Diverse animal models to examine potential role(s) and mechanism of endocrine disrupting chemicals on the tumor progression and prevention: Do they have tumorigenic or anti-tumorigenic property?

Min-Ah Park; Kyung-A Hwang; Kyung-Chul Choi

doi:10.5625/lar.2011.27.4.265

Journal List > Lab Anim Res > v.27(4) > 1053684

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Park, Hwang, and Choi: Diverse animal models to examine potential role(s) and mechanism of endocrine disrupting chemicals on the tumor progression and prevention: Do they have tumorigenic or anti-tumorigenic property?

Review

Laboratory Animal Research 2011; 27(4): 265-273.

Published online: 19 December 2011

DOI: https://doi.org/10.5625/lar.2011.27.4.265

Diverse animal models to examine potential role(s) and mechanism of endocrine disrupting chemicals on the tumor progression and prevention: Do they have tumorigenic or anti-tumorigenic property?

Min-Ah Park, Kyung-A Hwang, Kyung-Chul Choi

Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea.

Corresponding author: Kyung-Chul Choi, Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, 52 Naesudongro (Gaesin-dong), Cheongju, Chungbuk 361-763, Korea. Tel: +82-43-261-3664; Fax: +82-43-267-3150; kchoi@cbu.ac.kr

Received 8 November 2011 Revised 26 November 2011 Accepted 2 December 2011

(open-access, http://creativecommons.org/licenses/by-nc/3.0):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Acting as hormone mimics or antagonists in the interaction with hormone receptors, endocrine disrupting chemicals (EDCs) have the potentials of disturbing the endocrine system in sex steroid hormone-controlled organs and tissues. These effects may lead to the disruption of major regulatory mechanisms, the onset of developmental disorders, and carcinogenesis. Especially, among diverse EDCs, xenoestrogens such as bisphenol A, dioxins, and di(2-ethylhexyl)phthalate, have been shown to activate estrogen receptors (ERs) and to modulate cellular functions induced by ERs. Furthermore, they appear to be closely related with carcinogenicity in estrogen-dependant cancers, including breast, ovary, and prostate cancers. In in vivo animal models, prenatal exposure to xenoestrogens changed the development of the mouse reproductive organs and increased the susceptibility to further carcinogenic exposure and tumor occurence in adults. Unlike EDCs, which are chemically synthesized, several phytoestrogens such as genistein and resveratrol showed chemopreventive effects on specific cancers by contending with ER binding and regulating normal ER action in target tissues of mice. These results support the notion that a diet containing high levels of phytoestrogens can have protective effects on estrogen-related diseases. In spite of the diverse evidences of EDCs and phytoestrogens on causation and prevention of estrogen-dependant cancers provided in this article, there are still disputable questions about the dose-response effect of EDCs or chemopreventive potentials of phytoestrogens. As a wide range of EDCs including phytoestrogens have been remarkably increasing in the environment with the rapid growth in our industrial society and more closely affecting human and wildlife, the potential risks of EDCs in endocrine disruption and carcinogenesis are important issues and needed to be verified in detail.

Keywords: Endocrine disrupting chemicals, estrogen, cancer progression, estrogen receptor

Chemicals known to have a potential to disrupt the endocrine or hormone system in humans and wild animals by affecting endocrine signals are classified as endocrine disrupting chemicals (EDCs) [1]. Originally, EDCs are defined by the U.S. Environmental Protection Agency (EPA) as exogenous agents that interfere with synthesis, secretion, transport, metabolism, binding, action or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction and developmental process [2]. EDCs are contained in a variety of chemical classes, including drugs, pesticides, compounds used in the plastic industry, consumer products, industrial by-products and pollutants, and even some naturally produced botanical chemicals. They have been remarkably increasing in the environment with the rapid growth in these industries [3] and therefore, human and animals are sustainedly exposed to a wide variety of EDCs [4]. Health effects attributed to EDCs include a range of reproductive problems such as reduced fertility, male and female reproductive tract abnormalities, skewed male/female sex ratios, loss of fetus, and menstrual problems [5]. Specifically, EDCs have been generally supposed to affect sex steroid hormone-controlled organs and tissues in the reproductive tract through nuclear hormone receptors, such as estrogen receptors (ERs), androgen receptors (ARs), progesterone receptors (PRs) and thyroid receptors (ThRs) [2,6]. Among these receptors, estrogen-mimicking activities through ERs of some EDCs were first proved to cause endocrine disruption in the 1950s and these EDCs are generally called as 'xenoestrogens'. Xenoestrogens mean "foreign" estrogens having estrogenic effects on a living organism even though they differ chemically from the estrogenic substances internally produced by the endocrine system of the organism. Usually, xenoestrogens may act as false messengers and mainly disrupt the reproduction process related with endogeneous estrogen. Diethylstilbestrol (DES), alkylphenols (APs), bisphenol A (BPA), polychlorinated biphenyls (PCBs) and phthalates are representative xenoestrogens having similar structures to 17β-estradiol (E2) in EDCs. Starting in the 1990s, extra mechanisms related with other hormonal system were found in the endocrine disruption of industrial compounds. For instance, the disruption of thyroid hormone transport and the altered androgen antagonism were identified in the actions of other EDCs [7]. As a result of the endocrine disruption via several pathways, EDCs may cause hormone imbalance, early puberty, brain and behavior problems, impaired immune functions and various cancers [8]. When it comes to cancer, E2 itself is also known as one of risk factors in tumorigenesis of the estrogen-dependent organs, such as endometrium, breast, and ovary [4,6]. Therefore, xenoestrogens as estrogen mimics may increase the potential for cancer lesions by transforming normal patterns of tissue and interrupting dominant regulatory mechanisms in the estrogen dependent organs. Meanwhile, unlike most chemically synthesized EDCs, some phytoestrogens, which are produced as secondary metabolites in some plants and act as estrogen in animals [9,10], are known to have cancer chemopreventive effects. According to previous reports, high level diets of phytoestrogen may have protective effects on estrogen-related diseases, such as prostate and breast cancers [9,11]. In this respect, this review will focus on not only the xenoestrogenic properties of various EDCs and their carcinogenic potentials but the preventive effects of phytoestrogens on estrogen-dependant cancers substantiated from the in vivo studies. Until now, the roles of EDCs in carcinogenesis have been reviwed mainly focusing on the causation of specific cancers like mammary cancer by well known EDCs such as DES and BPA [7,12,13]. But, this review will be anticipated to provide a comprehensive point of view to understand cancer causation and prevention by various EDCs.

