lactational transfer and soy food

lactational transfer and soy food

Toxicology and Applied Pharmacology 254 (2011) 145–147 Contents lists available at ScienceDirect Toxicology and Applied Pharmacology j o u r n a l h...

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Toxicology and Applied Pharmacology 254 (2011) 145–147

Contents lists available at ScienceDirect

Toxicology and Applied Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y t a a p

Bioavailability of soy isoflavones through placental/lactational transfer and soy food Daniel R. Doerge ⁎ Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA

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Article history: Received 29 May 2009 Revised 2 April 2010 Accepted 24 October 2010 Available online 27 October 2010

Isoflavones are non-nutritive components of soy responsible for estrogenic responses observed in vitro and in experimental animals. Possible beneficial effects (e.g., reduction of serum lipids, increased bone mineral density, relief of hot flashes and other menopausal symptoms, mammary and prostate cancer chemoprevention) in humans have been attributed to consumption of isoflavones but evidence for potential adverse effects (e.g., stimulation of estrogen-dependent mammary tumors and aberrant perinatal development) has also been reported in experimental animal models. Bioavailability from appropriate food matrices and exposure during different life stages are both critical determinants of isoflavone effects. For these reasons, it is important to compare isoflavone bioavailability in adults to that in fetal and neonatal animals for a more complete understanding of potential susceptibility issues. Studies of the major soy isoflavone genistein were conducted in pregnant and lactating Sprague–Dawley rats to quantify placental and lactational transfer to plasma and brain to understand better biological effects observed in multigenerational studies. In addition, studies were conducted with genistein in adult Balb/c mice to define absolute bioavailability from both gavage and soy protein isolate (SPI)-containing food. The information derived from these studies makes it possible to predict internal exposures of children to genistein from soy infant formula, which is manufactured using SPI. Published by Elsevier Inc.

Keywords: Genistein Soy infant formula Bioavailability Perinatal

Contents Introduction . . . . . . . . Discussion and summary . . Conflict of interest disclosure Acknowledgments . . . . . References . . . . . . . . .

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Introduction Isoflavones are non-nutritive components of soy responsible for estrogenic responses observed in vitro and in experimental animals (Allred et al., 2005). Possible beneficial effects (e.g., reduction of serum lipids, increased bone mineral density, relief of hot flashes and other menopausal symptoms, mammary and prostate cancer chemoprevention) in humans have been attributed to consumption of isoflavones (Sacks et al., 2006) but evidence for potential adverse effects (e.g., stimulation of estrogen-dependent mammary tumors (Allred et al., 2005; National Toxicology Program, 2008a,b) and

⁎ Fax: +1 870 543 7720. E-mail address: [email protected]. 0041-008X/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.taap.2010.10.018

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aberrant perinatal development (National Toxicology Program, 2010)) has also been reported in experimental animal models. Plasma measurements in rats treated with several levels of dietary genistein exposure were conducted as part of a multigenerational study of genistein conducted at the NCTR (National Toxicology Program, 2008a,b; Twaddle et al., 2002). These measurements in rats showed that the dietary test doses produced circulating levels of genistein that are directly comparable to several populations of humans (Chang et al., 2000). These groups include adults consuming typical Western diets with negligible exposures to genistein, adults consuming traditional Asian foods with modest exposures, and Western infants who consume all their nutritional input from soy infant formula with much higher exposures. Bioavailability from appropriate food matrices and exposure during different life stages are critical determinants of isoflavone effects. For these reasons, it is important to compare isoflavone

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D.R. Doerge / Toxicology and Applied Pharmacology 254 (2011) 145–147

