Article

Exposure of infants to phytoestrogens from soy infant formulas

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Abstract

The isoflavones genistein, daidzein, and their glycosides, found in high concentrations in soybeans and soy-protein foods, may have beneficial effects in the prevention or treatment of many hormone-dependent diseases. Because these bioactive phyto-oestrogens possess a wide range of hormonal and non-hormonal activities, it has been suggested that adverse effects may occur in infants fed soy-based formulas. To evaluate the extent of infant exposure to phyto-oestrogens from soy formula, the isoflavone composition of 25 randomly selected samples from five major brands of commercially available soy-based infant formulas were analysed, and the plasma concentrations of genistein and daidzein, and the intestinally derived metabolite, equol, were compared in 4-month-old infants fed exclusively soy-based infant formula (n = 7), cow-milk formula (n = 7), or human breast-milk (n = 7). All of the soy formulas contained mainly glycosides of genistein and daidzein, and the total isoflavone content was similar among the five formulas analysed and was related to the proportion of soy isolate used in their manufacture. From the concentrations of isoflavones in these formulas (means 32-47 micrograms/mL), the typical daily volume of milk consumed, and average bodyweight, a 4-month-old infant fed soy formula would be exposed to 28-47 per day, or about 4.5-8.0 mg/kg bodyweight per day, of total isoflavones. Mean (SD) plasma concentrations of genistein and daidzein in the seven infants fed soy-based formulas were 684 (443) ng/mL and 295 (60) ng/mL, respectively, which was significantly greater (p < 0.05) than in the infants fed either cow-milk formulas (3.2 [0.7] and 2.1 [0.3] ng/mL), or human breast-milk (2.8 [0.7] and 1.4 [0.1] ng/mL), and an order of magnitude higher per bodyweight than typical plasma concentrations of adults consuming soy foods. The daily exposure of infants to isoflavones in soy infant-formulas is 6-11 fold higher on a bodyweight basis than the dose that has hormonal effects in adults consuming soy foods. Circulating concentrations of isoflavones in the seven infants fed soy-based formula were 13000-22000 times higher than plasma oestradiol concentrations in early life, and may be sufficient to exert biological effects, whereas the contribution of isoflavones from breast-milk and cow-milk is negligible.

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... Like adults, infants who are breast-fed or fed cow's milk-based formulas have minimal phytoestrogen exposure. In contrast, soy-based infant formulas are a source of concentrated phytoestrogen exposure and their use leads to high serum genistein levels in infants [16,94]. Use of soy-based infant formula exposes infants to an estrogenic EDC during the developmentally sensitive window of minipuberty. ...
... As a result, quantifying isoflavone intake based on unprocessed soy intake is challenging. However, the generally increased intake and subsequently elevated serum levels of genistein relative to daidzein following soy protein consumption [33,62,88,94,108], despite cultivation conditions, makes genistein the phytoestrogen of most concern to human health; therefore, the remainder of this review will focus on genistein. ...
... Adult populations in Asia tend to have higher circulating genistein levels than adult populations in the U.S. and Western Europe, and vegetarians/vegans have higher levels than omnivorous adults [72,88,92,108]. However, infants who regularly consume soy formula have the highest circulating levels of genistein compared with any other group studied [16,94]. ...
Article
Exposure to naturally derived estrogen receptor activators, such as the phytoestrogen genistein, can occur at physiologically relevant concentrations in the human diet. Soy-based infant formulas are of particular concern because infants consuming these products have serum genistein levels almost 20 times greater than those seen in vegetarian adults. Comparable exposures in animal studies have adverse physiologic effects. The timing of exposure is particularly concerning because infants undergo a steroid hormone-sensitive period termed “minipuberty” during which estrogenic chemical exposure may alter normal reproductive tissue patterning and function. The delay between genistein exposure and reproductive outcomes poses a unique challenge to collecting epidemiological data. In 2010, the U.S. National Toxicology Program monograph on the safety of the use of soy formula stated that the use of soy-based infant formula posed minimal concern and emphasized a lack of data from human subjects. Since then, several new human and animal studies have advanced our epidemiological and mechanistic understanding of the risks and benefits of phytoestrogen exposure. Here we aim to identify clinically relevant findings regarding phytoestrogen exposure and female reproductive outcomes from the past 10 years, with a focus on the phytoestrogen genistein, and explore the implications of these findings for soy infant formula recommendations. Research presented in this review will inform clinical practice and dietary recommendations for infants based on evidence from both clinical epidemiology and basic research advances in endocrinology and developmental biology from mechanistic in vitro and animal studies.
... Its production depends solely on the intestinal microflora. Germ-free animals do not excrete equol [107], just as it cannot be found in the plasma of the infants fed with infant formulae [108,109]. After isoflavone consumption, equol and its metabolites are excreted only by some human individuals [1]. ...
... If the breast-feeding mother consumes food made from soybean, the isoflavone concentration in the breast milk may rise up to ten times [219]. However, even in this case, the nursling daily isoflavone intake from the breast milk reaches only 5-10 µg [108]. The postnatal exposure to isoflavones is therefore connected primarily to the soy-based infant formulae usage, soy milk consumption, or taking children's food supplements containing soybean [109,221]. ...
... In this case, children may be exposed to higher isoflavone levels than adults. Evidence for this statement is given by Setchell et al. [108], who found out that children consuming soy-based infant formulae and foods ingest 6-9 mg of isoflavones per kg of body weight daily, while adults, who consume an adequate amount of soy products, ingest only 1 mg of isoflavones per kg of body weight daily [108]. Moreover, the isoflavone 'apparent bioavailability' was found to be higher in children of diverse age than in adults [116]. ...
Article
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Phytoestrogens are naturally occurring nonsteroidal phenolic plant compounds that, due to their molecular structure and size, resemble vertebrate steroids estrogens. This review is focused on plant flavonoids isoflavones, which are ranked among the most estrogenic compounds. The main dietary sources of isoflavones for humans are soybean and soybean products, which contain mainly daidzein and genistein. When they are consumed, they exert estrogenic and/or antiestrogenic effects. Isoflavones are considered chemoprotective and can be used as an alternative therapy for a wide range of hormonal disorders, including several cancer types, namely breast cancer and prostate cancer, cardiovascular diseases, osteoporosis, or menopausal symptoms. On the other hand, isoflavones may also be considered endocrine disruptors with possible negative influences on the state of health in a certain part of the population or on the environment. This review deals with isoflavone classification, structure, and occurrence, with their metabolism, biological, and health effects in humans and animals, and with their utilization and potential risks.
... However, prior to the breast cancer controversy, questions about the safety of soy infant formula (SIF) had already been raised (Irvine et al. 1995;Setchell et al. 1997), despite it having been widely used for many decades (Merritt and Jenks 2004) and the conclusion by the Committee on Nutrition of the American Academy of Pediatrics in 1983, that SIF produces normal growth and development in full-term infants (Committee on Nutrition 1983). In subsequent years, much in the same way interest in the benefits of isoflavones expanded, concern about isoflavones expanded to include areas such as thyroid function (Divi, Chang, and Doerge 1997;Divi and Doerge 1996) and cognitive function (White et al. 2000). ...
... 1. SIF has been extensively reviewed by previous authors (Vandenplas et al. 2014;Testa et al. 2018;Jefferson, Patisaul, and Williams 2012;Badger et al. 2009;Stevens 2017) and committees (McCarver et al. 2011;Bhatia and Greer 2008). 2. On a body weight (bw) basis, isoflavone exposure is much higher in infants fed SIF than in children or adults consuming soyfoods in amounts compatible with Asian consumption, as are blood isoflavone levels (Table 1) (Setchell et al. 1997;Badger et al. 2002). Isoflavone intake of older Asian children is approximately 1 mg/kg bw whereas in infants it is 1.8 to 9.5fold higher. ...
... Examples of the range of isoflavone intake in China and Japan are shown in Table 2. Isoflavone intake in Korea (Lee and Kim 2007; Kim et al. Yu et al. 2014) 61 (Hara et al. 2012;Matsushita et al. 2008) 62.5 (Matsushita et al. 2008) 39,569 40-69 Japan 0.23 0.45 0.68 1.26 Women (Hara et al. 2012;Matsushita et al. 2008) 54 (Matsushita et al. 2008) 45 (Yang et al. 2005;Ma et al. 2013) 61.4 (Setchell et al. 1997 (Wada et al. 2011) 198 5.14 ± 0.90 Japan 11.4 0.66 Boys/Girls (Surh et al. 2006) N I 1 -2 Korea 14.5 NC b Boys/Girls (Surh et al. 2006) N I 3 -6 Korea 8.9 NC Boys/Girls (Surh et al. 2006) N I 7 -12 Korea 12.4 NC Boys/Girls (Surh et al. 2006) N I 1 3 -19 Korea 10.1 NC Boys/Girls (Hsiao and Lyons-Wall 2000) 6 6 8 -9 Taiwan 36.6 1.13 Children/Adolescents 174 0-14 China 0.53 Children (Messina, Nagata, and Wu 2006;Kato et al. 2014) N I 1 -6 Japan $14 $1.0 c Adolescents (Messina, Nagata, and Wu 2006;Hatena Blog) NI 7-14 Japan $20 0.54 d a Estimates based on an isoflavone concentration of SIF of 18.0 to 46.7 mg/l and an intake of 800 or 1200 ml/d. b NC, not calculated. ...
Article
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Soybeans are a rich source of isoflavones, which are classified as phytoestrogens. Despite numerous proposed benefits, isoflavones are often classified as endocrine disruptors, based primarily on animal studies. However, there are ample human data regarding the health effects of isoflavones. We conducted a technical review, systematically searching Medline, EMBASE, and the Cochrane Library (from inception through January 2021). We included clinical studies, observational studies, and systematic reviews and meta-analyses (SRMA) that examined the relationship between soy and/or isoflavone intake and endocrine-related endpoints. 417 reports (229 observational studies, 157 clinical studies and 32 SRMAs) met our eligibility criteria. The available evidence indicates that isoflavone intake does not adversely affect thyroid function. Adverse effects are also not seen on breast or endometrial tissue or estrogen levels in women, or testosterone or estrogen levels, or sperm or semen parameters in men. Although menstrual cycle length may be slightly increased, ovulation is not prevented. Limited insight could be gained about possible impacts of in utero isoflavone exposure, but the existing data are reassuring. Adverse effects of isoflavone intake were not identified in children, but limited research has been conducted. After extensive review, the evidence does not support classifying isoflavones as endocrine disruptors.
... Genistein (Sigma) synthetic, ≥ 98% (HPLC), powder with molecular weight of 270.24g/mol was used in this study. In this investigation, two concentrations of genistein (10 and 50 mg genistein / Kg B.W.) were utilized, according to earlier studies such as Setchell et al., (1997) and Li et al., (2012). The low dose was ten mg/kg B.W. genistein (this dose, according to Setchell et al., (1997), is similar to the total quantity of soy phytoestrogens taken daily by children fed soy infant formula, and the high dose was 50 mg/kg B.W. genistein. ...
... In this investigation, two concentrations of genistein (10 and 50 mg genistein / Kg B.W.) were utilized, according to earlier studies such as Setchell et al., (1997) and Li et al., (2012). The low dose was ten mg/kg B.W. genistein (this dose, according to Setchell et al., (1997), is similar to the total quantity of soy phytoestrogens taken daily by children fed soy infant formula, and the high dose was 50 mg/kg B.W. genistein. Tween 80 (Merck-Schuchardt, Germany), was used as the vehicle and as negative control (Montani et al., 2008). ...