EDCs have estrogen-like properties via ERs signaling pathway

17β-Estradiol

E2 is an endogenous female sex steroid hormone and very important in the estrous cycle and the development of reproductive organs in human and animals. As a hormone binding to its receptor triggers a number of events, E2 preferentially binds to ERs. ERs are expressed in the estrogen-dependent organs such as endometrium, breast and ovary [14,15]. There are two forms of ERs, ERα and ERβ, which play unique physiological roles depending on the tissue and cell types [13]. ERs are activated by binding E2 and in turn modulate the expression of many related genes via ERs signaling pathways [16]. The genomic pathway is a well known classical pathway of ERs signaling and mediates target gene regulation via direct binding to an estrogen response element (ERE), which is a specific DNA sequence within the promoter, of an estrogen-ER complex [17-19]. The ERE/receptor complex then recruits other transcription factors that are responsible for the transcription of downstream target genes and finally induces protein synthesis. As a result, this pathway promotes the development of female secondary sexual characteristics and is involved in the thickening of the endometrium and in regulating the menstrual cycle.

Endocrine disrupting chemicals

Generally, as EDCs have similar structures to E2, they may exhibit an estrogenic activity through the interaction with ERs like E2. Though the binding affinities of EDCs are relatively low compared to E2, they can activate ERs and regulate cellular functions induced by ERs [3]. For instance, by way of the genomic pathway, EDCs mediate the expression of many genes through direct interaction with ERE or through interaction with transcription factors, including members of activator protein-1 (AP-1), nuclear factor-κB (NF-κB), signal transducer and activator of transcription (STATs), and families of specificity protein (SP-1), especially aryl hydrocarbon receptor (AhR), or via modification of estrogen metabolism [2,20]. In the previouse studies, the xenoestrogenic effects and the risks of endocrine disruption of diverse chemicals have been identified. The disruption effects of some well-known EDCs on estrogen signaling pathways by their xenoestrogenic properties are as in the following.

First, DES is a potent synthetic estrogen and a drug once prescribed during pregnancy to prevent miscarriages or premature deliveries from the 1940s to 1970s [21,22] and now classified as a representative harmful xenoestrogen by interacting with ERs with very high affinity and influencing genomic signaling [22,23]. Alkylphenols (APs) are common chemicals used to make alkylphenol ethoxylate surfactants in household detergents and personal care products and widely used as plasticizers and chemical stabilizers in various industries [24]. Nonylphenol (NP) and octylphenol (OP) are typical forms of APs and easily discharged through sewage disposal works [25]. APs bind ERα and prompt ligand-dependent gene expression via ERE promoter. Also, APs can reduce steroidgenesis and disrupt endocrine system via ER indirect pathways [26,27]. While they have been used in industry for over 40 years, the European Union has implemented sales and use restrictions on certain applications in which nonylphenols are used because of their alleged "toxicity, persistence, and the liability to bioaccumulate" [28]. BPA is one of the EDCs that has been the most completely studied. Because BPA is used in many consumer goods such as baby bottles, beverage cans, dental sealants and other many kinds of plastics, it has the highest opportunity to be exposed to the environment [29]. A 2011 study that investigated the number of chemicals pregnant women are exposed to in the U.S. found BPA in 96% of women [30]. The binding affinity of BPA to ERs is lower than E2 or DES, but BPA has been interacting with the ERs in a way that is completely unique in all known classes of ER ligands. BPA functions as a xenoestrogen by binding strongly to estrogen-related receptor γ (ERR-γ) which is an orphan receptor (endogenous ligand unknown) that behaves as a constitutive activator of transcription [31]. Also, BPA has been exhibited to interact with the ERs as a partial agonist with both AF-1 (ligand-independent activation) and AF-2 (ligand-dependent activation) [32,33].

Dichlorodiphenyl-trichloroethane (DDT) is one of the most well-known synthetic pesticides and is most commonly known among the EDCs. DDT is mainly metabolized to 1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene (DDE) and their effects have been widely studied [34,35]. DDE can activate multiple receptors such as ERα, AR, and PR and transcription factors and intrude on estrogen biosynthesis by increasing an aromatase activity, the key enzyme for catalyzing the rate-limiting step in the transformation of androgens into estrogen [36].