bioavailability in adults to that in fetal and neonatal animals for a more complete understanding of potential susceptibility issues. Studies of the major soy isoflavone genistein were conducted in pregnant and lactating Sprague–Dawley rats to quantify placental and lactational transfer to plasma and brain to understand biological effects observed in multigenerational studies. In addition, studies were conducted with genistein in adult Balb/c mice to define absolute bioavailability from both gavage and soy protein isolate (SPI)containing food (Andrade et al., 2010). The information about plasma and tissue internal exposures derived from these rodent studies makes it possible to predict internal exposures of humans to genistein from soy-based foods, which are often manufactured using SPI, and dietary supplements. This paper synthesizes results from a number of previous studies in an effort to describe the relationship between bioavailability of soy isoflavones, internal exposures to genistein at critical points during perinatal development, and the potential for adverse effects on important organ systems. Discussion and summary Exposures of Sprague–Dawley rats to the soy isoflavone, genistein, throughout the entire lifespan have produced a number of effects on reproductive tissues, immune function, neuroendocrine function, and behavior (National Toxicology Program, 2008a,b). These studies included 2-year dietary exposure with three exposure arms (Fig. 1): continuous exposure from conception through 2 years (designated F1 continuous, or F1C), exposure from conception through 20 weeks followed by control diet to 2 years [designated F1 truncated at postnatal day (PND) 140, or F1T140], and exposure from conception through weaning followed by control diet to 2 years (designated F3 truncated at PND 21, or F3T21). The “F3” designation for the F3T21 arm indicates that these animals were siblings of the F3 animals from the multigenerational reproductive toxicology study (NTP, 2008a,b). The animals in this study were exposed to dietary genistein (control, 5, 100, and 500 μg/g in feed) during various phases of their lives from conception until termination at 2 years, and the ingested doses varied over the course of the study. During pregnancy, the ingested doses of the dams were approximately 0, 0.5, 9, or 45 mg/kg body weight per day (mg/kg bw/d). During lactation, the dams' ingested doses were 0, 0.7, 15, or 75 mg/kg PND 42

bw/d. The mean doses of genistein ingested during the period prior to PND 140 were approximately 0.4, 8, or 44 mg/kg bw/d for females. For the period between PND 140 and the end of the study, mean ingested doses were approximately 0.3, 5, or 29 mg/kg bw/d for females. In females of all study arms, an early onset of aberrant estrous cycles, suggesting early reproductive senescence, was observed in the 500 μg/g diet groups. In the F3T21 arm, there were also significant effects on the onset of aberrant estrous cycles in the 5 and 100 μg/g groups. This group also showed a significant trend for increased incidences of mammary adenoma and adenocarcinomas, data supportive of previous investigations on the effect of early life estrogen exposures and mammary carcinogenesis (Hilakivi-Clarke et al., 1999). In F1C females, there was a significant positive trend in the incidences of mammary gland adenoma or adenocarcinoma (combined), and the incidence in the 500 μg/g diet group was significantly greater than that in the control group. These findings are supported by genistein-mediated tumor growth enhancement in animal models for post-menopausal breast cancer (Allred et al., 2005). A significant negative trend occurred in the incidences of benign mammary gland fibroadenoma in F1C females, and the incidence in the 500 μg/g diet group was significantly less than that in the control group. By the nature of the dietary exposure regimen, rats in all study arms were exposed to genistein in utero, through maternal milk, and as adults through postnatal day 140. Internal exposures to total and aglycone genistein were measured in serum and tissues from male and female adults and in serum from weanlings (Chang et al., 2000). Endocrine-responsive tissues examined including brain, liver, mammary, ovary, prostate, testis, thyroid, and uterus showed significant dose-dependent increases in total genistein concentration. Female liver contained the highest amount of genistein (7.3 pmol/mg tissue) and male whole brain contained the least (0.04 pmol/mg). The physiologically active aglycone form was present in tissues at fractions up to 100%, and the concentration was always greater than that observed in serum in which conjugated forms predominated (95–99%). These results for measured amounts of genistein, present as aglycone and conjugates in putative target tissues, provide a link with other studies in which blood concentrations and physiologic effects of genistein are measured. On the basis of the serum concentrations of total genistein (Chang et al., 2000), the doses administered through the diet to Sprague–Dawley rats in the multigeneration and chronic

PND 140 PND 140

F0 PND 21

F1T140 F1C

F1

Chronic

PND 140

F2

PND 140

F3T21

F3 PND 140

F4*

Dietary exposure

Nursing exposure

In utero exposure

Control diet

Fig 1. Multigeneration genistein dosing schedule.

