Environmental Estrogens Induce Mast Cell Degranulation and Enhance IgE-Mediated Release of Allergic Mediators

The prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years, particularly in industrial countries (Burr et al. 2006). The onset of asthma most commonly occurs in early childhood (Yunginger et al. 1992). Asthma is more common in males during infancy, childhood, and preadolescence (Yunginger et al. 1992). However, from late adolescence to middle age, females have a higher prevalence and morbidity from asthma (De Marco et al. 2002; Yunginger et al. 1992). Although the increase in overall prevalence and the cause of these pattern differences between the sexes are not well understood, we questioned whether female gonadal hormones and their mimetics might be involved. We recently found that physiologic concentrations of estradiol (E2) rapidly stimulate murine and human mast cell lines (RBL-2H3 and HMC-1) and primary cultures of bone marrow–derived mast cells (BMMC) to release β -hexosaminadase (β -hex), a marker for the granules that contain preformed allergic mediators (Zaitsu et al. 2006). These low doses of E2 also enhanced the synthesis and release of leukotriene C4 (LTC4) by RBL-2H3 cells. In addition to these direct effects, E2 potentiated IgE-dependent synthesis and release of β -hex, and particularly LTC4. The finding that the estrogen receptor (ER) antagonists tamoxifen and ICI 182,780 inhibited these effects suggested that these estrogenic effects were mediated through specific ERs (ER-α or ER-β ). This proposition was substantiated by demonstrating that BMMCs derived from ER-α knockout (KO) mice did not degranulate in response to E2. We also analyzed the expression of ER-α and ER-β by reverse transcriptase-polymerase chain reaction and could detect only ER-α on RBL-2H3, HMC-1, and BMMCs (Zaitsu et al. 2006). Another recent study provided evidence for estrogen effects on allergic sensitization/reactions by showing a relationship between an ER-α gene (ESR1) polymorphism and airway hypersensitivity, and an age-related decline in lung function in females with asthma (Dijkstra et al. 2006). Estrogens and other steroid hormones use two different major cellular pathways to exert their regulatory effects. One pathway is via genomic receptors acting as transcription factors on gene expression. However, an alternative pathway acting via plasma membrane receptors is more often involved in the rapid effects of steroids occurring within seconds to minutes (Watson et al. 1999; Watson and Gametchu 2003). This nongenomic pathway is involved in secretory responses to both physiologic and nonphysiologic estrogens (Bulayeva et al. 2005). Many environmental pollutants have estrogen-like activities and thus are termed environmental estrogens or xenoestrogens (Newbold et al. 2006; Wozniak et al. 2005). These components can be involved in both genomic and nongenomic pathways of estrogen action, but have recently been shown to be very potent when acting via the non-genomic pathway (Wozniak et al. 2005), although they are very weak activators of the genomic pathway. If environmental estrogens act at such low levels, then the widespread presence of these compounds in our environment are of concern as causes for the increasing prevalence of diseases such as asthma. Examples of environmental estrogens include the dioxins, dichlorodiphenyl-trichloroethane (DDT) and its metabolite dichlorodiphenylethylene (DDE), hexachloro-cyclohexane, polychlorinated biphenyls (PCBs), and alkylphenols and their derivatives (nonylphenol, octylphenol, bisphenol A). The most common source of these pollutants is through contaminated water and foods (Aravindakshan et al. 2004; Falconer et al. 2006). We therefore questioned whether environmental estrogens could have effects on allergic sensitization and clinically relevant reactions, such as for asthma. The goal of the present study was to identify possible mechanisms by which environmental estrogens, alone or in combination with endogenous estrogens, might promote the development of allergic diseases.