PCBs were widely used as dielectric and coolant fluids in transformers, capacitors, and electric motors. As omnipresent and persistant in the environment, they may cause the health problems in humans and wildlife such as disorders in reproductive, nervous, immune and endocrine system [37]. Concerns about the toxicity of PCBs are largely based on the similarity in chemical structure and toxic mode of action with dioxin. As one of EDCs, many parts of their effects are known to be ER-mediated by acting as estrogen mimics or as estrogen antagonists [37,38].

Phthalates are a class of chemicals widely known as plasticizers in personal-care products, children's toys, pharmaceuticals, food products, and textiles and so on. Dibutylphthalte (DBP), butyl benzyl phthalate (BBP), and di(2-ethylhexyl)phthalate (DEHP) are typical forms of phthalates. Recent studies report that several phthalates affect the developmental process in animals such as a significant increase in the number of aberrations in chromosome separations in oocytes at anaphase in various aquatic organisms and the alterations in gonadal development and spermatogenesis in amphibians [39-42] and also cause the developmental problems in human like a shortened anogenital distance among baby boys [43]. In addition, the exposure of phthalates was associated with mental, motor, and behavioral development problem in children and was harmful for formation of genital tract in both male and female [44,45]. In ligand binding assays, phthalates were shown to weakly compete with E2 for binding ER and to have weak ER-mediated activity [46]. In addition, fetal male rats exposed to DBP or DEHP ostensibly showed the deformities in androgen-dependent tissues in sexual differentiation in vivo by a non-receptor mediated mechanism [47].

EDCs have potential effects of carcinogenesis

Estrogen-dependent cancers

Regarding the carcinogenicity, previous studies of EDCs have described that developmental exposure to xenoestrogens can transform normal patterns of tissue, and these mutations may interrupt dominant regulatory mechanisms and improve the potential for cancer lesions [48,49]. Especially, the xenoestogens can be risk factors to estrogen dependant cancers such as breast, ovary and prostate cancers. Breast cancer is a multifactorial disease of humans and other mammals and is highly dependent on sex and the level of sex hormones such as estrogen and progesterone [50]. Therefore, breast cancer has relevance to exposure of exogeneous EDCs as well as endogeneous hormone level. Many epidemiological studies searched the relation between the exposure to EDCs and breast cancer [51,52]. For instance, women exposed to DES during pregnancy showed a modest increase in the incidence of breast cancer risks. Daughters born after in utero exposure to DES have shown the more development of breast cancer after the age of 40 when compared to unexposed women of the same age [53,54]. Ovarian cancer is a cancer arising from the ovary of women and most ovarian cancers are classified as "epithelial" believed to arise from the surface of the ovary. For ERs in normal condition, ERβ is highly expressed in granulose cells of the ovary, whereas ERα is expressed at relative low levels in thecal and interstitial cells. Several studies have reported that ERα is overexpressed in ovarian cancer compared to normal tissue and promotes the proliferation of cancer cells [6,55]. Prostate cancer is also a hormone-responsive cancer developing in the male reproductive system. Although prostate cancer is highly dependent on adrogens, estrogens also play a role in prostate cancer pathogenesis. ERα and ERβ are originally expressed in different cell types in prostates; ERα is mainly expressed in stroma and ERβ in epithelium. These two receptors are thought to play different and opposing roles in prostate cancer with ERα having proliferative properties and ERβ having anti-proliferative properties [56]. But other studies suggest that ERβ is highly expressed in the prostate and may be a susceptible target for treating prostate cancer lesions [57,58].

Carcinogenic effects of EDCs in in vivo animal models

Generally, prenatal exposure to EDCs can change the development of the mouse mammary gland and increase the susceptibility to further carcinogenic exposure in the adults. For example, mammary specific alterations due to early life BPA exposure have been identified by several studies, in which administrating low concentrations (25-1,000 µg/kg/day) of BPA via subcutaneously implanted osmotic pumps have shown the alterations to mammary gland morphology in adult animals following perinatal exposure to BPA in mice [59]. In rats, perinatal exposure to environmentally relevant doses of BPA enhanced the number of intraductal hyperplasias that occurs in adulthood, altered mammary gland morphogenesis at high doses, and induced precancerous lesions and the development of carcinomas in situ [60]. Exposure to BPA for 50 days in feeding period showed an increased number of dimetylbenz [a]anthracene (DMBA)-induced tumors per rat and a decreased latency period compared to animals not exposed to BPA [61]. At puberty, an enhanced sensitivity to estrogen was shown in the mammary glands of animals exposed to BPA, which led to increased duct lateral branching [62]. Additionally, ERα and PR overexpression was shown in the endometrial epithelium and lamina propria of adult mice that were exposed to BPA in uterus [63]. BPA was also shown to enhance the expression of vascular endothelial growth factor (VEGF) in the immature rat at 37 mg/kg of the lowest active dose [64]. When VEGF is overexpressed, it can contribute to cancer to grow and metastasize. Also, the vascular permeability in uterus of ovariectomized mice was increased by BPA [65].

For dioxins, its metabolite, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is reported to be strongly involved in carcinogenesis. Prenatal exposure to TCDD had shown a significant interference in mammary gland differentiation and morphogenesis as a greater number of terminal end buds [66]. In mice, TCDD blocks estrogen-induced responses in several tissues [67]. Exposure of rats to the carcinogen, dimetylbenz[a]anthracene (DMBA), at puberty enhanced the tumor occurrence and reduced the latency period as compared to animals not exposed to TCDD [68,69].

