. NTP Multigenerational Reproductive Study of Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (Feed Study). Natl Toxicol Program Tech Rep Ser 539:1-266.
128. Newbold RR, Banks EP, Bullock B, Jefferson WN. 2001. Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res 61:4325-4328.
129. Nielsen IL, Williamson G. 2007. Review of the factors affecting bioavailability of soy isoflavones in humans. Nutr Cancer 57:1-10.
130. Nikaido Y, Danbara N, Tsujita-Kyutoku M, et al. 2005. Effects of prepubertal exposure to xenoestrogen on development of estrogen target organs in female CD-1 mice. In Vivo 19:487-494.
131. Nikaido Y, Yoshizawa K, Danbara N, et al. 2004. Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring. Reprod Toxicol 18:803-811.
132. Odum J, Tinwell H, Jones K, et al. 2001. Effect of rodent diets on the sexual development of the rat. Toxicol Sci 61:115-127.
133. Padilla-Banks E, Jefferson WN, Newbold RR. 2006. Neonatal exposure to the phytoestrogen genistein alters mammary gland growth and developmental programming of hormone receptor levels. Endocrinology 147:4871-4882.
134. Pastuszewska B, Taciak M, Ochtabinska A, et al. 2008. Nutritional value and physiological effects of soya-free diets fed to rats during growth and reproduction. J Anim Physiol Anim Nutr (Berl) 92:63-74.
135. Patisaul HB, Fortino AE, Polston EK. 2006. Neonatal genistein or bisphenol-A exposure alters sexual differentiation of the AVPV. Neurotoxicol Teratol 28:111-118.
136. Patisaul HB, Fortino AE, Polston EK. 2007. Differential disruption of nuclear volume and neuronal phenotype in the preoptic area by neonatal exposure to genistein and bisphenol-A. Neurotoxicology 28:1-12.
137. Patisaul HB, Todd KL, Mickens JA, Adewale HB. 2009. Impact of neonatal exposure to the ERalpha agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats. Neurotoxicology 30:350-357.
138. Peeters PH, Slimani N, van der Schouw YT, et al. 2007. Variations in plasma phytoestrogen concentrations in European adults. J Nutr 137:1294-1300.
139. Prasain JK, Barnes S. 2007. Metabolism and bioavailability of flavonoids in chemoprevention: current analytical strategies and future prospectus. Mol Pharm 4:846-864.
140. Pumford SL, Morton MM, Turkes A, Griffiths K. 2002. Determination of the isoflavonoids genistein and daidzein in biological samples by gas chromatography-mass spectrometry. Ann Clin Biochem 39:281-292.
141. Rozman KK, Bhatia J, Calafat AM, et al. 2006. NTP-CERHR expert panel report on the reproductive and developmental toxicity of genistein. Birth Defects Res B Dev Reprod Toxicol 77:485-638.
142. Rufer CE, Bub A, Moseneder J, et al. 2008. Pharmacokinetics of the soybean isoflavone daidzein in its aglycone and glucoside form: a randomized, double-blind, crossover study. Am J Clin Nutr 87:1314-1323.
143. Ruhlen RL, Howdeshell KL, Mao J, et al. 2008. Low phytoestrogen levels in feed increase fetal serum estradiol resulting in the "fetal estrogenization syndrome" and obesity in CD-1 mice. Environ Health Perspect 116:322-328.
144. Scallet AC, Divine RL, Newbold RR, Delclos KB. 2004. Increased volume of the calbindin D28k-labeled sexually dimorphic hypothalamus in genistein and nonylphenol-treated male rats. Toxicol Sci 82:570-576.
145. Scientific Committee on Food. 2003. Report on the revision of essential requirements of infant formulae and follow-up formulae (adopted on April 4, 2003). SCF/CS/NUT/IF/65, Final May 18, 2003 Available at:.
146. Setchell KD. 1998. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 68:1333S-1346S.
147. Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE. 1997. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 350:23-27.
148. Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE. 1998. Isoflavone content of infant formulas and the metabolic fate of these phytoestrogens in early life. Am J Clin Nutr 68:1453S-1461S.
149. Setchell KD, Brown NM, Desai P, et al. 2001. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 131:1362S-1375S.
150. Sfakianos J, Coward L, Kirk M, Barnes S. 1997. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. J Nutr 127:1260-1268.
151. Sharpe RM, Martin B, Morris K, et al. 2002. Infant feeding with soy formula milk: effects on the testis and on blood testosterone levels in marmoset monkeys during the period of neonatal testicular activity. Hum Reprod 17:1692-1703.
152. Shepard T. 1960. Soybean goiter. N Engl J Med 262:1099-1103.
153. Shibayama T, Fukata H, Sakurai K, et al. 2001. Neonatal exposure to genistein reduces expression of estrogen receptor alpha and androgen receptor in testes of adult mice. Endocr J 48:655-663.
154. Simmen RC, Eason RR, Till SR, et al. 2005. Inhibition of NMU-induced mammary tumorigenesis by dietary soy. Cancer Lett 224:45-52.