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This study aimed to evaluate how genistein affected the weight and histological structure of the thymus gland in adult and postnatal (P22) female albino mice. Fifteen adult female albino mice and fifteen postnatal (P22) female albino mice were used and divided between two experiments. The animals were divided into three groups (n=5) in each experiment: Group (I), the control group, Group (II), and Group (III), which received 10mg and 50mg genistein/ kg B. W. respectively. In comparison to the control, treatment with 50mg genistein resulted in a significant increase in the weight of the thymus gland in both adult and postnatal mice. When compared to control, treatment with 10mg genistein resulted in a significant increase in this weight in adult females and a significant decrease in the weight of this gland in postnatal mice. Both genistein concentrations had a negative impact on the gland's histological features. The formation of a "Starry sky" in cortical and medullary regions, an increase in the thickness of regions due to an increase or decrease in the number of T cells depending on genistein concentration, as well as histiocyte hyperplasia and blood vessel congestion, are among these consequences. In conclusion, because genistein affects thymic tissue negatively, it has the potential to create thymic and immunological diseases.
... Genistein concentrations between Soy and M + G groups did not differ (Student's t-test, P = 0.29). These concentrations are comparable to circulating soy isoflavones, genistein, and daidzein concentrations reported in infants aged 4 mo consuming soy formula (37,38). ...
... This null finding is in stark contrast to the mammary histology and gene expression changes observed in the M + E2 group, which served as a positive control. These findings are particularly relevant to the risk assessment of soy infant formula given the relevance of the neonatal piglet model to infant feeding practices, especially considering the circulating isoflavones measured in our piglet model are similar to those observed in soy formula-fed infants (37,38). Our data are consistent with several clinical studies reporting no increases in breast bud growth in formula-fed female infants during the first Formula feeding increases proliferation in mammary glands 7 ...
Article
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Background: Soy infant formula contains isoflavones, which are able to bind to and activate estrogen receptor (ER) pathways. The mammary gland is sensitive to estrogens, raising concern that the use of soy formulas may promote premature development. Objective: We aimed to determine if soy formula feeding increases mammary gland proliferation and differentiation in comparison to other infant postnatal diets. Methods: White-Dutch Landrace piglets aged 2 d received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/(kg·d); M + E2), or milk formula supplemented with genistein (84 mg/L of diet; M + G) until day 21. Mammary gland proliferation and differentiation was assessed by histology, and real-time RT-PCR confirmation of differentially expressed genes identified by microarray analysis. Results: Mammary terminal end bud numbers were 19-31% greater in the Milk, Soy, and M + G groups relative to the Sow and M + E2, P <0.05. Microarray analysis identified differentially expressed genes between each formula-fed group relative to the Sow (±1.7-fold, P <0.05). Real-time RT-PCR confirmed 2- to 4-fold increases in mRNA transcripts of genes involved in cell proliferation, insulin-like growth factor 1 (IGF1), fibroblast growth factor 10 (FGF10), and fibroblast growth factor 18 (FGF18), in all groups relative to the Sow, P <0.05. In contrast, genes involved in cell differentiation and ductal morphogenesis, angiotensin II receptor type 2 (AGTR2), microtubule associated protein 1b (MAP1B), and kinesin family member 26b (KIF26B), were significantly upregulated by 2-, 4-, and 13-fold, respectively, in the M + E2 group. Additionally, mRNA expression of ER-specific gene targets, progesterone receptor (PGR), was increased by 12-fold, and amphiregulin (AREG) and Ras-like estrogen regulated growth inhibitor (RERG) expression by 1.5-fold in the M + E2 group, P <0.05. In the soy and M + G groups, mRNA expressions of fatty acid synthesis genes were increased 2- to 4-fold. Conclusions: Our data indicate soy formula feeding does not promote ER-signaling in the piglet mammary gland. Infant formula feeding (milk- or soy-based) may initiate proliferative pathways independently of estrogenic signaling.
... As a result, in 2011, the National Toxicology Program raised its level of concern about the potential reproductive toxicity of soy formula from negligible to minimal [13]. Isoflavones are similar structurally to 17β estradiol (E2) [14,15]. Genistein has been shown to be estrogenic in certain species and/or at high concentrations in cell culture [5,14,16,17]. ...
... Serum isoflavone concentrations in male piglets from this study were determined by LC-MS as previously described [34]. In the Soy-fed group we detected, genistein, daidzein and small amounts of glycitein, and o-desmethylangolansin (DMA) in the serum comparable to circulating soy isoflavones, reported in infants aged 4 months consuming soy formula [15]. Genistein values were 1712 ± 212 pg/mL and daidzein values were 1673 ± 374 pg/mL ( Table 1). ...
Article
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Soy infant formula which is fed to over half a million infants per year contains isoflavones such as genistein, which have been shown to be estrogenic at high concentrations. The developing testis is sensitive to estrogens, raising concern that the use of soy formulas may result in male reproductive toxicity. In the current study, male White-Dutch Landrace piglets received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/kg/d) (M + E2) or supplemented with genistein (84 mg/L of diet; (M + G) from postnatal day 2 until day 21. E2 treatment reduced testis weight (p < 0.05) as percentage of body weight, significantly suppressed serum androgen concentrations, increased tubule area, Germ cell and Sertoli cell numbers (p < 0.05) relative to those of Sow or Milk groups. Soy formula had no such effects relative to Sow or Milk groups. mRNAseq revealed 103 differentially expressed genes in the M + E2 group compared to the Milk group related to endocrine/metabolic disorders. However, little overlap was observed between the other treatment groups. These data suggest soy formula is not estrogenic in the male neonatal piglet and that soy formula does not significantly alter male reproductive development.
... In a small study of British women (n = 100) split into four groups ranging from no soy intake to high soy intake, the participants were found to have circulating levels of GEN from 14:3 to 378 nM (Verkasalo et al. 2001). A much higher exposure to isoflavones occurs in human infants fed soy-based infant formulas, with estimates of around 10 mg=kg per day in one small study (Setchell et al. 1997). The high intake of soy isoflavones in human infants most likely results in higher exposure rates than in adults. ...
... The high intake of soy isoflavones in human infants most likely results in higher exposure rates than in adults. Supporting this statement, a small study of human infants fed exclusively soy-based infant formula had serum circulating levels of GEN (1-10 lM), which is at least 10-fold higher than any natural exposure of adults (Cao et al. 2009;Setchell et al. 1997). ...
Article
Background: Embryo implantation relies on precise hormonal regulation, associated gene expression changes, and appropriate female reproductive tract tissue architecture. Female mice exposed neonatally to the phytoestrogen genistein (GEN) at doses similar to those in infants consuming soy-based infant formulas are infertile due in part to uterine implantation defects. Objectives: Our goal was to determine the mechanisms by which neonatal GEN exposure causes implantation defects. Methods: Female mice were exposed to GEN on postnatal days (PND)1-5 and uterine tissues collected on PND5, PND22-26, and during pregnancy. Analysis of tissue weights, morphology, and gene expression was performed using standard histology, confocal imaging with three-dimensional analysis, real-time reverse transcription polymerase chain reaction (real-time RT-PCR), and microarrays. The response of ovariectomized adults to 17 β -estradiol (E2) and artificial decidualization were measured. Leukemia inhibitory factor (LIF) injections were given intraperitoneally and implantation sites visualized. Gene expression patterns were compared with curated data sets to identify upstream regulators. Results: GEN-exposed mice exhibited reduced uterine weight gain in response to E2 treatment or artificial decidualization compared with controls; however, expression of select hormone responsive genes remained similar between the two groups. Uteri from pregnant GEN-exposed mice were posteriorized and had reduced glandular epithelium. Implantation failure was not rescued by LIF administration. Microarray analysis of GEN-exposed uteri during early pregnancy revealed significant overlap with several conditional uterine knockout mouse models, including Foxa2, Wnt4, and Sox17. These models exhibit reduced endometrial glands, features of posteriorization and implantation failure. Expression of Foxa2, Wnt4, and Sox17, as well as genes important for neonatal uterine differentiation (Wnt7a, Hoxa10, and Msx2), were severely disrupted on PND5 in GEN-exposed mice. Discussion: Our findings suggest that neonatal GEN exposure in mice disrupts expression of genes important for uterine development, causing posteriorization and diminished gland function during pregnancy that contribute to implantation failure. These findings could have implications for women who consumed soy-based formulas as infants. https://doi.org/10.1289/EHP6336.
... Currently, it is known that isoflavones act as endocrine disrupters leading to testicular dysfunction [8,12,13]. Once in the body, isoflavones can bind to α and β estrogen receptors inducing weak estrogenic effect [14] and agonistic and/or antagonistic effect on endogenous β-estrogen through competition for the same androgen receptors [15]. In addition, a direct inhibition possibly occurs in the germ cells or an alteration of the hypothalamic-pituitary axis [8]. ...
... However, discrepancies between the studies reviewed and included methods are shown as limitations considering the wide variety in animal models' characteristics such as age, weight, number of animals, and number of experimental groups. Another limitation was the wide variety of doses (0.465 to 2000 mg/kg and formulations around 6 to 9 mg/kg/day [14], the used doses in the included studies were high. However, many foods have traces of soy which increases the level of daily consumption. ...
Article
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Isoflavone is a phytoestrogen found in different types of food that can act as endocrine disrupters leading to testicular dysfunction. Currently, fragmented data on the action of this compound in the testicles make it difficult to assess its effects to define a safe dose. Thus, we systematically reviewed the preclinical evidence of the impact of isoflavone on testicular function. We also determined which form (aglycones or glycosylated) was the most used, which allowed us to understand the main biological processes involved in testicular function after isoflavone exposure. This systematic review was carried out according to the PRISMA guidelines using a structured search on the biomedical databases MEDLINE (PubMed), Scopus, and Web of Science, recovering and analyzing 22 original studies. The bias analysis and the quality of the studies were assessed by the criteria described in the risk of bias tool developed by SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation). The aglycones and glycosylated isoflavones proved to be harmful to the reproductive health, and the glycosylates at doses of 50, 100, 146, 200, 300, 500, and 600 mg/kg, in addition to 190 and 1000 mg/L, appear to be even more harmful. The main testicular pathologies resulting from the use of isoflavones are associated with Leydig cells resulting from changes in molecular functions and cellular components. The most used isoflavone to evaluate testicular changes was the genistein/daidzein conjugate. The consumption of high doses of isoflavones promotes changes in the functioning of Leydig cells, inducing testicular changes and leading to infertility in murine models.
... A substantial percentage (12%) of infant formulas are soy-based and have phytoestrogen levels in the range of 4.5-8 mg/kg/day [7][8][9][10][11]. Taking into consideration body weight, infants fed soy-based formulas consume 6-11 times the amount of phytoestrogens necessary to produce hormone-like effects in adults [14]. ...
... In the study population, 45 out of 199 caregivers indicated that their child with FXS had been fed soy-based formula during their first year of life, 132 respondents checked "No" to Q28, 3 respondents left the question blank, and 19 respondents checked "Don't know". This corresponds to a 25% usage rate of soy-based infant formula among Yes/No respondents compared to 17% in the SFARI population [5] and 12% in the general population [5][6][7][8][9][10][11][12][13][14][15][16]. Binning the infant feeding data by cases and controls indicated no statistically significant differences dependent on infant diet ( Table 4). ...
