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[Cancer Research 61, 4325-4328, June 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Uterine Adenocarcinoma in Mice Treated Neonatally with Genistein

Retha R. Newbold1, Elizabeth Padilla Banks, Bill Bullock and Wendy N. Jefferson

Developmental Endocrinology Section, Laboratory of Toxicology, Environmental Toxicology Program, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [R. R. N., E. P. B., W. N. J.], and Department of Pathology, Wake Forest University School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157 [B. B.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The developing fetus is uniquely sensitive to perturbation with estrogenic chemicals. The carcinogenic effect of prenatal exposure to diethylstilbestrol (DES) is the classic example. Because phytoestrogen use in nutritional and pharmaceutical applications for infants and children is increasing, we investigated the carcinogenic potential of genistein, a naturally occurring plant estrogen in soy, in an experimental animal model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal DES exposure. Outbred female CD-1 mice were treated on days 1–5 with equivalent estrogenic doses of DES (0.001 mg/kg/day) or genistein (50 mg/kg/day). At 18 months, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation. Thus, the use of soy-based infant formulas in the absence of medical necessity and the marketing of soy products designed to appeal to children should be closely examined.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Studies in our laboratory have shown long-term consequences of exposure to estrogens during critical periods of development (1) . In particular, DES,2 a potent synthetic estrogen, has been shown to cause adverse reproductive effects including structural abnormalities, infertility, and neoplasia after prenatal exposure (2) . Furthermore, mice treated neonatally with 2 µg/pup/day (1000 µg/kg/day) DES on days 1–5 have a 90–95% incidence of uterine carcinoma at 18 months of age (3) . The background incidence of this lesion is rare in this strain of mouse (3) . The naturally occurring phytoestrogen, genistein, is found in many soy products. Humans may be exposed to high levels of genistein during development through soy-based infant formulas and soy products marketed specifically for children (4) . The concentrations of genistein and other isoflavones found in some of these soy formulas can far exceed the amount found in an adult diet (4) . Infants consuming a diet of soy-based formula may be exposed to ~20–40 mg per day (4–6 mg/kg/day) of soy isoflavones, of which genistein makes up >65%, whereas adults consuming a moderate to large amount of soy in the diet are exposed to ~1 mg/kg/day soy isoflavones (4) . Earlier reports suggested beneficial effects of genistein exposure early in life, e.g., breast cancer prevention (5 , 6) and improved cholesterol synthesis rates (7) , but an increasing number of reports are now describing long-term deleterious effects of genistein (8) and of another phytoestrogen, coumestrol (9 , 10) . One recent report showed an increase in carcinogen-induced mammary carcinogenesis after prenatal exposure of rats to genistein (11) , and another associated a diet high in phytoestrogens with the development of insulin-dependent diabetes (12) . Still another report highlighted the increased incidence of hypospadias in male offspring of vegetarian mothers (13) . To further study the effects of phytoestrogen exposure early in life, we treated mice neonatally with genistein or an equivalent estrogenic dose of DES and determined the long-term carcinogenic potential.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Animals.
Adult female CD-1 [Crl:CD-1 (ICR) BR] mice were obtained from Charles River Breeding Laboratories (Raleigh, NC) and bred to male mice of the same strain in the breeding facility at the NIEHS (Research Triangle Park, NC). Vaginal plug detection was considered day 0 of pregnancy. Pregnant mice were individually housed in plastic cages with hardwood chip bedding under controlled lighting (12 h light and 12 h dark) and temperature (21–22°C) conditions. Mice were fed NIH 31 mouse chow, which contained a moderately low amount of genistein (46 µg/g; Ref. 14 ) and fresh water ad libitum. All animal procedures complied with NIEHS/NIH animal care guidelines. At delivery, pups from all litters were pooled, then separated by sex, and standardized to eight female pups per dam. Dams with male pups were used in another experiment.

Comparison of the Estrogenicity of Genistein and DES in Neonatal Pups.
Female pups were given daily s.c. injections of genistein or DES dissolved in corn oil or of corn oil alone (as control) on days 1–5 of neonatal life. A minimum of eight pups per compound was used. On the afternoon of day 5, mice were killed and body weights and uterine weights recorded. Data are expressed as percentage uterine weight increase over values in corn oil-treated control mice. A dose response for genistein has been previously reported in the immature mouse uterotropic bioassay (15) .