DEHP, a typical phthalate, is known as a peroxisome proliferator and a anticipated human carcinogen because it induces 5- to 10-fold dose-related increase in liver tumor proliferation in both sexes of rats and mice [70,71]. DEHP was also identified to have estrogenic response in uterotrophic and vaginal cornification assay [72]. Also, in immature ovariectomized SD rats, DEHP caused the significant growth in uterine weight by oral injection (20, 200 or 2,000 mg/kg) [73].

Chemopreventive effects of phytoestrogens in in vivo animal models

Phytoestrogens are poly-phenolic non-steroidal substances such as isoflavonodis, flavonoids, stilbenes and lignans. Many phytoestrogens are shown to have estrogenic effects by selectivity binding ERβ in competitive ER binding and transcriptional assay [74]. Several animal studies showed that phytoestrogens contended with estrogen in ERs binding and regulated normal ERs action in target tissues [75,76]. As the most examined phytoestrogen, genistein is an isoflavone present in much higher quantities in human diet and in serum when compared to endogenous estrogen, E2. Many studies have shown that genistein is able to binding to both of the ERs, has 20-fold expanded affinity to ERβ as compared with ERα and has more mighty transcriptional activity in cells transfected with ERβ [77-79]. In the respect of cancer prevention, genistein has been shown to inhibit cell growth in breast and prostate cancers by regulating genes responsible for the cell proliferation, cell cycle, apoptosis, and transcriptional regulations [12]. In the molecular level, exposure of genistein reduced mRNA level of transforming growth factor-α (TGF-α) and epidermal growth factor (EGF), and also reduced the protein level of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGF-R2) in the mammary gland [80,81]. As another well-known phytoestrogen, resveratrol (3,5,4'-trihydroxy-trans-stilbene), is a naturally appearing phytoalexin present mainly in grapes and therefore occurrs high levels in red wine [82,83]. This is a compound generated by plants in reaction to environmental stress or pathogen attack and also demonstrated to have chemopreventive capabilites [75]. This is structurally similar to DES and can bind to both ERα and ERβ. Also, resveratrol reduced E2 stimulated cell growth and constrained transcription of PR in breast cancer cell line [12,84]. But, the antagonist activity of resveratrol is only for ERα and not for ERβ. In mammary carcinogenesis, subcutaneous injections of reveratrol (0, 10 or 100 mg/kg) significantly decreased NMU-induced tumor incidence and diversity [83,85]. Also, other studies showed that in the developing tumors of rats treated with resveratrol, the expressions of COX-2 and matrix metalloproteinase-9 (MMP-9) proteins had significantly decreased [86,87]. Additionally, it was reported that in a mammary tumorigenesis, resveratrol (1, 3 or 5 mg/kg) reduced tumor size and angiogenesis by increasing the apoptotic quotient in mice and rats [88,89]. While many studies support the protective properties of phytoestrogens on cancer formation, some studies insist their tumor progression activities. For instance, it was reported that dietary genistein stimulated tumor growth and antagonized the cytotoxic effects of Tamoxifen and the aromatase inhibitor, Letrozole [90]. Resveratrol also showed detrimental effects on mammary tumor progression [88] or no effect on the same cancer in another study [91]. Although there is a controversy for these mixed results, epidemiological evidences that individuals consuming a diet high in phytoestrogens have a reduced risk of developing various cancers and substantial experimental outcoms are still convincing of the chemopreventive effects of phytoestrogens.

Conclusions

Nowadays, the chemicals classified as EDCs are rapidly increasing in environment and therefore, human and animals have been continually exposed to the risks of EDCs. Among diverse EDCs, as xenoestrogens are structurally similar to E2, an endogeneous estrogen, and act as false messengers, they may disrupt the reproduction process related with endogeneous estrogen. Chemically synthetic EDCs such as BPA, DDT, PCB and phthalate are shown to act as estrogen mimics or as antagonists by affecting ERs, ERα and ERβ, and further disturb various cellular functions induced by ERs as shown in Figure 1. As a result, these EDCs may cause hormone imbalance, early puberty, reproduction problems, impaired immune functions and various cancers. In the respect of cancer, many studies of EDCs using in vivo mouse models have described that the exposure to xenoestrogens can transform normal patterns of tissue, interrupt dominant regulatory mechanisms and increase the carcinogenic potential for estrogen-dependant cancers such as breast, ovary, endometrium and prostate cancers. On the other hand, some EDCs have protective effects against estrogen-related diseases. They are mostly phytoestrogens such as genistein and resveratrol and were shown to inhibit cell growth in breast, ovary and prostate cancers by inducing cell cycle arrest, apoptosis, and metastasis suppression via ER-related pathways or non ER-related pathways. Nevertheless, as other studies suggest that phytoestrogens also have tumorigenic properties like other EDCs, the chemopreventive effects of phytoestrogens on estrogen-dependant cancers are still debating.

The studies of EDCs investigated in this article sufficiently substantiate that EDCs can be sufficient risk factors in various reproduction problems and diseases including specific cancers, but this assertion is somewhat controversal. This is mainly about the validity of dosage of EDCs used in laboratory experiments [92,93]. This is mainly about the validity of dosage of EDCs used in laboratory experiments. Critics argue that the concentrations of chemicals in the experiments are relatively high and that their actual amounts in the environment are too low to cause an endocrine disrupting effect. But, others insist that high dosage effects are appropriate because of EDCs' accumulating properties in living bodies and the environment and high frequency of exposure to EDCs [94]. Therefore, it is prerequisite to validate the effective dosage of chemicals before elucidating their endocrine disruption effects and risk potentials in many disorders. In addition, the health effects of EDCs identified in in vivo studies using animal models should be verified in huamn and other animals. Despite the debate and need for validation, the potential risks of EDCs in endocrine disruption and carcinogenesis are considerbly noteworthy issues in industrialized societies.