Article
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A large number of adults and children consume soy in various forms, but little information is available regarding potential neurological side effects. Prior work indicates an association between the consumption of soy-based diets and seizure prevalence in mouse models of neurological disease and in children with autism. Herein, we sought to evaluate potential associations between the consumption of soy-based formula during infancy and disease comorbidities in persons with fragile X syndrome (FXS), while controlling for potentially confounding issues, through a retrospective case-control survey study of participants with FXS enrolled in the Fragile X Online Registry with Accessible Research Database (FORWARD). There was a 25% usage rate of soy-based infant formula in the study population. We found significant associations between the consumption of soy-based infant formula and the comorbidity of autism, gastrointestinal problems (GI) and allergies. Specifically, there was a 1.5-fold higher prevalence of autism, 1.9-fold GI problems and 1.7-fold allergies in participants reporting the use of soy-based infant formula. The major reason for starting soy-based infant formula was GI problems. The average age of seizure and allergy onset occurred long after the use of soy-based Nutrients 2020, 12, 3136 2 of 15 infant formula. We conclude that early-life feeding with soy-based infant formula is associated with the development of several disease comorbidities in FXS.
... Additionally, these isoflavones are also present in breast milk (10). Setchell et al. reported that circulating isoflavones of infants were 13,000-22,000 times higher than the estradiol level, and the exposure level was 6-11 times higher than the dose in adults with regular soy food intake (11). The American Academy of Pediatrics Committee on Nutrition only recommends soy formula to infants with inherited galactosemia, lactose intolerance, or from vegan families (12). ...
Article
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Isoflavones are dietary phytoestrogens commonly found in soy-based products. The widespread presence of isoflavones in soy infant formula and breast milk may have long-lasting effects on the development of sex hormone-sensitive organs like the skeleton. Animal early-life programming models are suitable for testing the skeletal effects of pre- and neonatal exposure of soy isoflavones. This review aims to collate the impacts of early-life exposure of soy isoflavones as evidenced in animal models. The isoflavones previously studied include daidzein, genistein, or a combination of both. They were administered to rodent pups during the first few days postnatal, but prolonged exposure had also been studied. The skeletal effects were observed when the animals reached sexual maturity or after castration to induce bone loss. In general, neonatal exposure to soy isoflavones exerted beneficial effects on the skeletal system of female rodents, but the effects on male rodents seem to depend on the time of exposure and require further examinations. It might also protect the animals against bone loss due to ovariectomy at adulthood but not upon orchidectomy. The potential benefits of isoflavones on the skeletal system should be interpreted together with its non-skeletal effects in the assessment of its safety and impacts.
... Gut microbes are thought to play an essential, non-redundant role in the metabolism of phytoestrogens in humans. This notion is supported by the fact that both GF mice on a soy-based diet and newborn infants up to 4 months of age (both of which lack diverse microbiota) lack equol (97,136,137). Additionally, culturing of human fecal matter from equol-producing individuals with soy or daidzein resulted in the formation of S-EQL (138,139), and the inclusion of antibiotics in these cultures resulted in inhibition of equol production (139). ...
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The human body has a large, diverse community of microorganisms which not only coexist with us, but also perform many important physiological functions, including metabolism of dietary compounds that we are unable to process ourselves. Furthermore, these bacterial derived/induced metabolites have the potential to interact and influence not only the local gut environment, but the periphery via interaction with and modulation of cells of the immune and nervous system. This relationship is being further appreciated every day as the gut microbiome is researched as a potential target for immunomodulation. A common feature among inflammatory diseases including relapsing-remitting multiple sclerosis (RRMS) is the presence of gut microbiota dysbiosis when compared to healthy controls. However, the specifics of these microbiota-neuro-immune system interactions remain unclear. Among all factors, diet has emerged as a strongest factor regulating structure and function of gut microbial community. Phytoestrogens are one class of dietary compounds emerging as potentially being of interest in this interaction as numerous studies have identified depletion of phytoestrogen-metabolizing bacteria such as Adlercreutzia, Parabacteroides and Prevotella in RRMS patients. Additionally, phytoestrogens or their metabolites have been reported to show protective effects when compounds are administered in the animal model of MS, Experimental Autoimmune Encephalomyelitis (EAE). In this review, we will illustrate the link between MS and phytoestrogen metabolizing bacteria, characterize the importance of gut bacteria and their mechanisms of action in the production of phytoestrogen metabolites, and discuss what is known about the interactions of specific compounds with cells immune and nervous system. A better understanding of gut bacteria-mediated phytoestrogen metabolism and mechanisms through which these metabolites facilitate their biological actions will help in development of novel therapeutic options for MS as well as other inflammatory diseases.
... Using this "one size fits all" approach, tofu was the only food examined that might be expected to contribute significantly to the estrogenicity of circulating serum. In concordance with modeled results, circulating plasma concentrations of genistein in 4-month old infants on soy-based infant formula of 684 versus 3 ng/mL in plasma of infants fed cow's milk (Setchell, Zimmer-Nechemias, Cai, & Heubi, 1997). By E-Screen, 684 ng/mL of genistein would result in 103 pg/mL E 2 Eq, compared to circulating E 2 concentrations reported in infants of ࣘ25 pg/mL (Konforte et al., 2013). ...
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The public assumes that some foods, such as milk and ground beef from cattle receiving steroidal implants, are associated with estrogenic hormones, while other foods are presumed “safe” or nonestrogenic. Here, we investigate these assumptions by assessing the relative estrogenic activity of a serving size of four foods: skim milk (8 oz), rice (48 g dry wt) in cooking bag, ground beef patties from steers raised with or without hormone implantation (quarter lb each, 114 g), and tofu burgers (isocaloric to beef burger, 198 g), using an in vitro assay (E‐Screen). Mean picogram (pg) estradiol equivalents (E2Eqs) on a serving basis were as follows: skim milk 120; rice 400; rice prepared in cooking bag 370; rice boiling bag alone 4 pg per bag, ground beef burger (obtained from the tissue of cattle that had received no hormone implants) 389, beef burger (obtained from cattle that had received hormone implant) 384, and tofu burger 1,020,000. Rice E2Eqs were highly variable, but the plastic cooking bags provided by the manufacturer added negligible E2Eqs. The source of estrogenic activity in rice may have been due to contamination with the mycotoxin zearalenone. The E‐Screen E2Eqs of tofu burger extracts agreed with those predicted based on chemical concentrations of the most estrogenic component times their E2Eq factor. While a tofu burger contained around three times the estrogenic activity of a daily dose of estrogen replacement therapy (125 mg, Premarin®, 303,000 pg); the other foods––a quarter pound ground beef burger at approximately equal calorie count, a serving of milk, or rice, were all at least 750‐fold less estrogenic. Practical Application When consuming the recognized serving size of a food, how much estrogenic activity can we expect? While the public assumes that some foods, such as milk and ground beef from cattle receiving steroidal implants, are associated with estrogenic hormones, other foods are presumed “safe” or nonestrogenic. Using one assay, a tofu burger contained three times the estrogenic activity of a dose of hormone replacement therapy commonly prescribed for women after hysterectomy or menopause (Premarin®); while other foods––a quarter pound ground beef burger at approximately equal calorie count, a serving of milk, or rice, were all at least 750‐fold less estrogenic.
... During lactation, lactose intolerant infants, who are fed with soy milk supplements, can reach circulating levels of isoflavones in a range of 552 μg/L to 1775 μg/L (Setchell et al., 1997). At this stage, the endogenous values of estradiol are 40-80 pg/mL, so the levels of isoflavones are 13,000 to 22,000 times higher than the endogenous levels of estradiol (Zung et al., 2001). ...
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The research group Morphophysiology and Biochemistry of Spermatozoa at the Autonomous Metropolitan University (Iztapalapa Unit, UAM-I) as well as the members of the Animal Reproduction Research Laboratory (LIRA) at the Autonomous University of Oaxaca Benito Juárez began the Statewide Reproduction Seminars in 2010, aiming to open a space in which the students from both groups could show their research advances and providing a forum of critic thought that allowed them to express freely, so as to raise questions from the most basic level and gain firm knowledge from there on. This forum has grown year after year, adding workshops that allow the students to standardize the techniques they use in the lab, and to make their first incursions as handlers. The workshops have tackled a wide range of practical field subjects, from artificial insemination and the transfer of embryos in sheep and goats, to the evaluation and freezing of semen at the lab. The seminars have also involved the participation of members from the research group Ecophysiology of Vertebrate Reproduction and the academic body of Fertilization of Mammals, both from UAM-I, of Dr. Ávalos from the Autonomous Metropolitan University (Xochimilco Unit), and of Dr. Arturo Gómez, from the Autonomous University of the State of Mexico; and in 2017, the signing of an agreement of academic collaboration between the research group Biotechnology Applied to the Veterinary (UABJO), the Laboratory of Morphophysiology and Biochemistry of the Spermatozoon (UAM-I), the Consortium of Spermatozoon Physiology of the Biotechnology Institute (UNAM), the Biology Laboratory of the Reproduction of the Faculty of Biological Sciences at the Autonomous University of Puebla, and the Biology of Animal Reproduction Postgraduate Institute at the UAM-I. For most people, the spermatozoon is just “the other cell participating in reproduction”; for us it’s a unique cell, with fascinating characteristics that captures our attention and keeps us eternally amazed. So, we hope this book will allow the reader to consider some of the contributions made on this subject from Mexico, aiming to further what we know about this cell.
... The Japanese Food Safety Commission has set the upper limit of intake of soy isoflavone aglycones as 70-75 mg/day, the Italian Ministry of Health recommended that isoflavone supplements should not exceed 80mg/day, and the French Food Safety Agency set the quantity of isoflavone aglycone at 1 mg/kg/day (Setchell et al., 1997). The risks of phytoestrogen have also been assessed by the U.S. FDA (Food and Drug Administration) and the AHRQ (Agency for Healthcare Research and Quality). ...
Article
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Soybeans contain the isoflavone aglycone, an endocrine disrupter. To determine the effects of small amounts of isoflavones on developmental processes, we administered 6.25, 62.5, or 625 µg isoflavone per egg to early stage (stage 10) developing chick embryos via the yolk just beneath the embryo. Eggs were kept at 37±0.5 °C and >80% relative humidity, with one rotation per hour for 48 hrs. The embryos were observed under a stereomicroscope for morphological abnormalities and number of somites. Relative to control eggs, there were no significant differences in the average number of somites in eggs administered isoflavone aglycone. Isoflavone, however, had a dose associated effect on abnormal embryogenesis. Embryos treated with isoflavone aglycone showed developmental arrest not reaching somitegenesis, dysmorphology of the neural tube, and shortening of entire embryos.
... Infants provided soy formula can have circulating concentrations of isoflavones (genistein, daidzein, and their glycosides) that are up to 13,000 to 22,000 higher than plasma estradiol, whereas, infants provided breast milk or cow milk have neglible amounts of these chemicals (51). ...