Tumor Induction.
Female pups were treated by daily s.c. injections on days 1–5 with genistein (50 mg/kg) or DES (0.001 mg/kg) dissolved in corn oil or with corn oil alone (as control). These doses are ~100 µg/pup/day genistein and 0.002 µg/pup/day DES and are equal in estrogenic potency. Mice were weaned on day 21 and housed four per cage. Mice were killed by cervical dislocation at 18 months of age. Reproductive tract tissues were removed, fixed in 10% neutral buffered formalin, embedded in paraffin, and sectioned at 6 µm. Tissue sections were stained with H&E and evaluated by light microscopy. If a microscopic lesion was observed, additional serial sections were made to include the entire area of pathological change.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Comparison of Hormonal Activity of DES and Genistein in the Neonate.
Genistein (50 mg/kg/day) and DES (0.001 mg/kg/day) induced a 202% and 190% gain in uterine weights, respectively, compared with control animals treated with corn oil (Table 1)Citation . Both compounds caused a significant increase in uterine wet weight compared with controls from this experiment by Fisher’s exact test.


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  		Table 1 Uterotropic bioassay in day-5 mice treated neonatally with DES or with genistein

 
Reproductive Tract Abnormalities.
A comparison of reproductive tract abnormalities observed in mice treated neonatally on days 1–5 with Genistein or DES is shown in Table 2Citation . At 18 months of age, cystic ovaries were common in all of the treatment groups (46% in controls, 41% in the genistein group, and 58% in the DES group). Corpora lutea were absent in 100% (17 of 17) of the genistein-treated mice, whereas only 33% (4 of 12) of the DES-treated mice lacked corpora lutea. All 13 of the control mice had corpora lutea. In the DES-treated mice, 17% (2 of 12) had ovarian stromal tumors; ovarian tumors were not seen in the control or genistein-treatment group.


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  		Table 2 Incidence of benign and malignant abnormalities in 18-month-old mice treated neonatally with DES or with genistein

 
Abnormalities in the oviduct were seen in both the DES and genistein treatment groups in this study (Table 2)Citation . As described previously with DES (16) , the pattern of tubal plications of oviductal mucosa was distorted and characterized by lack of plications or by irregularities in the size and shape of the mucosal folds relative to the control animals. The mucosal folds had an adenomatous (gland-like) appearance but maintained connection with the oviductal lumen. This abnormality in proliferation was termed PPL in DES-treated animals (16) because it did not spread along the serosal surface nor metastasize. In this study, sections were not always available through the entire length of the oviduct for each animal, but PPL was observed in 50% (5 of 10) of the available sections of DES-treated mice, whereas all (14 of 14) of the genistein-treated mice had this abnormality.

The range of uterine abnormalities in the uteri of mice exposed neonatally to genistein or DES is also shown in Table 2Citation . The incidence of CEH of the uterus was similar in both DES- and genistein-treatment groups [54% (7 of 13) and 47% (8 of 17), respectively]. A low incidence of CEH occurred in the control mice in this study [19% (3 of 16)]. Squamous metaplasia of the uterus occurred in 38% (5 of 13) of the DES and 64% (11 of 17) of the genistein groups. In addition to these uterine lesions, more severe pathologies occurred after neonatal exposure to both compounds. Atypical hyperplasia of the uterus occurred in 5% (1 of 17) of the genistein-treated mice. Furthermore, some animals had cellular alterations that progressed to uterine adenocarcinoma (Fig. 1, A and B)Citation . These tumors were usually well differentiated and characterized by irregularly shaped glands with little intervening stroma. Some lesions extended through the myometrium to the serosal surface of the uterus. Nuclear pleomorphism and mitotic figures were frequently observed. In genistein-treated mice, 35% (6 of 17) developed this tumor, and at the approximate equal estrogenic dose of DES, 31% (4 of 13) had uterine adenocarcinoma; there were no cases of uterine adenocarcinoma in any controls in this study.