Acknowledgments

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) of Korea government (No. 2011-0015385).

References

1. Murono EP, Derk RC, de Leon JH. Differential effects of octylphenol, 17β-estradiol, endosulfan, or bisphenol A on the steroidogenic competence of cultured adult rat Leydig cells. Reprod Toxicol. 2001; 15(5):551–560. PMID: 11780963.

2. Bredhult C, Backlin BM, Olovsson M. Effects of some endocrine disruptors on the proliferation and viability of human endometrial endothelial cells in vitro. Reprod Toxicol. 2007; 23(4):550–559. PMID: 17493787.

3. Shanle EK, Xu W. Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action. Chem Res Toxicol. 2011; 24(1):6–19. PMID: 21053929.

4. Takamiya M, Lambard S, Huhtaniemi IT. Effect of bisphenol A on human chorionic gonadotrophin-stimulated gene expression of cultured mouse Leydig tumour cells. Reprod Toxicol. 2007; 24(2):265–275. PMID: 17706920.

5. Harrison PT. Endocrine disrupters and human health. BMJ. 2001; 323(7325):1317–1318. PMID: 11739203.

6. Hwang KA, Park SH, Yi BR, Choi KC. Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011; 27(2):99–107. PMID: 21826169.

7. Soto AM, Sonnenschein C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010; 6(7):363–370. PMID: 20498677.

8. Barry JM, John M. Barry: distinguished scholar at the Center for Bioenvironmental Research, Tulane and Xavier Universities [Interview by Madeline Drexler]. Biosecur Bioterror. 2009; 7(2):127–133. PMID: 19485709.

9. Shao ZM, Shen ZZ, Fontana JA, Barsky SH. Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. Anticancer Res. 2000; 20(4):2409–2416. PMID: 10953303.

10. Cotroneo MS, Wang J, Fritz WA, Eltoum IE, Lamartiniere CA. Genistein action in the prepubertal mammary gland in a chemoprevention model. Carcinogenesis. 2002; 23(9):1467–1474. PMID: 12189189.

11. Chen XW, Garner SC, Anderson JJ. Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway. Biochem Biophys Res Commun. 2002; 295(2):417–422. PMID: 12150965.

12. Jenkins S, Betancourt AM, Wang J, Lamartiniere CA. Endocrine-active chemicals in mammary cancer causation and prevention. J Steroid Biochem Mol Biol. 2011; in press.

13. Ma L. Endocrine disruptors in female reproductive tract development and carcinogenesis. Trends Endocrinol Metab. 2009; 20(7):357–363. PMID: 19709900.

14. Watanabe J, Kamata Y, Seo N, Okayasu I, Kuramoto H. Stimulatory effect of estrogen on the growth of endometrial cancer cells is regulated by cell-cycle regulators. J Steroid Biochem Mol Biol. 2007; 107(3-5):163–171. PMID: 17681750.

15. Craig ZR, Wang W, Flaws JA. Endocrine disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling. Reproduction. 2011; 142(5):633–646. PMID: 21862696.

16. Pelletier G. Localization of androgen and estrogen receptors in rat and primate tissues. Histol Histopathol. 2000; 15(4):1261–1270. PMID: 11005250.

17. Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM, Webb P. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol. 2000; 74(5):311–317. PMID: 11162939.

18. Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, Gustafsson JA, Safe S. Ligand-, cell-, and estrogen receptor subtype (α/β)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem. 2000; 275(8):5379–5387. PMID: 10681512.

19. Glidewell-Kenney C, Weiss J, Lee EJ, Pillai S, Ishikawa T, Ariazi EA, Jameson JL. ERE-independent ERα target genes differentially expressed in human breast tumors. Mol Cell Endocrinol. 2005; 245(1-2):53–59. PMID: 16298037.

20. Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, Eppenberger U, Eppenberger-Castori S, Benz CC. Enhanced NF-κB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer. 2007; 7:59. PMID: 17407600.

21. Imaida K, Shirai T. Endocrine disrupting chemicals and carcinogenesis - breast, testis and prostate cancer. Nihon Rinsho. 2000; 58(12):2527–2532. PMID: 11187749.

22. Hutchinson TH. Reproductive and developmental effects of endocrine disrupters in invertebrates: in vitro and in vivo approaches. Toxicol Lett. 2002; 131(1-2):75–81. PMID: 11988360.

23. Swan SH. Intrauterine exposure to diethylstilbestrol: long-term effects in humans. APMIS. 2000; 108(12):793–804. PMID: 11252812.

24. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, Gore AC. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009; 30(4):293–342. PMID: 19502515.

25. Iwata M, Eshima Y, Kagechika H, Miyaura H. The endocrine disruptors nonylphenol and octylphenol exert direct effects on T cells to suppress Th1 development and enhance Th2 development. Immunol Lett. 2004; 94(1-2):135–139. PMID: 15234545.

26. Jakacka M, Ito M, Martinson F, Ishikawa T, Lee EJ, Jameson JL. An estrogen receptor (ER)α deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Mol Endocrinol. 2002; 16(10):2188–2201. PMID: 12351685.

27. Cheung E, Acevedo ML, Cole PA, Kraus WL. Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1. Proc Natl Acad Sci USA. 2005; 102(3):559–564. PMID: 15642950.