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Many pregnant and nursing women consume high amounts of soy and other plant products that contain phytoestrogens, such as genistein (GEN) and daidzein. Infants may also be provided soy based formulas. With their ability to bind and activate estrogen receptors (ESR) in the brain, such compounds can disrupt normal brain programming and lead to later neurobehavioral disruptions. However, other studies suggest that maternal consumption of soy and soy based formulas containing such phytoestrogens might lead to beneficial behavioral effects. Select gut microbes might also convert daidzein and to a lesser extent genistein to even more potent forms, e.g., equol derivatives. Thus, infant exposure to phytoestrogens may result in contrasting effects dependent upon the gut flora. It is also becoming apparent that consumption or exposure to these xenoestrogens may lead to gut dysbiosis. Phytoestrogen-induced changes in gut bacteria might in turn affect the brain through various mechanisms. This review will consider the evidence to date in rodent and other animal models and human epidemiological data as to whether developmental exposure to phytoestrogens, in particular genistein and daidzein, adversely or beneficially impact offspring neurobehavioral programming. Consideration will be given to potential mechanisms by which such compounds might affect neurobehavioral responses. A better understanding of effects perinatal exposure to phytoestrogen can exert on brain programming will permit pregnant women and those seeking to become pregnant to make better-educated choices. If phytoestrogen-induced gut dysbiosis contributes to neurobehavioral disruptions, remediation strategies may be designed to prevent such gut microbiota alterations and thereby improve neurobehavioral outcomes.
... During lactation, lactose intolerant infants, who are fed with soy milk supplements, can reach circulating levels of isoflavones in a range of 552 μg/L to 1775 μg/L (Setchell et al., 1997). At this stage, the endogenous values of estradiol are 40-80 pg/mL, so the levels of isoflavones are 13,000 to 22,000 times higher than the endogenous levels of estradiol (Zung et al., 2001). ...
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Presents the work of some groups in Mexico, which will be dedicated to the study of sperm.
... In 1997, researchers published that daily exposure of infants to the bio-active isoflavones in soy infant-formulas is 6-11 times higher on a body weight basis than the dose necessary to cause hormonal effects in adults consuming soy foods. 6 The implications of such excessive exposure to endocrine-disrupting agents during fetal and infant development are grave. Advocating exclusive breast-feeding when safe and possible (the mother is not on social drugs, heavily medicated or have infectious disease, etc and the baby can latch) reduces this dangerous risk while aiding proper jaw and airway development. ...
Article
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Abstract: This article describes seven Medical Dentistry steps that may help more patients live healthier, happier and longer--per already published research. Functional Jaw Orthopedic (FJO) and Orthodontic treatments from pre-conception to death hold tremendous promise for future better lifelong health. All dental doctors can quickly implement some or all of the seven steps, and help bring a new era of preventive Medical Dentistry for people worldwide. #1) Dental doctors need to take urgent action to help eliminate the ignored Silent Global Pandemic of Vitamin D Deficiency (VDD) beginning pre-conception. VDD can affect teeth, bone, malocclusion and overall health, even in utero. #2) Dental doctors need to learn FJO techniques and begin to apply them. The jaws form the gateway to the human airway and too little attention is paid to jaw structures until the need for CPR. #3) Dental doctors need to recommend “exclusive” breastfeeding for at least 3-6 months, for those who can breastfeed, and lactation consultant counseling before delivery. #4) Dental doctors need to recommend and deliver early FJO treatments beginning at or near birth and continuing especially during early and teenage years of rapid teeth and jaw growth. #5) Dental Doctors need to teach the health value of lifelong routine oral care. #6) Dental Doctors need to call on public officials to take swift action against the Silent Global Pandemic of VDD and direct dental schools to teach FJO therapies. 7) Dental doctors, tax payers and elected officials need to call for a massive review of decades of government funded research and the bias therein. It is time to globally treat VDD, globally promote profound FJO treatments, and globally bring about Medical Dentistry.
... Notably, a study on mice reports that the neonatal administration of genistein at 18 months increases the incidence of uterine adenocarcinoma, suggesting that genistein exposure during critical periods of differentiation may be cancerogenic [169]. The dose of isoflavones ingested by neonates fed with soy-formula is very high, reaching plasma levels even higher than those reported for Japanese men fed with a soybased diet [170,171] and exceed 13,000-22,000 times their own endogenous estrogen ( [157] and cited literature), altering reproductive hormones [172]. Soy-formula fed infants have higher urine concentrations of isoflavones than cow-milk-formula-fed infants [173]. ...
Article
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Phenols are a wide family of phytochemicals that are characterized by large chemical diversity and are considered to bioactive molecules of foods, beverages, and botanicals. Although they have a multitude of biological actions, their beneficial effects are rarely evidenced in clinical practice. This may occur due to the presence of numerous confounders, such as the modulation of phenol bioavailability, which can be regulated by microbiota, age, sex-gender. Sex-gender is an important determinant of health and well-being, and has an impact on environmental and occupational risks, access to health care, disease prevalence, and treatment outcomes. In addition, xenobiotic responses may be strongly influenced by sex-gender. This review describes how sex–gender differentially influences the activities of phenols also in some critical periods of women life such as pregnancy and lactation, considering also the sex of fetuses and infants. Thus, sex–gender is a variable that must be carefully considered and should be used to propose directions for future research on the road to tailored medicine and nutrition.
... Terpenoids, flavonoids, and their glycosides from S. scandens are estrogenic (Wang et al., 2013;Shrestha et al., 2014). Higher doses of phytoestrogens induced adverse effect on brain aromatase and neurobehavioral activities but lower doses did not (Setchell et al., 1997;Wisniewski et al., 2005). In this study, <391 mg/kg/d of SSE caused no marked perinatal development toxicity in mice. ...
Article
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This study assessed the effects of Senecio scandens Buch. Ham.extract on reproductive spectrum in female mice using a three phase reproductive assessment method. Sperm abnormality rate was used to evaluate effect on genetic reproductive toxicity. Senecio scandens extract was relatively non-toxic at low doses in all phases of reproduction in female mice. However, it showed a dose-response effect on sperm abnormality rate, and at high doses has the potential to induce genetic reproductive toxicity in male mice. It is suggested that the well-understood pharmacological benefits of S. scandens extract as an herbal medicine far outweigh the minimal reproductive toxicity effects observed in this study.
... We have to be careful regarding the consumption of diets rich in phytoestrogens in higher concentrations since the consequences of an exaggerated consumption remains unknown. Among the population groups that can be affected, children who drink soy milk (as a substitute for maternal or cow milk) are more susceptible, since the concentration of isoflavones in the blood is 1,000 times higher than that found in children's blood when nursed by mothers who consume diets rich in soybean (67,69). Studies made with wildlife and other animals show that the fetal or perinatal exposure to endocrine disruptors, such as phytoestrogens, originate an altered sexual differentiation and urogenital malformations, which lead to reproductive disorders in adult life (70); besides, a recent meta-analysis evidences that phytoestrogen intake via food might, at least in part, be responsible for sperm concentration trends (71) . ...
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Introduction: this study presents the results regarding diet and an analysis of natural estrogens (phytoestrogens) intake and how they affect other important aspects, which can modulate biological health functions among university students. Objectives: assessing nutritional habits and estimating the intake of phytoestrogens in the population under study. Materials and methods: Costa Rican female (n: 211, 18.83 ± 2.06 years) and male (n: 199, 19.64 ± 3.05 years) university population of the University of Costa Rica applied anthropometric tests using DEXA, the Food Frequency Questionnaire (FFQ) and the 24-hour Reminder (R-24). Results: the most serious nutritional bad habits were high ingestion of sodium, lipids and animal origin proteins in men and women and a deficit of fiber and folic acid in women. The total intake of phytoestrogens referred to: daidzein 0.23 ± 0.40 mg/day and 7.01 ± 11.94 mg/month in women and 0.17 ± 0.13 mg/day and 5.14 ± 3.96 mg/month in men; mainly consumed in the form of lignans 0.24 ± 0.12 mg/day (women) and 0.23 ± 0.14 mg/day (men). The intake of isoflavones was 0.09 ± 0.38 mg/day (women) and 0.04 ± 0.08 mg/day (men). Conclusions: the study population presented high fat percentage although the consumption of vegetables, cereals, whole grains and fruits tends slightly to be a Mediterranean diet; their food pattern was much closer to the Western diet.
... La exposición en la etapa neonatal a este tipo de compuestos sucede por medio de la lactancia; los niveles de fitoestrógenos van a depender de la dieta, ya que se reportan variaciones de 14.3 nM/L hasta 378nM/L. Durante la lactancia, los bebés intolerantes a la lactosa que son alimentados con suplementos de leche de soya pueden alcanzar niveles circulantes de isoflavonas en un rango de 552 μg/L a 1775 μg/L (Setchell et al., 1997); en esta etapa los valores endógenos de estradiol son de 40-80 pg/mL, por lo que los niveles de isoflavonas son de 13,000 a 22,000 veces más altas que los niveles endógenos de estradiol (Zung et al., 2001). ...
... The widespread use of soy-based infant formula, which is now known to contain physiologically relevant concentrations of the isoflavones genistein and genistin, has stimulated research on phytoestrogen exposure during key developmental periods in humans, and to a much larger extent in rodents (88,89). Infants that consume soy-based formula have circulating levels of genistein that are 13,000 to 68,000-fold higher than the normal biological concentration of estradiol in non-exposed infants in the same age bracket (88). ...
Article
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Phytoestrogens can impact on reproductive health due to their structural similarity to estradiol. Initially identified in sheep consuming estrogenic pasture, phytoestrogens are known to influence reproductive capacity in numerous species. Estrogenic pastures continue to persist in sheep production systems, yet there has been little headway in our understanding of the underlying mechanisms that link phytoestrogens with compromised reproduction in sheep. Here we review the known and postulated actions of phytoestrogens on reproduction, with particular focus on competitive binding with nuclear and non-nuclear estrogen receptors, modifications to the epigenome, and the downstream impacts on normal physiological function. The review examines the evidence that phytoestrogens cause reproductive dysfunction in both the sexes, and that outcomes depend on the developmental period when an individual is exposed to phytoestrogen.
... Physiology of Adult Female Laboratory Mouse 9192 | P a g e adult diet; one study estimates that infants fed soy-based formulas consume approximately 6-9 mg/kg/day of genistein compared to 1 mg/kg/day for an adult vegetarian (Setchell et al., 1997). Soybeans also have extremely variable isoflavone content depending on variety and environmental conditions such as growing season and location (Wang et al., 1994) and the USDA reports variable amounts of genistein in various soy products (USDA, 1999). ...
Article
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Purpose: The purpose of the present study was to check deleterious effects of genistein on the reproduction of albino female mouse Mus musculus. Methods: Pregnant mice were treated with genistein at 0, 0.5 and 10 mg/ kg body weight (BW) by a daily subcutaneous injection from the tenth day of gestation till the dams delivered their pups. Results: Genistein exposed pups showed accelerated body growth and onset of puberty as compared to control. At the adult stage genistein exposed mice found with altered estrous cyclicity and hormone levels as compared to control mice. Histological observation revealed presence of less number of healthy follicles and some abnormal follicles, like cystic follicle as well as more atretic follicles in ovary and decreased lumen size and less proliferation of uterine glands in the uterus of genistein exposed mice as compared to control mice. During fertility test genistein exposed dams were found with significantly low litter size and hormone levels. Conclusion: The results of the present study substantiate that developmental exposure to genistein induces abnormal development and affects reproductive physiology of female mice at adult stage.
... Based on previous studies, the pharmacokinetics of isoflavones in humans have been exhaustively cognized [35][36][37]. Genistein and daidzein are the most abundant isoflavones in soybeans [38][39][40], which are absorbed through the intestine and liver relative rapidly, and reach the maximum plasma concentration in 2 and 8 h post-intake, and are excreted in urine as glucuronides [41]. ...