Chronic

D.R. Doerge / Toxicology and Applied Pharmacology 254 (2011) 145–147

exposure studies described below were comparable to discrete human populations: serum concentrations in rats fed the control and low dose (5 μg/g) diets are similar to those in human adults consuming a typical Western diet (b0.1 μmol/L); rats fed the 100 μg/g genistein diet are similar to human adults consuming a typical Asian diet (0.1–1.2 μmol/L or soy nutritional supplements (0.5–0.9 μmol/L, Doerge et al., 2000); and rats fed the 500 μg/g genistein diet are similar to infants consuming soy formulas (2–7 μmol/L, Cao et al., 2009). The higher levels of genistein aglycone observed in many endocrine-responsive rat tissues relative to the blood suggest that accumulation is typical and that similar tissue levels could occur in human populations. Placental transfer of genistein in rats was also examined as a possible route of developmental exposure (Doerge et al., 2001). Pregnant Sprague–Dawley rats were administered genistein orally, either by diet or by gavage at doses of approximately 50 mg/kg bw/d. Concentrations of genistein aglycone and conjugates were measured in maternal and offspring serum and brain using HPLC with isotope dilution electrospray tandem mass spectrometry (LC/MS/MS). Although fetal or neonatal serum concentrations of total genistein were approximately 20-fold lower than maternal serum concentrations, the biologically active genistein aglycone concentration was only 5-fold lower. Fetal brain contained predominately genistein aglycone at levels similar to those in the maternal brain. These results showed that genistein aglycone crosses the rat placenta and can reach fetal brain from maternal serum genistein levels that are relevant to those observed in humans consuming soy foods and dietary supplements. Another study measured the internal exposures of postnatal day 10 (PND10) rat pups due to lactational transfer of genistein (Doerge et al., 2006). Conjugated and aglycone forms of genistein were measured by using LC/MS/MS in serum (PND10) and milk (PND7) from lactating dams consuming a genistein-fortified soy-free diet that delivered a dose of approximately 50 mg/kg bw/d and in serum from their pups at a time when milk was the only food source (PND10). This study showed that limited lactational transfer of genistein to rat pups occurs and that internal exposures to the active aglycone form of genistein are generally lower than those measured previously in the fetal period. These results suggested that developmental effects attributable to genistein exposure in the previously published chronic and multigeneration studies are more likely to result from fetal exposures because of the higher levels of the active estrogenic aglycone form of genistein in utero, although the possibility of neonatal responses cannot be excluded. A recent study determined the bioavailability of genistein and daidzein in Balb/c mice by comparing plasma pharmacokinetics of aglycone and conjugated forms following administration of identical doses (1.2 mg/kg genistein and 0.55 mg/kg daidzein) by either an intravenous injection or gavage of the aglycones vs. a bolus administration of equimolar doses delivered in a food pellet prepared using commercial SPI as the isoflavone source (Andrade et al., 2010). The bioavailability of genistein and daidzein was equivalent for the gavage and dietary routes of administration despite the use of isoflavone aglycones in the former and SPI-derived glucosides in the latter. While absorption of total isoflavones was nearly quantitative from both oral routes, presystemic and systemic Phase II conjugation greatly attenuated internal exposures to the receptor-active aglycone isoflavones. These results show that SPI, a major form of soy used in the manufacture of food and infant formula, is an efficient isoflavone delivery vehicle capable of providing significant proportions of the total dose into the circulation in the active aglycone form for distribution to receptor-bearing tissues and subsequent pharmacological effects that determine possible health benefits and/or risks. These published toxicology and exposure assessments of rats treated with dietary genistein demonstrate clearly adverse effects from chronic (e.g., increased incidences of mammary adenoma/carcinoma in females) and developmental exposures (e.g., accelerated reproductive senescence in females and increased incidences of mammary adenoma/