28. Renner R. European bans on surfactant trigger transatlantic debate. Environ Sci Technol. 1997; 31(7):316A–320A.

29. Barrett JR. Estrogens from the outside in: alkylphenols, BPA disrupt ERK signaling in vitro. Environ Health Perspect. 2011; 119(1):A34. PMID: 21196144.

30. Woodruff TJ, Zota AR, Schwartz JM. Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect. 2011; 119(6):878–885. PMID: 21233055.

31. Matsushima A, Kakuta Y, Teramoto T, Koshiba T, Liu X, Okada H, Tokunaga T, Kawabata S, Kimura M, Shimohigashi Y. Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERRγ. J Biochem. 2007; 142(4):517–524. PMID: 17761695.

32. Lamartiniere CA, Jenkins S, Betancourt AM, Wang J, Russo J. Exposure to the endocrine disruptor bisphenol A alters susceptibility for mammary cancer. Horm Mol Biol Clin Investig. 2011; 5(2):45–52.

33. Riu A, le Maire A, Grimaldi M, Audebert M, Hillenweck A, Bourguet W, Balaguer P, Zalko D. Characterization of novel ligands of ERα, ERβ, and PPARγ: the case of halogenated bisphenol A and their conjugated metabolites. Toxicol Sci. 2011; 122(2):372–382. PMID: 21622942.

34. Iasinskaia IM, Rozanov A. Effect of nonsteroidal estrogen-like substances on aromatase activity. Ukr Biokhim Zh. 2001; 73(3):121–125. PMID: 12035542.

35. Mussi P, Ciana P, Raviscioni M, Villa R, Regondi S, Agradi E, Maggi A, Di Lorenzo D. Activation of brain estrogen receptors in mice lactating from mothers exposed to DDT. Brain Res Bull. 2005; 65(3):241–247. PMID: 15811587.

36. You L, Sar M, Bartolucci E, Ploch S, Whitt M. Induction of hepatic aromatase by p,p'-DDE in adult male rats. Mol Cell Endocrinol. 2001; 178(1-2):207–214. PMID: 11403911.

37. Xu Y, Yu RM, Zhang X, Murphy MB, Giesy JP, Lam MH, Lam PK, Wu RS, Yu H. Effects of PCBs and MeSO₂-PCBs on adrenocortical steroidogenesis in H295R human adrenocortical carcinoma cells. Chemosphere. 2006; 63(5):772–784. PMID: 16216300.

38. Ulbrich B, Stahlmann R. Developmental toxicity of polychlorinated biphenyls (PCBs): a systematic review of experimental data. Arch Toxicol. 2004; 78(5):252–268. PMID: 15064922.

39. Kim YH, Kim SH, Lee HW, Chae HD, Kim CH, Kang BM. Increased viability of endometrial cells by in vitro treatment with di-(2-ethylhexyl) phthalate. Fertil Steril. 2010; 94(6):2413–2416. PMID: 20493477.

40. Ghisari M, Bonefeld-Jorgensen EC. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett. 2009; 189(1):67–77. PMID: 19463926.

41. Oehlmann J, Schulte-Oehlmann U, Kloas W, Jagnytsch O, Lutz I, Kusk KO, Wollenberger L, Santos EM, Paull GC, Van Look KJ, Tyler CR. A critical analysis of the biological impacts of plasticizers on wildlife. Philos Trans R Soc Lond B Biol Sci. 2009; 364(1526):2047–2062. PMID: 19528055.

42. Ohtani H, Miura I, Ichikawa Y. Effects of dibutyl phthalate as an environmental endocrine disruptor on gonadal sex differentiation of genetic males of the frog Rana rugosa. Environ Health Perspect. 2000; 108(12):1189–1193. PMID: 11133400.

43. Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, Mao CS, Redmon JB, Ternand CL, Sullivan S, Teague JL. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005; 113(8):1056–1061. PMID: 16079079.

44. Erkekoglu P, Giray B, Rachidi W, Hininger-Favier I, Roussel AM, Favier A, Hincal F. Effects of di(2-ethylhexyl)phthalate on testicular oxidant/antioxidant status in selenium-deficient and selenium-supplemented rats. Environ Toxicol. 2011.

45. Herr C, zur Nieden A, Koch HM, Schuppe HC, Fieber C, Angerer J, Eikmann T, Stilianakis NI. Urinary di(2-ethylhexyl)phthalate (DEHP) - Metabolites and male human markers of reproductive function. Int J Hyg Environ Health. 2009; 212(6):648–653. PMID: 19733116.

46. Lovekamp TN, Davis BJ. Mono-(2-ethylhexyl)phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicol Appl Pharmacol. 2001; 172(3):217–224. PMID: 11312650.

47. Lovekamp-Swan T, Davis BJ. Mechanisms of phthalate ester toxicity in the female reproductive system. Environ Health Perspect. 2003; 111(2):139–145. PMID: 12573895.

48. Stevens RG, Rea MS. Light in the built environment: potential role of circadian disruption in endocrine disruption and breast cancer. Cancer Causes Control. 2001; 12(3):279–287. PMID: 11405333.

49. Choi SM, Yoo SD, Lee BM. Toxicological characteristics of endocrine-disrupting chemicals: developmental toxicity, carcinogenicity, and mutagenicity. J Toxicol Environ Health B Crit Rev. 2004; 7(1):1–24. PMID: 14681080.