Article
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Soy diet is thought to help prevent cardiovascular diseases in humans. Isoflavone, which is abundant in soybean and other legumes, has been reported to possess antiplatelet activity and potential antithrombotic effect. Our study aims to elucidate the potential target of soy isoflavone in platelet. The anti-thrombosis formation effect of genistein and daidzein was evaluated in ex vivo perfusion chamber model under low (300 s−1) and high (1800 s−1) shear forces. The effect of genistein and daidzein on platelet aggregation and spreading was evaluated with platelets from both wildtype and GPIbα deficient mice. The interaction of these soy isoflavone with 14-3-3ζ was detected by surface plasmon resonance (SPR) and co-immunoprecipitation, and the effect of αIIbβ3-mediated outside-in signaling transduction was evaluated by western blot. We found both genistein and daidzein showed inhibitory effect on thrombosis formation in perfusion chamber, especially under high shear force (1800 s−1). These soy isoflavone interact with 14-3-3ζ and inhibited both GPIb-IX and αIIbβ3-mediated platelet aggregation, integrin-mediated platelet spreading and outside-in signaling transduction. Our findings indicate that 14-3-3ζ is a novel target of genistein and daidzein. 14-3-3ζ, an adaptor protein that regulates both GPIb-IX and αIIbβ3-mediated platelet activation is involved in soy isoflavone mediated platelet inhibition.
... Genistein and daidzein are of particular interest due to their high concentration in soy products [60]. Genistein is an estrogen derivative available at health food stores as dietary and menopausal supplements, and a soy phytoestrogen present in foods, particularly soybeans, and infant soy formulas [23,64,65]. ...
Chapter
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Eukaryotic cells use homologous recombination (HR), classical end-joining (C-NHEJ), and alternative end-joining (Alt-EJ) to repair DNA double-strand breaks (DSBs). Repair pathway choice is controlled by the activation and activity of pathways specific proteins in eukaryotes. Activity may be regulated by cell cycle stage, tissue type, and differentiation status. Bioflavonoids and other environmental agents such as pesticides have been shown to biochemically act as inhibitors of topoisomerase II (Top2). In cells, bioflavonoids directly lead to DNA double-strand breaks through both Top2-dependent and independent mechanisms, as well as induce DNA damage response (DDR) signaling, and promote alternative end-joining and chromosome alterations. This chapter will present differences in expression and activity of proteins in major DNA repair pathways, findings of Top2 inhibition by bioflavonoids and cellular response, discuss how these compounds trigger alternative end-joining, and conclude with implications for genome instability and human disease. https://www.intechopen.com/online-first/dna-damage-and-repair-mechanisms-triggered-by-exposure-to-bioflavonoids-and-natural-compounds
... However, it is otherwise not recommended for use during the first 6 months of life [32]. Soy is recognized as being one of the richest sources of phytoestrogens, which are plant ingredients similar in composition to mammalian estrogens [33,34]. In addition, soy products are relatively rich in phytate, which binds calcium and impairs its absorption, and a soy-based formula contains significantly more aluminum than other formulas [35,36]. ...
Article
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Background: Commercial infant formulas attempt to imitate human milk's unique composition. However, lactose-free and milk protein-free formulas are often chosen due to medical reasons or personal preferences. The aim of this study was to determine the glycemic and insulinemic indices of a variety of infant formulas. Methods: We conducted a three-arm, randomized, double-blind, crossover study. Participants were 25-40-year-old healthy adults. Three commercial infant formulas (cow's milk protein-based ["standard"], soy protein-based, and lactose-free) were randomly given to each participant. Glycemic and insulinemic responses were determined and compared between the three formulas. Results: Twenty subjects were enrolled (11 females/9 males, mean age 32.8 ± 2.9 years). No significant difference was found in the glycemic index between the three formulas (21.5, 29.1, and 21.5 for the standard, soy protein-based, and lactose-free formulas, respectively, p = 0.21). However, maximal glucose levels were significantly higher for the soy protein-based formula compared to both the standard and lactose-free formulas (111.5 compared to 101.8 and 105.8 mg/dL, respectively, p = 0.001). Conclusion: Cow's milk protein-based, soy protein-based, and lactose-free formulas have a similar glycemic index. However, soy protein-based formula produced a significantly higher increase in postprandial glucose levels. The implication and biological significance of these results have yet to be determined.
... Women who were fed soy formula in infancy, which includes high concentrations of phytoestrogens, including genistein [31,32], were more likely to experience very early and very late thelarche. The effects of phytoestrogens on reproductive development in animal and human studies have varied by timing and dose of exposure [33]. ...
Article
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Background Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974. Methods Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11–13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood. Results Early thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09–1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04–1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13–1.27), young maternal age (OR 1.30, 95% CI 1.16–1.47 for < 20 vs. 25–29 years), and being firstborn (OR = 1.25, 95% CI 1.17–1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche. Conclusions Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.
... The total isoflavone concentration ranged from 16.2 to 85.4 μg/g (Fonseca et al., 2014). In the light of this information, it is known that the daily intake of the isoflavones of a baby fed soy-based formulas can rise up to 11 mg/kg, which is a much higher amount than that of adults (Setchell et al., 1997). In addition, differences in isoflavone content in soy-based formulas may be due to differences in the manufacturing process, analysis methods and biological properties of the product (Westmark, 2017). ...
Article
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Baby formulas are foods designed and marketed for feeding babies. The use of baby formulas is increasing worldwide due to various reasons. In parallel, there is increasing concern about endocrine disrupting compounds (EDCs) in baby formulas. EDCs cover a large class of compounds able to interact with the endocrine system. EDCs can disrupt many different hormones, so they are linked to numerous adverse outcomes in human health. Babies are more sensi-tive to environmental toxins than adults. In this review, the type and amount of some EDCs in the composition of baby formulas in addition to their effects on health are examined. The evaluation of EDCs in baby formulas, which are considered a source for EDCs, has become necessary. Soy-based baby formu-las are seen as a source of phytoestrogens for newborns. Organohalogens are high in especially milk-based. Pesticides are generally below the maximum limits. Phthalate levels vary depending on the package content of baby formu-las. The phthalate level is higher in formulas with metal packaging. Although bisphenol A (BPA) exposure decreases with the spread of BPA-free packaging, it should be kept in mind that even very low exposures can cause significant health problems. With strict legal regulations, melamine exposure has de-creased considerably. Given the susceptibility of babies to EDCs, it is essential to closely monitor the EDCs content of baby formulas.
... Adults consuming soy-based foods, particularly vegetarians, circulate 50 to 200 ng/mL total isoflavones. Infants fed soy-based infant formula circulate approximately 700 ng/mL genistein (119). While soy-based foods have been promoted as having beneficial effects in adults, there is increasing evidence that developmental exposure during differentiation of the uterus may be detrimental (120)(121)(122)(123). ...
... However, it is otherwise not recommended for use during the rst 6 months of life [32]. Soy is recognized as being one of the richest sources of phytoestrogens, which are plant ingredients similar in composition to mammalian estrogens [33,34]. In addition, soy products are relatively rich in phytate, which binds calcium and impairs its absorption, and a soy-based formula contains signi cantly more aluminum than other formulas [35,36]. ...
Preprint
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Objectives: Commercial infant formulas attempt to imitate the unique composition of human milk, which contributes to its distinctive influence on glycemic and insulinemic responses. However, lactose-free and milk protein-free formulas are often recommended due to medical reasons or chosen due to personal preferences (e.g., veganism). The aim of this study was to determine the glycemic and insulinemic indices of a variety of infant formulas. Methods: We conducted a three-arm, randomized, double-blind, crossover study. The participants were healthy adult volunteers aged 25-40 years. Each participant randomly drank three commercially available infant formulas (cow's milk protein-based ["standard"], soy protein-based, and lactose-free). Glycemic and insulinemic responses and glucose and insulin blood levels were determined and compared between the three formulas. Results: Twenty subjects were enrolled (11 females/9 males, mean age 32.8 ± 2.9 years). No significant difference was found in the glycemic index between the three formulas (21.5, 29.1, and 21.5 for the standard, soy protein-based, and lactose-free formulas, respectively, p = 0.21). However, maximal glucose levels were significantly higher for the soy protein-based formula compared to both the standard and lactose-free formulas (111.5 mg/dL compared to 101.8 mg/dL and 105.8 mg/dL, respectively, p = 0.001). Conclusion: A cow's milk protein-based formula, a lactose-free formula, and a soy protein-based formula elicited similar glycemic index. However, soy protein-based formula produced a significantly higher increase in postprandial glucose levels. The implication and the biological significance of these results has yet to be determined.
... Infants consuming soy-based formulas can achieve intakes over 5 mg/kg body weight genistein daily (Setchell, et al., 1997). Women who regularly consume soy foodstuffs exhibit plasma genistein concentrations of 0.7-6.0 ...
Article
Homeostasic balance of one-carbon metabolism is highly dependent upon derivatives of folate and is vital for the prevention of multiple disease states, including vascular disease, birth defects, neurological disorders, and cancer. Homocysteine, a non-protein forming amino acid, accumulates in the absence of 5-methyltetrahydrofolate and represents both a marker for reduced cellular methylation potential and elicitor of pathogenesis (Cattaneo, 1999). In addition to cofactors like folate, vitamin B6, B12, and B2, various bioactive compounds are believed to influence the same cellular processes either directly or indirectly (Strain et al., 2004). The isoflavone genistein exhibits estrogen-like properties and has been implicated in the prevention of various diseases, including those involving hyperhomocysteinemia (Marini et al., 2009). Genistein has been shown to stably alter DNA methyltransferase and histone acetyltransferase activities independently of folate (Dolinoy et al, 2006; Li et al., 2009). This study was conducted to determine if genistein could modulate one-carbon metabolism during diet-induced folate deficiency. Specifically, we aimed to determine whether genistein is able to prevent hyperhomocysteinemia caused by moderate folate deficiency and classify any changes in relevant enzyme function, including those related to transmethylation, remethylation, and transsulfuration pathways, as well as alterations in genomic DNA methylation patterns. Administration of genistein (300 mg/kg diet) reduced plasma homocysteine concentrations in rats fed a folate-deficient diet in three independent studies without consistent alterations in enzyme activity or expression. Attenuation of plasma homocysteine was similar and occurred independently across each study at 10, 24, and 59 d of supplementation. There were no differences in genomic DNA methylation patterns or measured hepatic transmethylation, remethylation, and transsulfuration enzymes as determined by analysis of enzyme expression and activity. Future research is warranted to determine the specific actions of genistein related to its ability to mediate one-carbon metabolism during moderate folate deficiency.
Article
Soy isoflavones are natural tyrosine kinase inhibitors closely associated with decreased morbidity and mortality of various tumors. The activation of tyrosine kinases such as ERBB2 is the mechanism by which cholecystitis transforms into gallbladder cancer (GBC), therefore, it is important to investigate the relationship between long-term exposure to soy isoflavones and the occurrence and progression of GBC. This case-control study (n = 85 pairs) found that the high level of plasma soy isoflavone—genistein (GEN) was associated with a lower risk of gallbladder cancer (≥326.00 ng/mL compared to ≤19.30 ng/mL, crude odds ratio 0.15, 95% CI 0.04–0.59; P for trend = 0.016), and that the level of GEN exposure negatively correlated with Ki67 expression in GBC tissue (n = 85). Consistent with these results, the proliferation of GBC cells was inhibited in the long-term exposure models of GEN in vitro and in vivo. The long-term exposure to GEN reduced the tyrosine kinase activity of ERBB2 and impaired the function of the PTK6-AKT-GSK3β axis, leading to downregulation of the expression of the MCM complex in GBC cells. In summary, long-term exposure to GEN associated with soy products intake might play a certain role in preventing GBC and even inhibiting the proliferation of GBC cells.