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carcinoma in females). In addition, plasma measurements in the dietary genistein-treated group rats show that these doses produce circulating levels, and presumably tissue levels, that are similar to identifiable humans groups. Of particular note are babies consuming their entire nutritional input from soy infant formula. The circulating levels in these infants overlap the range of serum concentrations measured in rats consuming the high dose of genistein, for which the aforementioned adverse effects were observed. The very low margin of exposure between doses of genistein that produce demonstrably adverse effects in experimental animal models and those in 20–25% of all formula-fed children in the United States suggests that the possibility of adverse effects should be considered. Conflict of interest disclosure statement The authors declare that they have no conflicts of interest. Acknowledgments This research was supported in part by Interagency Agreement 22407-007 between the National Center for Toxicological Research/U.S. Food and Drug Administration and the National Institute for Environmental Health Sciences/National Toxicology Program and by the National Institute on Aging with additional support from National Institute for Complementary and Alternative Medicine, Office of Dietary Supplements, and Women's Health Initiative (P01 AG024387). The views presented do not necessarily reflect those of the U.S. Food and Drug Administration. References Allred, C.D., Twaddle, N.C., Allred, K.F., Churchwell, M.I., Ju, Y.H., Helferich, W.G., Doerge, D.R., 2005. The effect of processing on soy isoflavone metabolism and disposition following dietary exposure in ovariectomized Balb/c mice. J. Agric. Food Chem. 53, 8542–8550. Andrade, J.E., Twaddle, N.C., Helferich, W.G., Doerge, D.R., 2010. Absolute bioavailability of isoflavones from soy protein isolate-containing food in female Balb/c mice. J. Agric. Food Chem. 58, 529–536. Cao, Y., Calafat, A.M., Doerge, D.R., Umbach, D.M., Bernbaum, J.C., Twaddle, N.C., Ye, X., Rogan, W.J., 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. Chang, H.C., Churchwell, M.I., Delclos, K.B., Newbold, R.R., Doerge, D.R., 2000. Mass spectrometric determination of genistein tissue distribution in Sprague–Dawley rats from dietary exposure. J. Nutr. 130, 1963–1970. Doerge, D.R., Chang, H.C., Holder, C.L., Churchwell, M.I., 2000. Enzymatic conjugation of the soy isoflavones, genistein and daidzein, and analysis in human blood using liquid chromatography and mass spectrometry. Drug Metab. Dispos. 28, 298–307. Doerge, D.R., Churchwell, M.I., Chang, H.C., Newbold, R.R., Delclos, K.B., 2001. Placental transfer of the soy isoflavone, genistein, following oral administration to Sprague– Dawley rats. Reprod. Toxicol. 15, 105–110. Doerge, D.R., Twaddle, N.C., Newbold, R.R., Delclos, K.B., 2006. Lactational transfer of the soy isoflavone, genistein, in Sprague–Dawley rats consuming dietary genistein. Reprod. Toxicol. 21, 307–312. Hilakivi-Clarke, L., Cho, E., Onojafe, I., Raygada, M., Clarke, R., 1999. Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring. Oncol. Rep. 6, 1089–1095. National Toxicology Program (NTP), 2008a. Multigenerational Reproductive Toxicology Study of Genistein (CAS No. 446-72-0) in Sprague–Dawley Rats (Feed Study). Technical Report Series No. 539. NIH Publication No. 08-4477. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC. National Toxicology Program (NTP), 2008b. Multigenerational Reproductive Toxicology and Carcinogenesis Study of Genistein (CAS No. 446-72-0) in Sprague–Dawley Rats (Feed Study). Technical Report Series No. 545. NIH Publication No. 08-4430. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC. National Toxicology Program (NTP), 2010. Draft NTP Brief on Soy Infant Formula. http://cerhr.niehs.nih.gov/evals/genistein-soy/soyformula/soyformula.html. Sacks, F.M., Lichtenstein, A., Van Horn, L., Harris, W., Kris-Etherton, Winston, M., American Heart Association Nutrition Committee, 2006. Soy Protein, Isoflavones, and Cardiovascular Health: an American Heart Association Science Advisory for Professionals from the Nutrition Committee. Circulation 113, 1034–1044. Twaddle, N.C., Churchwell, M.I., Doerge, D.R., 2002. High throughput quantification of soy isoflavones in human and mouse plasma using LC with electrospray-MS and MS/MS detection. J. Chromatogr. B 777, 137–143.