50. Negoita M, Mihailovici MS. Expression of hormonal receptors (α-estrogen, β-estrogen, progesteron), Ki-67 and P53 in endometrium of tamoxifen treated breast cancer patients. Rev Med Chir Soc Med Nat Iasi. 2011; 115(3):834–838. PMID: 22046795.

51. Swart JC, Pool EJ. Development of a bio-assay for estrogens using estrogen receptor alpha gene expression by MCF7 cells as biomarker. J Immunoassay Immunochem. 2009; 30(2):150–165. PMID: 19330641.

52. Berckmans P, Leppens H, Vangenechten C, Witters H. Screening of endocrine disrupting chemicals with MELN cells, an ER-transactivation assay combined with cytotoxicity assessment. Toxicol In Vitro. 2007; 21(7):1262–1267. PMID: 17572059.

53. Titus-Ernstoff L, Hatch EE, Hoover RN, Palmer J, Greenberg ER, Ricker W, Kaufman R, Noller K, Herbst AL, Colton T, Hartge P. Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy. Br J Cancer. 2001; 84(1):126–133. PMID: 11139327.

54. Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS. In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer. 2010; 1(3):146–155. PMID: 21761357.

55. Tanaka T, Kohno H, Suzuki R, Sugie S. Lack of modifying effects of an estrogenic compound atrazine on 7,12-dimethylbenz(a)anthracene-induced ovarian carcinogenesis in rats. Cancer Lett. 2004; 210(2):129–137. PMID: 15183528.

56. Attia DM, Ederveen AG. Opposing roles of ERα and ERβ in the genesis and progression of adenocarcinoma in the rat ventral prostate. Prostate. 2011; in press.

57. Shah S, Hess-Wilson JK, Webb S, Daly H, Godoy-Tundidor S, Kim J, Boldison J, Daaka Y, Knudsen KE. 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene stimulates androgen independence in prostate cancer cells through combinatorial activation of mutant androgen receptor and mitogen-activated protein kinase pathways. Mol Cancer Res. 2008; 6(9):1507–1520. PMID: 18819937.

58. Nelles JL, Hu WY, Prins GS. Estrogen action and prostate cancer. Expert Rev Endocrinol Metab. 2011; 6(3):437–451. PMID: 21765856.

59. Wadia PR, Vandenberg LN, Schaeberle CM, Rubin BS, Sonnenschein C, Soto AM. Perinatal bisphenol A exposure increases estrogen sensitivity of the mammary gland in diverse mouse strains. Environ Health Perspect. 2007; 115(4):592–598. PMID: 17450229.

60. Durando M, Kass L, Piva J, Sonnenschein C, Soto AM, Luque EH, Munoz-de-Toro M. Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats. Environ Health Perspect. 2007; 115(1):80–86. PMID: 17366824.

61. Murray TJ, Maffini MV, Ucci AA, Sonnenschein C, Soto AM. Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reprod Toxicol. 2007; 23(3):383–390. PMID: 17123778.

62. Jenkins S, Raghuraman N, Eltoum I, Carpenter M, Russo J, Lamartiniere CA. Oral exposure to bisphenol a increases dimethylbenzanthracene-induced mammary cancer in rats. Environ Health Perspect. 2009; 117(6):910–915. PMID: 19590682.

63. Vandenberg LN, Maffini MV, Schaeberle CM, Ucci AA, Sonnenschein C, Rubin BS, Soto AM. Perinatal exposure to the xenoestrogen bisphenol-A induces mammary intraductal hyperplasias in adult CD-1 mice. Reprod Toxicol. 2008; 26(3-4):210–219. PMID: 18938238.

64. Long X, Burke KA, Bigsby RM, Nephew KP. Effects of the xenoestrogen bisphenol A on expression of vascular endothelial growth factor (VEGF) in the rat. Exp Biol Med (Maywood). 2001; 226(5):477–483. PMID: 11393178.

65. Buteau-Lozano H, Velasco G, Cristofari M, Balaguer P, Perrot-Applanat M. Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism. J Endocrinol. 2008; 196(2):399–412. PMID: 18252963.

66. Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Sci. 2002; 67(1):63–74. PMID: 11961217.

67. Lewis BC, Hudgins S, Lewis A, Schorr K, Sommer R, Peterson RE, Flaws JA, Furth PA. In utero and lactational treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs mammary gland differentiation but does not block the response to exogenous estrogen in the postpubertal female rat. Toxicol Sci. 2001; 62(1):46–53. PMID: 11399792.

68. Chow LW, Cheung MN, Loo WT, Guan XY. A rat cell line derived from DMBA-induced mammary carcinoma. Life Sci. 2003; 73(1):27–40. PMID: 12726884.

69. La Merrill M, Kuruvilla BS, Pomp D, Birnbaum LS, Threadgill DW. Dietary fat alters body composition, mammary development, and cytochrome p450 induction after maternal TCDD exposure in DBA/2J mice with low-responsive aryl hydrocarbon receptors. Environ Health Perspect. 2009; 117(9):1414–1419. PMID: 19750107.

70. Melnick RL. Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of di(2-ethylhexyl) phthalate (DEHP)? Environ Health Perspect. 2001; 109(5):437–442. PMID: 11401753.

71. Rusyn I, Peters JM, Cunningham ML. Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol. 2006; 36(5):459–479. PMID: 16954067.

72. Xu C, Chen JA, Qiu Z, Zhao Q, Luo J, Yang L, Zeng H, Huang Y, Zhang L, Cao J, Shu W. Ovotoxicity and PPAR-mediated aromatase downregulation in female Sprague-Dawley rats following combined oral exposure to benzo[a]pyrene and di-(2-ethylhexyl) phthalate. Toxicol Lett. 2010; 199(3):323–332. PMID: 20920559.

