Endocrinology. 2006 Jun;147(6 Suppl):S25-32.
Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function.
Henley DV, Korach KS.
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
[ Free full text ]

The term endocrine-disrupting chemicals is used to define a structurally diverse class of synthetic and natural compounds that possess the ability to alter various components of the endocrine system and potentially induce adverse health effects in exposed individuals and populations. Research on these compounds has revealed that they use a variety of both nuclear receptor-mediated and non-receptor-mediated mechanisms to modulate different components of the endocrine system. This review will describe in vitro and in vivo studies that highlight the spectrum of unique mechanisms of action and biological effects of four endocrine-disrupting chemicals - diethylstilbestrol [DES], genistein, di(n-butyl)phthalate, and methoxyacetic acid - to illustrate the diverse and complex nature of this class of compounds.

From the full text article:

Several nonsteroidal plant-derived compounds known as phytoestrogens signal through the ER and therefore may act as endocrine disruptors. The potential benefits of phytoestrogens in preventing hormone-dependent cancers and lowering cholesterol have raised interest in studying the biological effects of these compounds. One such compound is Gen [genistein], an isoflavone present at high concentrations in soy-based products, which exhibits in vitro and in vivo estrogenic activity (31, 32, 33) as well as tyrosine kinase inhibitory properties (34). Although convincing evidence for both the beneficial and detrimental effects of Gen exposure is limited, it has been reported to reduce mammary cancer in rats (35, 36) and to lower cholesterol levels in humans (37, 38). However, it has also been associated with diminished reproductive capacity in animals (39, 40) and has been shown to induce uterine adenocarcinomas in a neonatal mouse model (41) and to increase the incidence of mammary tumors in rats (42). Further interest in studying Gen has resulted from the observation that humans, particularly infants, are exposed to it through their diet. It has been estimated that adults consuming modest amounts of soy-containing foods have a total isoflavone intake of approximately 1 mg/kg·d, whereas infants fed soy formula ingest significantly higher amounts, consuming 6–9 mg/kg·d of isoflavones, approximately 65% of which is Gen (43). This dose of isoflavones in infants is six to 11 times higher than the amount reported to have hormonal effects that alter the menstrual cycle in adult women (44).

Actions on the uterus

Given the ubiquitous nature of isoflavones in the human diet and the potential for both beneficial and adverse health consequences after exposure to Gen, efforts have been made to characterize the mechanism of action of Gen and to more clearly define the health effects of Gen exposure. In an immature mouse model, Gen elicits classical estrogenic uterotropic responses including increases in uterine wet weight, epithelial cell height, gland number, and lactoferrin expression (45). Receptor-binding assays indicate that Gen preferentially binds to ERbeta in comparison with ER, with relative binding affinities reported from 20- to 30-fold higher for ERbeta (46, 47). Despite these differences in ligand binding affinity, Gen has only a slight preference for transactivation of gene expression in vitro through ERbeta compared with ER, suggesting that Gen may elicit effects in vivo through both ER- and ERß-mediated pathways (47). Evidence for ER-mediated actions of Gen in vivo is derived from studies showing Gen-induced effects in the mouse uterus, which predominantly expresses ER (45). In addition, Gen activates the IGF-I signaling pathway in the mouse uterus via an ER-dependent mechanism (48). Taken together, these data suggest Gen acts through an ER-mediated mechanism in the uterus.

Evidence suggesting an ER-mediated mechanism for Gen action in the uterus has prompted studies in our laboratory to definitively establish the role of ER in the uterine response to Gen. In these studies, ovariectomized WT and ERKO mice were treated with corn oil, estradiol (10 µg/kg·d), or Gen (50 µg/kg·d) for 3 d, and uterine weights were determined. Both the estradiol and Gen treatments significantly increased uterine wet weights in WT mice, whereas neither ligand increased uterine wet weights in the ERKO mice, providing direct evidence that ER is necessary for Gen-induced uterotropic effects (unpublished data).

Actions on the ovary

To further determine the contributions of ER and ERbeta to Gen-induced effects in tissues other than the uterus, studies using ER null mice were incorporated into the neonatal mouse model described earlier, and the effects of Gen on the ovary were determined. Initial studies in WT CD-1 mice treated with Gen for 5 d showed a dose-dependent increase in multioocyte follicles by 19 d (49) (Table 2). To prove that the mechanism was due to the estrogenic properties of Gen and not to tyrosine kinase inhibitory properties, the nonestrogenic tyrosine kinase inhibitor lavendustin was incorporated into these experiments. No multioocyte follicles were observed after treatment with lavendustin regardless of dose, indicating that the increased incidence of multioocyte follicles was due to the estrogenic properties of Gen. Similar experiments were performed in C57BL/6 mice and in both ERKO and betaERKO mice to determine whether Gen was signaling in the ovary through ER, ERbeta, or a non-receptor-mediated mechanism. Neonatal treatment with Gen increased the incidence of multioocyte follicles in WT C57BL/6 and ERKO mice in a dose-dependent manner. In contrast, betaERKO mice treated with Gen had a significant decrease in the incidence of multioocyte follicles, suggesting that the induction of multioocyte follicles after neonatal Gen exposure requires ERbeta (49) (Table 2).

Taken together, studies focused on the mouse uterus and ovary show that Gen is capable of signaling in a tissue-specific manner through both ERalpha- and ERbeta-mediated mechanisms. Although a variety of physiological and toxicological effects of Gen exposure have been illustrated in animal studies, conflicting data reported in epidemiological studies make it difficult to correlate animal models with human exposure (50). Additional studies characterizing other possible mechanisms of Gen action, such as non-receptor mediated, epigenetic, and transgenerational effects, are needed to broaden our understanding of the potential beneficial and detrimental effects of human exposure and to clarify inconsistencies between epidemiological studies.

Categories: 2006, Soy, Phytoestrogens, Endocrine, Estrogen, Cancer, Sexual development, Nutrition and diet