Background-Allergic airway diseases are more common in females than in males during early adulthood. A relationship between female hormones and asthma prevalence and severity has been suggested, but the cellular and molecular mechanisms are not understood.Objective-To elucidate the mechanism(s) by which estrogens enhance the synthesis and release of mediators of acute hypersensitivity.Methods-Two mast cell/basophil cell lines (RBL-2H3 and HMC-1) and primary cultures of bone marrow derived mast cells, all of which naturally express estrogen receptor-α, were examined. Cells were incubated with physiological concentrations of 17-β-estradiol with and without IgE and allergens. Intracellular Ca 2+ concentrations and the release of β-hexosaminidase and leukotriene C 4 were quantified.Results-Estradiol alone induced partial release of the preformed, granular protein β-hexosaminidase from RBL-2H3, BMMC and HMC-1, but not from BMMC derived from estrogen receptor-α knock-out mice. The newly synthesized LTC 4 was also released from RBL-2H3. Estradiol also enhanced IgE-induced degranulation and potentiated LTC 4 production. Intracellular Ca 2+ concentration increased prior to and in parallel with mediator release. Estrogen receptor antagonists or Ca 2+ chelation inhibited these estrogenic effects.Conclusion-Binding of physiological concentrations of estradiol to a membrane estrogen receptor-α initiates a rapid onset and progressive influx of extracellular Ca 2+ , which supports the synthesis and release of allergic mediators. Estradiol also enhances IgE-dependent mast cell activation, resulting in a shift of the allergen dose response.

BackgroundPrevalence and morbidity of allergic diseases have increased over the last decades. Based on the recently recognized differences in asthma prevalence between the sexes, we have examined the effect of endogenous estrogens on a key element of the allergic response. Some lipophilic pollutants have estrogen-like activities and are termed environmental estrogens. These pollutants tend to degrade slowly in the environment and to bioaccumulate and bioconcentrate in the food chain; they also have long biological half-lives.ObjectivesOur goal in this study was to identify possible pathogenic roles for environmental estrogens in the development of allergic diseases.MethodsWe screened a number of environmental estrogens for their ability to modulate the release of allergic mediators from mast cells. We incubated a human mast cell line and primary mast cell cultures derived from bone marrow of wild type and estrogen receptor α (ER-α )–deficient mice with environmental estrogens with and without estradiol or IgE and allergens. We assessed degranulation of mast cells by quantifying the release of β -hexosaminidase.ResultsAll of the environmental estrogens tested caused rapid, dose-related release of β -hexosaminidase from mast cells and enhanced IgE-mediated release. The combination of physiologic concentrations of 17β -estradiol and several concentrations of environmental estrogens had additive effects on mast cell degranulation. Comparison of bone marrow mast cells from ER-α –sufficient and ER-α –deficient mice indicated that much of the effect of environmental estrogens was mediated by ER-α .ConclusionsOur findings suggest that estrogenic environmental pollutants might promote allergic diseases by inducing and enhancing mast cell degranulation by physiologic estrogens and exposure to allergens.

The GSK-3β gene, GSK3B, codes for an enzyme that is a target for the action of mood stabilizers, lithium and possibly valproic acid.In this study, the relationship between haplotypes consisting of single nucleotide polymorphisms (SNPs) of GSK3B −50T/C and −1727A/T and the effect of lithium was studied among Japanese bipolar disorder lithium nonresponders and responders.The distributions of the GSK3B haplotypes (−50T/C and −1727A/T) showed a trend for significant difference between the lithium nonresponders and responders (global P=0.07074). Haplotype 1 (T-A) was associated with a higher lithium response (haplotype-specific P=0.03477), whereas haplotype 2 (C-A) was associated with a lower lithium response (haplotype-specific P=0.03443).The pairwise D′ and r2 values between the 2 SNPs in this study were 1.0 and 0.097, respectively. The 2 SNPs showed weak linkage disequilibrium with each other.

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