Article
Soybeans and their food products exist in the market in various forms, ranging from crude oils and bean meals to nutritious products (e.g. soy milk powers). With the availability of technologies for mass production of soy products and for enrichment of soy components (e.g. phospholipids, saponins, isoflavones, oligosaccharides and edible fiber), the nutritional values of soy products have been enhanced remarkably, offering the potential for functional food development. Among different bioactive components in soybeans, one important component is isoflavones, which have been widely exploited for health implications. While there are studies supporting the health benefits of isoflavones, concerns on adverse effects have been raised in the literature. The objective of this article is to review the recent understanding of the biological activities, adverse effects, and use of isoflavones in functional food development.
Chapter
Endocrine disrupters, chemicals that interfere with normal hormone activity, may get into foods by several different routes, including food-packaging materials, environmental pollutants, and natural plant components. Regulatory assessments of chemical effects on reproduction require research data on gamete production, fertilization, fetal development, postnatal sexual development, and potential transgenerational effects. Several validated assays exist to test for possible endocrine disruptive effects at these different stages. However, strategic tools are needed to assess epigenetic effects emerging during later life stages caused by endocrine disrupter exposure during fetal or pubertal development. Current efforts at Health Canada are addressing the need for the collection of robust data sets that support linkages between genomic/proteomic and in vivo apical end points, as well as the integration of such data to further enhance risk assessment including the characterization and management of the potential risks associated with endocrine disruptors in food.
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Objective: To investigate whether phytoestrogens (genistein and daidzein) alter in vitro decidualization of human endometrial stromal cells (ESCs). Design: Isolated primary ESCs were exposed to phytoestrogens and decidualized in vitro. Setting: Academic fertility center. Patient(s): Twenty fertile oocyte donors attending the IVI Valencia clinic. Intervention(s): Treatment of ESC with phytoestrogens at 0, 10, 20, 50, and 100 μM. Main outcome measure(s): The ESC proliferation was analyzed by MTS assay. In vitro decidualization was induced in the presence of phytoestrogens by medroxyprogesterone acetate/cyclic adenosine 3':5' monophosphate and evaluated by prolactin (PRL) ELISA and F-actin immunostaining. The Ki67 proliferative marker was analyzed by immunofluorescence. The ESC apoptosis was assessed by annexin V/propidium iodide detection using flow cytometry. Estrogen (ERβ) and P receptor (PR) localization were evaluated by immunofluorescence. Result(s): The ESC exposed to 0, 19, 20, 50, and 100 μM of genistein, daidzein, and genistein + daidzein showed a dose-dependent proliferation decrease. After 48-96 hours of culture, this reduction was significant in the presence of 50 μM of phytoestrogens versus 10 μM untreated ESC. The ESC decidualized in the presence of phytoestrogens did not rearrange their cytoskeletons and showed a significant decrease in PRL secretion compared with untreated decidualized ESCs (dESCs). However, phytoestrogens did not alter proliferative status or the percentage of viable/apoptotic cells in dESC compared with untreated dESC. During decidualization, phytoestrogens induced the same nuclear translocation of ERβ and PR as the control dESC. Conclusion(s): This study reveals that high doses of phytoestrogens could affect the in vitro decidualization process.
Chapter
Hundreds of anthropogenic chemicals occupy our bodies, a situation that threatens the health of present and future generations. This chapter focuses on endocrine disrupting compounds (EDCs), both naturally occurring and man-made, that affect the neuroendocrine system to adversely impact health, with an emphasis on reproductive and metabolic pathways. The neuroendocrine system is highly sexually dimorphic and essential for maintaining homeostasis and appropriately responding to the environment. Comprising both neural and endocrine components, the neuroendocrine system is hormone sensitive throughout life and touches every organ system in the body. The integrative nature of the neuroendocrine system means that EDCs can have multi-system effects. Additionally, because gonadal hormones are essential for the sex-specific organization of numerous neuroendocrine pathways, endocrine disruption of this programming can lead to permanent deficits. Included in this review is a brief history of the neuroendocrine disruption field and a thorough discussion of the most common and less well understood neuroendocrine disruption modes of action. Also provided are extensive examples of how EDCs are likely contributing to neuroendocrine disorders such as obesity, and evidence that they have the potential for multi-generational effects.
Article
Numerous studies have examined the association of soy isoflavones or soy-based food intake with the risk of uterine fibroids (UF), but the results are inconsistent. The purpose of this meta-analysis was to quantitatively assess whether high soy isoflavones intake is associated with an increased risk of UF. PUBMED and EMBASE databases were reviewed to screen for relevant published studies up to December 2018. Using key words of uterine fibroid and isoflavone, we identified 4 studies focusing on infancy intake and 7 studies evaluating intake during adulthood. The pooled odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated using a random-effect model. In addition, subgroup analyses and 2-stage random-effect dose-response were also performed. When comparing high vs low intake of soy isoflavones, we found that there were positive associations of UF among patients being fed soy formula during infancy (OR, 1.19; 95% CI, 0.99-1.43; P = .06) and with high consumption of soy-based foods in adulthood (OR, 2.50; 95% CI, 1.09-5.74; P = .03), respectively. Additionally, dose-response analysis showed the pooled ORs (95% CIs) of UF risk for low, moderate, and high intake of soy isoflavones were 1.00 (0.87-1.14), 1.08 (0.94-1.24), and 1.23 (0.99-1.53) when compared to occasional intake, respectively. Our findings suggest that high soy isoflavones or soy-based food intake during infancy and in adulthood is associated with an increased risk of uterine fibroids in premenopausal women. There is a need for large-scale prospective cohort studies using more accurate measurements of soy isoflavones to further ascertain our study findings.
Article
A 7-month-old female infant presented with failure to thrive. She was breastfed till 3 months of age, thereafter switched to soy-based milk formula. There was no history to suggest excess energy losses, recurrent infections or chronic diarrhoea. Three months after switching to exclusive soy-based milk formula, parents noticed significant enlargement of both breasts. Clinical examination was unremarkable except for enlargement of both breasts. None of the other secondary sexual characteristics were present. Initial blood investigations showed hyponatraemic hypokalaemic hypochloraemic metabolic alkalosis, which corrected after 2 days with intravenous hydration. The patient subsequently maintained normal electrolyte balance with recommended intake of cow’s milk-based standard formula milk. Further exploration of her soy-based milk revealed that it was low in sodium and calories, unsuitable for children. This was not a standard and approved infant soy-based formula milk. She achieved excellent weight gain and reduction of breast size on cessation of soy-based milk formula.
Chapter
Milk is the most important nutritional source for newborns and infants during the initial months of their lives. Breast milk is healthy for infants as it is easily digestible. Apart from its nutritional value, breast milk is known to have a positive impact on infants’ growth and development as it provides biochemical and immunological components including proteins, cytokines and hormones. Breast milk also decreases the risk of diarrhea, and morbidity from respiratory tract and urinary tract infections. In addition, breast feeding helps mothers to regain pre-pregnancy body weight and to return the uterus to its normal size and shape. In a few cases, however, breastfeeding is not possible due to conditions associated with the modern era such as malnutrition, the absence of the mother, insufficient lactation, food allergies and other maternal health issues. Because of these problems, infant milk formula may be preferred as an alternative, and is manufactured by industries to mimic the nutritional value of breast milk. Infant formulas, baby formulas or baby milk commonly use cow’s milk or soymilk as a base with added nutritional supplements. Nevertheless, infants fed with formula are at a higher risk from acute otitis media, asthma, type 1 and 2 diabetes, eczema, lower respiratory tract infections, sudden infant death syndrome (SIDS) and obesity. This article reviews human breast milk and problems associated with breast feeding, the need for infant formulas as an alternative form of nutrition, different types of infant formulas, the health benefits and risks of infant formulas, guidelines for the manufacture of infant formulas, and the global market.
Article
Genistein is naturally occurring in plants and binds to estrogen receptors. Humans are mainly exposed through diet, but the use of supplements is increasing as genistein is claimed to promote health and alleviate menopausal symptoms. We analyzed diverse uterine features in adult mice chronically fed genistein for different times. The luminal epithelium height was increased in females treated with 500 and 1000 ppm at PND 95, and the width of the outer myometrium was increased in females treated with 1000 ppm at PND 65 compared to that in controls. An increase in proliferation was noted in the inner myometrium layer of animals exposed to 300 ppm genistein at PND 185 compared to that in controls. Luminal hyperplasia was greater in the 1000 ppm group at PND 65, 95, and 185, although not statistically different from control. These results indicate that genistein may exert estrogenic activity in the uterus, without persistent harm to the organ.
Article
Soy-based foods are consumed for their health beneficial effects, implying that the population is exposed to soy isoflavones in the diet. Herein, male rats at 21, 35 and 75 days of age were maintained either on a casein control diet, soybean meal (SBM), or control diet supplemented with daidzin and genistin (G + D) for 14 days. Feeding of SBM and G + D diets decreased testicular testosterone (T) secretion regardless of age. Altered androgen secretion was due to decreased (p < 0.05) Star and Hsd17β protein in the testes and were associated with increased (p < 0.05) Lhβ and Fshβ subunit protein expression in pituitary glands. Second, male rats were fed either a casein control diet, control diet+daidzin, control diet+genistin, or control diet+genistin+daidzin (G + D). Compared to control, feeding of all isoflavone-containing diets decreased (p < 0.05) testicular T concentrations, and more so in the G + D diet group. Interestingly, (Esr1 and androgen receptor (Ar) protein and pituitary Fshβ with Lhβ subunit protein were increased (p < 0.05) by feeding genistin and G + D diets, but not the daidzin diet. However, daidzein and genistein both caused a concentration dependent inhibition (p < 0.05) of T secretion by Leydig cells in vitro with IC50 of 184 ηM and 36 ηM, respectively. Results demonstrated that altered testicular steroidogenic capacity and pituitary FSHβ and LHβ subunit expression due to soy-based diets result from specific actions by genistein and daidzein. Experiments to assess effects of isoflavone regulation of intratesticular androgen concentrations on male fertility are warranted.
Article
Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN’s developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 μg/mouse for PND 240 and 290, and 50 μg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.