155. Soucy NV, Parkinson HD, Sochaski MA, Borghoff SJ. 2006. Kinetics of Genistein and its Conjugated Metabolites in Pregnant Sprague-Dawley Rats Following Single and Repeated Genistein Administration. Toxicol Sci 90:230-240.
156. Soyfoods Associations of North America. 2009. Soyfood sales & trends. Available at:. Accessed October 10, 2009. Soyfoods Association of North America.
157. Steichen JJ, Tsang RC. 1987. Bone mineralization and growth in term infants fed soy-based or cow milk-based formula. J Pediatr 110:687-692.
158. Strauss L, Makela S, Joshi S, et al. 1998. Genistein exerts estrogen-like effects in male mouse reproductive tract. Mol Cell Endocrinol 144:83-93.
159. Strom BL, Schinnar R, Ziegler EE, et al. 2001. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA 286:807-814.
160. Takagi H, Shibutani M, Lee KY, et al. 2004. Lack of modifying effects of genistein on disruption of the reproductive system by perinatal dietary exposure to ethinylestradiol in rats. Reprod Toxicol 18:687-700.
161. Takagi H, Shibutani M, Lee KY, et al. 2005. Impact of maternal dietary exposure to endocrine-acting chemicals on progesterone receptor expression in microdissected hypothalamic medial preoptic areas of rat offspring. Toxicol Appl Pharmacol 208:127-136.
162. Tan KA, Walker M, Morris K, et al. 2006. Infant feeding with soy formula milk: effects on puberty progression, reproductive function and testicular cell numbers in marmoset monkeys in adulthood. Hum Reprod 21:896-904.
163. Tang L, Singh R, Liu Z, Hu M. 2009. Structure and concentration changes affect characterization of UGT isoform-specific metabolism of isoflavones. Mol Pharmacol 6:1466-1482.
164. Taylor H, Quintero EM, Iacopino AM, Lephart ED. 1999. Phytoestrogens alter hypothalamic calbindin-D28k levels during prenatal development. Brain Res Dev Brain Res 114:277-281.
165. Thomsen AR, Almstrup K, Nielsen JE, et al. 2006. Estrogenic effect of soy isoflavones on mammary gland morphogenesis and gene expression profile. Toxicol Sci 93:357-368.
166. Thuillier R, Manku G, Wang Y, Culty M. 2009. Changes in MAPK pathway in neonatal and adult testis following fetal estrogen exposure and effects on rat testicular cells. Microsc Res Tech 87:1-26.
167. Thygarajan A, Burks AW. 2008. American Academy of Pediatrics recommendations on the effects of early nutritional interventions on the development of atopic disease. Curr Opin Pediatr 20:698-702.
168. Tuohy PG. 2003. Soy infant formula and phytoestrogens. J Paediatr Child Health 39:401-405.
169. Turck D. 2007. Soy protein for infant feeding: what do we know? Curr Opin Clin Nutr Metab Care 10:360-365.
170. U.S. Centers for Disease Control and Prevention. 2008. National report on biochemical indicators of diet and nutrition in the U.S. population 1999-2002. Atlanta, GA: National Center for Environmental Health; July 2008. Available at:.
171. UK-Committee-on-Toxicity. 2003. Phytoestrogens and health. London, UK: Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. Available at:.
172. United Soybean Board. 2009. 16th annual survey: consumer attitudes about nutrition. Available at:. Accessed October 10, 2009.
173. Valentin-Blasini L, Blount BC, Caudill SP, Needham LL. 2003. Urinary and serum concentrations of seven phytoestrogens in a human reference population subset. J Expo Anal Environ Epidemiol 13:276-282.
174. Venkataraman PS, Luhar H, Neylan MJ. 1992. Bone mineral metabolism in full-term infants fed human milk, cow milk-based, and soy-based formulas. Am J Dis Child 146:1302-1305.
175. Vilela ML, Willingham E, Buckley J, et al. 2007. Endocrine disruptors and hypospadias: role of genistein and the fungicide vinclozolin. Urology 70:618-621.
176. Wagner JD, Jorgensen MJ, Cline JM, et al. 2009. Effects of soy vs. casein protein on body weight and glycemic control in female monkeys and their offspring. Am J Primatol. 2009 Sep; 71(9):802-811.
177. Wang XJ, Bartolucci-Page E, Fenton SE, You L. 2006. Altered mammary gland development in male rats exposed to genistein and methoxychlor. Toxicol Sci 91:93-103.
178. Weber KS, Setchell KD, Lephart ED. 2001. Maternal and perinatal brain aromatase: effects of dietary soy phytoestrogens. Brain Res Dev Brain Res 126:217-221.
179. Whitten PL, Patisaul HB. 2001. Cross-species and interassay comparisons of phytoestrogen action. Environ Health Perspect 109:5-20.
180. You L, Casanova M, Bartolucci EJ, et al. 2002a. Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor. Toxicol Sci 66:91-104.
181. You L, Sar M, Bartolucci EJ, McIntyre BS. 2002b. Modulation of mammary gland development in prepubertal male rats exposed to genistein and methoxychlor. Toxicol Sci 66:216-225.