73. Green R, Hauser R, Calafat AM, Weuve J, Schettler T, Ringer S, Huttner K, Hu H. Use of di(2-ethylhexyl)phthalate-containing medical products and urinary levels of mono(2-ethylhexyl)phthalate in neonatal intensive care unit infants. Environ Health Perspect. 2005; 113(9):1222–1225. PMID: 16140631.

74. Mersereau JE, Levy N, Staub RE, Baggett S, Zogovic T, Chow S, Ricke WA, Tagliaferri M, Cohen I, Bjeldanes LF, Leitman DC. Liquiritigenin is a plant-derived highly selective estrogen receptor â agonist. Mol Cell Endocrinol. 2008; 283(1-2):49–57. PMID: 18177995.

75. Levenson AS, Gehm BD, Pearce ST, Horiguchi J, Simons LA, Ward JE 3rd, Jameson JL, Jordan VC. Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells stably transfected with ERα. Int J Cancer. 2003; 104(5):587–596. PMID: 12594813.

76. Dai Z, Li Y, Quarles LD, Song T, Pan W, Zhou H, Xiao Z. Resveratrol enhances proliferation and osteoblastic differentiation in human mesenchymal stem cells via ER-dependent ERK1/2 activation. Phytomedicine. 2007; 14(12):806–814. PMID: 17689939.

77. Meng QS, Zhu XY, Tang XL, Ma B, Ni X. Effect of isoflavones in regulating the transcription of target genes through estrogen receptors. Zhong Xi Yi Jie He Xue Bao. 2007; 5(5):577–580. PMID: 17854564.

78. Ye L, Chan MY, Leung LK. The soy isoflavone genistein induces estrogen synthesis in an extragonadal pathway. Mol Cell Endocrinol. 2009; 302(1):73–80. PMID: 19356625.

79. Mai Z, Blackburn GL, Zhou JR. Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells. Mol Carcinog. 2007; 46(7):534–542. PMID: 17295235.

80. Rowell C, Carpenter DM, Lamartiniere CA. Chemoprevention of breast cancer, proteomic discovery of genistein action in the rat mammary gland. J Nutr. 2005; 135(12 Suppl):2953S–2959S. PMID: 16317154.

81. Brown NM, Lamartiniere CA. Genistein regulation of transforming growth factor-α, epidermal growth factor (EGF), and EGF receptor expression in the rat uterus and vagina. Cell Growth Differ. 2000; 11(5):255–260. PMID: 10845426.

82. Brisdelli F, D'Andrea G, Bozzi A. Resveratrol: a natural polyphenol with multiple chemopreventive properties. Curr Drug Metab. 2009; 10(6):530–546. PMID: 19702538.

83. Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α and β. Endocrinology. 2000; 141(10):3657–3667. PMID: 11014220.

84. Aziz MH, Nihal M, Fu VX, Jarrard DF, Ahmad N. Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins. Mol Cancer Ther. 2006; 5(5):1335–1341. PMID: 16731767.

85. Banerjee S, Bueso-Ramos C, Aggarwal BB. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 2002; 62(17):4945–4954. PMID: 12208745.

86. Provinciali M, Re F, Donnini A, Orlando F, Bartozzi B, Di Stasio G, Smorlesi A. Effect of resveratrol on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Int J Cancer. 2005; 115(1):36–45. PMID: 15688416.

87. Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res. 2001; 61(20):7456–7463. PMID: 11606380.

88. Bove K, Lincoln DW, Tsan MF. Effect of resveratrol on growth of 4T1 breast cancer cells in vitro and in vivo. Biochem Biophys Res Commun. 2002; 291(4):1001–1005. PMID: 11866465.

89. Whitsett TG Jr, Lamartiniere CA. Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat. Expert Rev Anticancer Ther. 2006; 6(12):1699–1706. PMID: 17181483.

90. Ju YH, Doerge DR, Woodling KA, Hartman JA, Kwak J, Helferich WG. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis. 2008; 29(11):2162–2168. PMID: 18632754.

91. Garvin S, Ollinger K, Dabrosin C. Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett. 2006; 231(1):113–122. PMID: 16356836.

92. Cooper RL, Kavlock RJ. Endocrine disruptors and reproductive development: a weight-of-evidence overview. J Endocrinol. 1997; 152(2):159–166. PMID: 9071972.

93. Safe SH. Endocrine disruptors and human health - Is there a problem? An update. Environ Health Perspect. 2000; 108(6):487–493. PMID: 10856020.

94. Talsness CE, Kuriyama SN, Sterner-Kock A, Schnitker P, Grande SW, Shakibaei M, Andrade A, Grote K, Chahoud I. In utero and lactational exposures to low doses of polybrominated diphenyl ether-47 alter the reproductive system and thyroid gland of female rat offspring. Environ Health Perspect. 2008; 116(3):308–314. PMID: 18335096.

Figure 1

Genomic pathways of estrogen and EDCs in ER-dependent signaling mechanisms. Estrogen and EDCs can lead to cell proliferation in the genomic pathway in which ER dimers directly bind to EREs following ligands binding or ERs interact with other transcription factors (TFs), including AP-1, by action of transcription factor cross-talk. EDCs can compete with estrogen in ERs binding and induce estrogenic effects.

TOOLS

Similar articles