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Isoflavones are phytoestrogen compounds with important biological activities, including improvement of cardiovascular health. This activity is most evident in populations with a high isoflavone dietary intake, essentially from soybean-based products. The major isoflavones known to display the most important cardiovascular effects are genistein, daidzein, glycitein, formononetin, and biochanin A, although the closely related metabolite equol is also relevant. Most clinical studies have been focused on the impact of dietary intake or supplementation with mixtures of compounds, with only a few addressing the effect of isolated compounds. This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus given to their effect on the determinants of blood pressure regulation. Isoflavones exert vasorelaxation due to a multitude of pathways in different vascular beds. They can act in the endothelium to potentiate the release of NO and endothelium-derived hyperpolarization factors. In the vascular smooth muscle, isoflavones modulate calcium and potassium channels, leading to hyperpolarization and relaxation. Some of these effects are influenced by the binding of isoflavones to estrogen receptors and to the inhibition of specific kinase enzymes. The vasorelaxation effects of isoflavones are mostly obtained with plasma concentrations in the micromolar range, which are only attained through supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal. Nonetheless, more studies are needed to better establish their safety profile and elect the most useful applications
Article
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Background: Phytoestrogens are non-endocrine, non-steroidal secondary derivatives of plants and consumed through plant-based diet also named as "dietary estrogens". The major sources of phytoestrogens are soy and soy-based foods, flax seed, chickpeas, green beans, dairy products, etc. The dietary inclusion of phytoestrogen based foods play a crucial role in the maintenance of metabolic syndrome cluster including obesity, diabetes, blood pressure, cancer, inflammation, cardiovascular diseases, postmenopausal ailments and their complications. In recent days, phytoestrogens are the preferred molecules for hormone replacement therapy. On the other hand, they act as endocrine disruptors via estrogen receptor mediated pathways. These effects are not restricted to adult males or females and identified even in development. Objective: Since phytoestrogenic occurrence is high at daily meal for most people from all over the world, they focused to study for its beneficiary effects towards developing pharmaceutical drugs for treating various metabolic disorders by keeping an eye on endocrine disruption. Conclusion: The present review emphasizes the pros and cons of phytoestrogens on human health, which may help to direct the pharmaceutical industry to produce various phytoestrongen based drugs against various metabolic disorders.
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Tyrosine-specific protein kinase activity of the epidermal growth factor (EGF) receptor, pp60v-src and pp110gag-fes was inhibited in vitro by an isoflavone genistein. The inhibition was competitive with respect to ATP and noncompetitive to a phosphate acceptor, histone H2B. By contrast, genistein scarcely inhibited the enzyme activities of serine- and threonine-specific protein kinases such as cAMP-dependent protein kinase, phosphorylase kinase, and the Ca2+/phospholipid-dependent enzyme protein kinase C. When the effect of genistein on the phosphorylation of the EGF receptor was examined in cultured A431 cells, EGF-stimulated serine, threonine, and tyrosine phosphorylation was decreased. Phosphoamino acid analysis of total cell proteins revealed that genistein inhibited the EGF-stimulated increase in phosphotyrosine level in A431 cells.
Article
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The identification (by gas chromatography-mass spectrometry and n.m.r.) for the first time of the weak oestrogen equol [7-hydroxy-3-(4'-hydroxyphenyl)chroman] in human urine is described. Preliminary results of its quantitative excretion in urine are reported and the potential significance of the occurrence of this compound is discussed.
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Plasma levels of the lignans enterodiol and enterolactone, and also the isoflavonic phyto-oestrogens daidzein, equol and genistein, are reported for postmenopausal Australian women consuming a traditional diet supplemented with linseed, soya flour or clover sprouts. Analysis was performed by gas chromatography-mass spectrometry, after enzymatic hydrolysis and ion-exchange chromatography. Following linseed supplementation, combined levels of enterolactone and enterodiol reached 500 ng/ml, whereas after soya flour or clover sprouts the respective concentrations of equol, daidzein and genistein reached 43, 312 and 148 ng/ml. Not all subjects were able to produce equol from daidzein. The possible relationship and role of these weak dietary oestrogens as restraining factors in the development of hormone-dependent cancers in Asian populations is discussed. Journal of Endocrinology (1994) 142, 251–259
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Soy isoflavones were quantified from human milk by a fast, precise, and selective HPLC method after enzymatic hydrolysis of conjugated isoflavones and extraction with ethyl acetate. Isoflavone aglycones and their mammalian metabolites equol and O-desmethylangolensin were separated selectively and identified by absorbance patterns, fluorometric and electrochemical detection, gas chromatography-mass spectrometric analysis after trimethylsilylation, and with internal and external authentic standards. HPLC injections of 20 microL of human milk showed detection limits of 1-3 pmol for all analytes by using diode-array detection. The detection limit could be improved by as much as 1000-fold by extended concentration through partitioning with ethyl acetate, by using electrochemical detection, by increasing the injection volumes, or by combining these techniques. We used the proposed method to monitor isoflavone concentrations in human milk and in human urine after challenge with 5, 10, and 20 g of roasted soybeans in the diet. Implications of the results for the potential of isoflavones to prevent cancer in newborn infants exposed to these agents are discussed.
Article
A method is described for the separation and analysis of isoflavone beta-glycoside conjugates and aglucones in various foods derived from soybeans. After initial extraction using 80% aqueous methanol and defatting of the extract with hexane, the isoflavones were analyzed by gradient elution reversed-phase high-pressure liquid chromatography. Their structures were confirmed by fast atom bombardment ionization mass spectrometry and by proton nuclear magnetic resonance spectroscopy. The results reveal that most Asian and American soy products, with the exception of soy sauce, alcohol-extracted soy protein concentrate, and soy protein isolate, have total isoflavone concentrations similar to those in the intact soybean. Asian fermented soy foods contain predominantly isoflavone aglucones, whereas in nonfermented soy foods of both American and Asian origin isoflavones are present mainly as beta-glycoside conjugates. Since the much larger estimated daily intake of these isoflavones by Asians compared to Americans is similar on a body weight basis to the isoflavones in soybean-containing diets which inhibit mammary tumorigenesis in animal models of breast cancer, it is possible that dietary isoflavones are an important factor accounting for the lower incidence and mortality from breast cancer in Asian women.
Article
A HPLC-MS procedure for the rapid, sensitive and specific measurement of the isoflavones, daidzein, dihydrodaidzein, O-desmethylangolensin and genistein, in human plasma has been developed. Synthetic radiolabeled genistein conjugates were used for evaluation of optimum conditions for solid phase extraction. Biochanin A was added to plasma as a recovery marker for isoflavones and phenolphthalein glucuronide and 4-methylumbelliferone sulfate were added to ensure completeness of hydrolysis with ß-glucuronidase/sulfatase. Isoflavones in plasma extracts were separated using an isocratic HPLC method and analyzed by negative ion multiple reaction ion monitoring-mass spectrometry using a heated nebulizer-atmospheric pressure chemical ionization interface. Using plasma samples from four subjects consuming two servings a day of an isolated soy protein beverage for 14 days, the mean plasma genistein and daidzein concentrations were 556 and 345 nM, respectively. Within assay and between assay coefficients of variation for measurement of daidzein and genistein in five aliquots of the same plasma sample were 8.51% and 7.76%, and 5.98% and 6.12%, respectively.
Article
The individual and total isoflavone content in commercial soybean protein products has been determined by high-performance liquid chromatography. Dehulled, defatted soybean flours contain the following mean isoflavone content (mg/100 g): daidzin, 61.7; glycitein 7-β-glucoside, 12.9; genistin, 119.8; daidzein, 32.8; genistein, 26.7. The same isoflavones were found in soybean protein concentrates and soybean protein isolates but in decreased amounts.
Article
Testosterone, estradiol, 170H-progesterone, and androstenedione (except in cord samples) concentrations were determined in cord sera (30 male and 14 female) and in peripheral sera from infants (121 male and 110 female), age 1 day to 2 years. Male and female cord serum levels of these steroids were not significantly different. In both sexes levels during the first week were lower than those in cord sera. In male infants serum testosterone and 170H-progesterone levels rose sharply in the second week of life, reached a peak at 1-2 months, and then declined to the range seen in later childhood by 6 months of age; male serum androstenedione and estradiol concentrations were higher during the first 2 months of life, but no distinct pattern of rise and fall was seen. In girls serum testosterone levels fell in the first week to the range seen throughout childhood; serum concentration of estradiol, androstenedione, and 17OH-progesterone in girls were markedly variable, with many values above the childhood range being seen, particularly in the first 6 months. These data provide further evidence of active Leydig cell function in male infants. They suggest that there is also ovarian secretion of sex steroids in some female infants in response to the elevated FSH and LH levels which are seen at this time.
Article
It is suspected that diet influences the risk of getting breast cancer. A study of diet and breast cancer was done among 200 Singapore Chinese women with histologically confirmed disease and 420 matched controls. A quantitative food-frequency questionnaire was used to assess intakes of selected nutrients and foods 1 year before interview. Daily intakes were computed and risk analysed after adjustment for concomitant risk factors. In premenopausal women, high intakes of animal proteins and red meat were associated with increased risk. Decreased risk was associated with high intakes of polyunsaturated fatty acids (PUFA), beta-carotene, soya proteins, total soya products, a high PUFA to saturated fatty acid ratio, and a high proportion of soya to total protein. In multiple analysis, the variables which were significant after adjustment for each other were red meat (p less than 0.001) as a predisposing factor, and PUFA (p = 0.02), beta-carotene (p = 0.003), and soya protein (p = 0.02) as protective factors. The analysis of dietary variables in postmenopausal women gave uniformly non-significant results. Our finding that soya products may protect against breast cancer in younger women is of interest since these foods are rich in phyto-oestrogens.
The isoflavonoid diphenol 3',7-dihydroxyisoflavan, an isomer of the known compound equol (4',7-dihydroxyisoflavan), has been identified in human urine and in cow's milk. The compound was isolated as the glucuronide, purified by column chromatography and identified after hydrolysis to the aglycon. The trimethylsilyl ether derivative was characterized by comparison of its mass spectrum and chromatographic properties with those of synthesized silylated isomers of equol.
Article
The cheetah in the wild is "racing towards extinction" mostly due to habitat destruction. Its survival will probably depend on accelerated captive breeding. At this time, however, reproductive failure and liver disease threaten the future of the captive cheetah population. Histopathological evaluation of more than 100 cheetah livers identified venocclusive disease as the main hepatic lesion responsible for liver disease in this species. Analysis of the commercial feline diet by high-performance liquid chromatography and gas-liquid chromatography-mass spectrometry revealed large amounts of two phytoestrogens identified as daidzein and genistein. These compounds were found to be derived from a soybean product that was a component of the cheetah diet, and their concentrations both ranged from 18 to 35 micrograms/g diet. The adult cheetah consequently consumes approximately 50 mg/day of these weak estrogens. When extracts of the diet were tested for estrogenicity using a bioassay, a dose-related increase in uterine weight was observed. In 4 cheetahs studied, withdrawal of this feline diet by substitution with a chicken diet resulted in an improvement in conventional liver function tests and a normalization in the appearance of hepatic mitochondria. We conclude that the relatively high concentrations of phytoestrogens from soybean protein present in the commercial diet fed to captive cheetahs in North American zoos may be one of the major factors in the decline of fertility and in the etiology of liver disease in this species. The survival of the captive cheetah population could depend upon a simple change of diet by excluding exogenous estrogen.
Article
The phytoestrogens daidzein, genistein, coumestrol, formononetin, and Biochanin A are separated on a C18 reversed-phase column (Hypersil ODS) with methanol-0.1 M ammonium acetate buffer, pH 4.6 (60:40, v/v) as eluent. The retention and resolution are affected by buffer concentrations, pH type, and proportion of organic solvent in the mobile phase. Detection in the (low pg range) is achieved with an electrochemical detector, and the compounds are positively identified by high-performance liquid chromatography-thermospray mass spectrometry. Daidzein and genistein were found in high concentrations in all soy protein preparations analyzed.