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  		Fig. 1. A, well-differentiated invasive uterine adenocarcinoma in an 18-month-old mouse treated neonatally with genistein (100 mg/kg/day) on days 1–5 of life. Neoplastic endometrial tissue is present between strands of smooth muscle. There are irregularly shaped glands with little intervening stroma and eosinophilic material in the lumen (arrow). (H&E; bar, 0.5 mm.) B, higher magnification of uterine adenocarcinoma in an 18-month-old mouse treated neonatally with genistein (100 mg/kg/day). There are irregularly shaped glands, many with eosinophilic material in the lumen (arrow). Some irregularly shaped endometrial glands are packed together between bundles of smooth muscle (arrowheads). (H&E; bar, 0.5 mm.)

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
This report describes the induction of benign and malignant lesions of the reproductive tract, including uterine adenocarcinoma in the reproductive tract of mice treated neonatally with the phytoestrogen genistein. Similar malignant lesions have never been observed in control mice of this strain in our laboratory. The dose of genistein used in this study is within the range to which humans may be exposed in soy-based infant formulas (4) . In addition, mice exposed to a dose of DES that is approximately equal in estrogenic activity gave similar incidences of uterine adenocarcinoma under the same treatment conditions. The association of estrogenicity and carcinogenicity in the neonate is further supported by the results of another study from our lab that compared metabolites of estradiol (17) ; based on the day-5 uterotropic bioassay, compounds with the highest estrogenic potency in the neonatal mouse uterus showed the highest percentage of uterine adenocarcinoma after neonatal exposure. The data shown in this report shows a close association between the estrogenic activity of the compound in the neonate and the incidence of uterine adenocarcinoma after neonatal exposure.

Of particular significance in this study is the incidence of uterine adenocarcinoma after neonatal exposure to genistein. This compound is readily available to many infants during the first year of life as a component of soy-based formulas. The amount of soy isoflavones found in some infant formulas, of which genistein and its conjugates account for >65%, approaches 40 mg/liter of formula (4) . An infant consuming 1 liter of soy-based infant formula would ingest ~27 mg of genistein per day. The amount of genistein used in our study (50 mg) is slightly higher than the amount consumed by infants, but it is certainly within one order of magnitude of the level of human exposure. We are currently evaluating the carcinogenic potential of lower doses of genistein as well as investigating the effects of genistein if exposure occurs through the diet instead of s.c. injection as described in this study.

In another report from our laboratory, lower doses of genistein caused alterations in the ovary such as multioocyte follicles (18) ; a dose-related increase in multioocyte follicles starting at a dose of 5 mg/kg/day was observed in 2-month-old mice. Previous work by Iguchi et al. (19) has shown that multioocyte follicles resulting from neonatal DES exposure are less fertile than single oocyte follicles. This data suggest that fertility could also be affected in mice exposed neonatally to genistein. Future studies in our laboratory will investigate fertility in genistein-treated mice as well as mechanisms involved in the formation of multioocyte follicles.

The findings of the present study raise concerns over the amount of phytoestrogens in soy-based infant formulas and other soy-based products that are fed to young children. Additional studies are needed to determine the potential effects in humans exposed to high quantities of phytoestrogens during critical stages of neonatal or early development. Ongoing National Toxicology Program (NTP) studies designed to address multigenerational effects of genistein,3 will help to determine the risks of developmental exposure to genistein and other endocrine-disrupting chemicals. The potential risks and benefits need to be thoroughly assessed to determine the appropriate balance of exposures of these chemicals during development and the permanent effects that may follow.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at National Institute of Environmental Health Sciences, MD E4-02, P. O. Box 12233, Research Triangle Park, NC 27709. Phone: (919) 541-0738; Fax: (919) 541-4634; E-mail: newbold1{at}niehs.nih.gov Back

2 The abbreviations used are: DES, diethylstilbestrol; NIEHS, National Institute of Environmental Health Sciences; PPL, progressive proliferative lesion; CEH, cystic endometrial hyperplasia. Back

3 B. Delclos and R. R. Newbold. Dose range studies ofgenistein in the rat, submitted for publication. Back

Received 2/ 6/01. Accepted 4/ 3/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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L. R. Goldman, R. Newbold, S. H. Swan, B. L. Strom, R. Schinnar, K. T. Barnhart, M. D. Sammel, G. A. Macones, and V. A. Stallings
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