Article
Equol, a nonsteroidal estrogen of dietary origin, was recently identified in human urine, and is excreted in amounts comparable to the classical steroidal estrogens. We confirm here that phytoestrogens which are abundant in dietary soya protein are converted by human gastrointestinal flora to this weak estrogen. After the ingestion of meals containing cooked soya protein the urinary excretion of equol in four of six subjects studied increased by up to 1000-fold and this compound was the major phenolic compound found in the urine. These data also indicate that some subjects are unable to either produce or excrete equol despite the challenge of a diet containing soya. In view of the increasing use of commercial soya products in the diet and the capacity of human bacterial flora to synthesize this weak estrogen from the abundance of phytoestrogens in soya, the potential relevance of these observations to the diseases implicating steroid hormones is discussed.
Article
Urinary lignan and isoflavonoid excretion were examined in 11 men and 9 women consuming four nine-day controlled experimental diets: basal (vegetable free), carotenoid vegetable (carrot and spinach), cruciferous vegetable (broccoli and cauliflower), and soy (tofu and textured vegetable protein product). Three-day urine collections (Days 7-9) were analyzed for lignans and isoflavonoids with use of isotope-dilution gas chromatography-mass spectrometry. Urinary excretion of the lignans enterodiol and enterolactone was higher during the carotenoid and cruciferous vegetable diets than during the basal diet (p = 0.0001), suggesting that these vegetables may provide a source of mammalian lignan precursors. Urinary excretion of the isoflavonoids equol, O-desmethylangolensin, daidzein, and genistein was higher when subjects consumed soy diets than when they consumed the other test diets (p < 0.02). Gender differences in lignan excretion were observed. Men excreted more enterolactone (p = 0.006) and less enterodiol (p = 0.013) than women, implying a gender difference in colonic bacterial metabolism of lignans. There was no effect of gender on isoflavonoid excretion.
Article
The metabolic fate of the dietary isoflavones daidzein and genistein was investigated in human volunteers challenged with soya. Urinary diphenols, isolated by partition chromatography on Sephadex LH-20, were characterized and identified by profile capillary gas chromatography (GC) and electron ionization mass spectrometry (GC-EIMS) analysis of the trimethylsilyl ether (TMS) derivatives. Novel isoflavonic phytoestrogens found in the urine of volunteers were those of tetrahydrodaidzein, dihydrogenistein, 6'-hydroxy-O-demethylangolesin and 2-dehydro-O-demethylangolensin. Other known diphenols identified were those of equal, dehydrodaidzein, O-demethylangolensin, daidzein, genistein, glycitein, and the lignan enterolactone. Two other urinary isomers with a fragmentation pattern closely resembling that of the persilylated TMS ethers of cis/trans-isomers of tetrahydrodaidzein, were characterized based on the elucidation of fragments associated with the loss of a non-phenolic-OTMS functional group in ring-C. These are fragments presented in the persilylated mass spectra of isoflavan-4-ols and isoflav-3-ene-4-ols, demonstrated here by a combination of simple and tandem mass spectrometry study of the deuterated persilylated TMS ethers of dihydrodaidzein. In a similar study we also present the data on the structural identification and fragment elucidation of the keto/enol tautomers of the TMS ether derivatives of the dihydro derivatives of daidzein and genistein, observed in the urine of volunteers and considered probable products of the derivatization process. Finally, the GC and GC-MS data of two unknown isoflavonoids and that of a lignan-like compound are presented together with those of dihydrodaidzein, dihydrogenistein, tetrahydrodaidzein and 2-dehydro-O-demethylangolensin. The latter four were obtained here as products of small scale chemical synthesis in a preliminary study on the tentative identification of urinary isoflavonoids in human volunteers challenged with soya.
Article
Due to growing evidence suggesting that phytoestrogens might protect against various cancers, particularly against breast and prostate cancer, it is important to measure the exposure of populations to these compounds by determining levels in food and in human tissue or body fluids to assess the possible cancer protective properties of these agents. Therefore, we developed a simple and fast procedure to extract and simultaneously hydrolyze phytoestrogens and their conjugates from food items, and present a fast and selective high-performance liquid chromatography (HPLC) method for precise determinations of the most common dietary phytoestrogens genistein, biochanin-A, daidzein, formononetin, and coumestrol using flavone as internal standard. For the first time HPLC was applied to measure these phytoestrogens and their most abundant metabolites equol and O-desmethyl-angolensin from human urine. The proposed methodology has been evaluated for losses due to thermal degradation during extraction and hydrolysis and due to sample handling during the entire work-up including solid phase extraction, and values are given for inter- and intra-assay variability. We present isoflavonoid levels of most common peas and beans used in "western" and "eastern" diets and compare isoflavonoid and coumestrol levels of raw, canned, and cooked foods which can be used in future epidemiological studies. We also determined human urinary levels with our methodology comparing values before and after soybean intake.
Article
We have investigated the potential of genistein, an estrogenic component of soy, when administered neonatally, to manifest a protective effect against chemically induced mammary cancer. Female Sprague-Dawley rats were treated on Day 2, 4, and 6 postpartum with genistein or dimethylsulfoxide (vehicle). To induce mammary carcinogenesis, all animals were subsequently exposed on Day 50 postpartum to dimethylbenz(a)anthracene. Animals treated neonatally with genistein had increased latency and reduced incidence and multiplicity of mammary tumors compared with vehicle-treated animals. Cell differentiation studies in mammary whole mounts revealed that neonatal genistein treatment resulted in decreased numbers of terminal end buds and increased numbers of lobular structures. A precocious maturation of undifferentiated terminal end buds to more differentiated lobules may account for neonatal genistein treatment protecting against chemically induced mammary cancer.
Article
Dietary intake of soy is associated with a decreased risk of both hormone-dependent and hormone-independent cancers. It has been proposed that genistein, the predominant isoflavone in soy foods, is responsible for this effect. In this review, the potential mechanisms of action of genistein at the cellular level are critically examined to determine which are physiologically relevant. We concluded that (i) only those mechanisms requiring genistein concentrations below 5 micrograms/ml (18 microM) should be considered, and (ii) more emphasis should be placed on the effects of genistein on events in normal cells or those from the early stages of the cancer process.
Article
A low mortality from prostatic cancer is found in Japanese men consuming a low-fat diet with high content of soy products, a rich source of isoflavonoids. We therefore assayed four isoflavonoids in plasma of 14 Japanese and 14 Finnish men. The geometric mean plasma total individual isoflavonoid levels were 7 to 110 times higher in the Japanese than in the Finnish men. Genistein, a tyrosine kinase inhibitor, occurred in the highest concentration (geometric mean 276 nmol/L). We hypothesise that these high phyto-oestrogen levels may inhibit the growth of prostatic cancer in Japanese men, which may explain the low mortality from prostatic cancer in that country.
Article
International variations in cancer rates have been attributed, at least in part, to differences in dietary intake. Recently, it has been suggested that consumption of soyfoods may contribute to the relatively low rates of breast, colon, and prostate cancers in countries such as China and Japan. Soybeans contain a number of anticarcinogens, and a recent National Cancer Institute workshop recommended that the role of soyfoods in cancer prevention be investigated. In this review, the hypothesis that soy intake reduces cancer risk is considered by examining relevant in vitro, animal, and epidemiological data. Soybeans are a unique dietary source of the isoflavone genistein, which possesses weak estrogenic activity and has been shown to act in animal models as an antiestrogen. Genistein is also a specific inhibitor of protein tyrosine kinases; it also inhibits DNA topoisomerases and other critical enzymes involved in signal transduction. In vitro, genistein suppresses the growth of a wide range of cancer cells, with IC50 values ranging from 5 to 40 microM (1-10 micrograms/ml). Of the 26 animal studies of experimental carcinogenesis in which diets containing soy or soybean isoflavones were employed, 17 (65%) reported protective effects. No studies reported soy intake increased tumor development. The epidemiological data are also inconsistent, although consumption of nonfermented soy products, such as soymilk and tofu, tended to be either protective or not associated with cancer risk; however, no consistent pattern was evident with the fermented soy products, such as miso. Protective effects were observed for both hormone- and nonhormone-related cancers. While a definitive statement that soy reduces cancer risk cannot be made at this time, there is sufficient evidence of a protective effect to warrant continued investigation.
Article
The influence of a diet containing soy protein on the hormonal status and regulation of the menstrual cycle was examined in six premenopausal women with regular ovulatory cycles. Soy protein (60 g containing 45 mg isoflavones) given daily for 1 mo significantly (P < 0.01) increased follicular phase length and/or delayed menstruation. Midcycle surges of luteinizing hormone and follicle-stimulating hormone were significantly suppressed during dietary intervention with soy protein. Plasma estradiol concentrations increased in the follicular phase and cholesterol concentrations decreased 9.6%. Similar responses occur with tamoxifen, an antiestrogen undergoing clinical trial as a prophylactic agent in women at high risk for breast cancer. These effects are presumed to be due to nonsteroidal estrogens of the isoflavone class, which behave as partial estrogen agonists/antagonists. The responses to soy protein are potentially beneficial with respect to risk factors for breast cancer and may in part explain the low incidence of breast cancer and its correlation with a high soy intake in Japanese and Chinese women.
Article
Nutrient effects on cholesterol fractional synthesis rates (FSR) in infancy by stable isotope determination have not been studied. We hypothesized that FSR is significantly reduced with high dietary cholesterol and phytoestrogen intake and increased with low dietary cholesterol and phytoestrogen intake. We prospectively studied 33 term male infants exclusively fed human milk (high cholesterol, low phytoestrogen, n = 12), cow milk-based formula (low cholesterol, low phytoestrogen, n = 8), soy milk-based formula (zero cholesterol, high phytoestrogen, n = 7), or soy milk-based formula modified to contain cholesterol (low cholesterol, high phytoestrogen, n = 6) during the first 4 mo of life. Cholesterol FSR was determined from rate of incorporation of deuterium into erythrocyte membrane cholesterol, and urinary isoflavone excretion (an index of dietary phytoestrogen exposure) was measured by gas chromatography-mass spectrometry. Significant differences in cholesterol FSR were found. FSR (%/d) was lowest in human milk (2.62 +/- 0.38), highest in soy milk-based formula (9.40 +/- 0.51), and intermediate in cow milk-based and modified soy milk-based formula (6.90 +/- 0.48 and 8.03 +/- 0.28, respectively), p < 0.0001. Cholesterol FSR was significantly lower in modified soy milk-based compared with soy milk-based formula, p < 0.05. We also show for the first time that dietary phytoestrogens are absorbed and excreted by the infant fed soy protein-based formula. Urinary isoflavone excretion was inversely related to cholesterol FSR, but it was not significantly related to serum cholesterol concentration. We conclude that the type of infant nutrition and dietary cholesterol are major factors influencing cholesterol fractional synthesis rates in infancy.
Article
Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that the Western diet, compared to a vegetarian or semivegetarian diet, may alter hormone production, metabolism, or action at the cellular level by some biochemical mechanisms. Recently, our interest has been mainly focused on the cancer-protective role of some hormonelike diphenolic phytoestrogens of dietary origin, the lignans and the isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids), whole grain cereal food, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormonelike compounds with weak estrogenic but also antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, and angiogenesis in a way that makes them strong candidates for a role as natural cancer-protective compounds. Epidemiologic investigations strongly support this hypothesis because the highest levels of these compounds in the diet are found in countries or regions with low cancer incidence. This report is a review on recent results suggesting that the diphenolic isoflavonoids and lignans are natural cancer-protective compounds.
Soy intake and cancer risk: a review of the in vitro and in vivo data
  • Messina
Japanese swallow western diseases
  • P Hadfield