The phytoestrogen genistein induces thymic and immune changes: A human health concern?

Abstract

Use of soy-based infant formulas and soy͞isoflavone supplements has aroused concern because of potential estrogenic effects of the soy isoflavones genistein and daidzein. Here we show that s.c. genistein injections in ovariectomized adult mice produced doseresponsive decreases in thymic weight of up to 80%. Genistein's thymic effects occurred through both estrogen receptor (ER) and non-ER-mediated mechanisms, as the genistein effects on thymus were only partially blocked by the ER antagonist ICI 182,780. Genistein decreased thymocyte numbers up to 86% and doubled apoptosis, indicating that the mechanism of the genistein effect on loss of thymocytes is caused in part by increased apoptosis. Genistein injection caused decreases in relative percentages of thymic CD4 ؉ CD8 ؊ and double-positive CD4 ؉ CD8 ؉ thymocytes, providing evidence that genistein may affect early thymocyte maturation and the maturation of the CD4 ؉ CD8 ؊ helper T cell lineage. Decreases in the relative percentages of CD4 ؉ CD8 ؊ thymocytes were accompanied by decreases in relative percentages of splenic CD4 ؉ CD8 ؊ cells and a systemic lymphocytopenia. In addition, genistein produced suppression of humoral immunity. Genistein injected at 8 mg͞kg per day produced serum genistein levels comparable to those reported in soy-fed human infants, and this dose caused significant thymic and immune changes in mice. Critically, dietary genistein at concentrations that produced serum genistein levels substantially less than those in soy-fed infants produced marked thymic atrophy. These results raise the possibility that serum genistein concentrations found in soy-fed infants may be capable of producing thymic and immune abnormalities, as suggested by previous reports of immune impairments in soy-fed human infants. S oy-based formula for human infant nutrition is widely used, with approximately 25% of formula-fed infants in the U.S. consuming soy-based formula (1). This number represents 15% of all infants in the U.S., or about 750,000 infants͞year (1, 2). Infants consuming soy formula are exposed to high levels of genistein and daidzein, estrogenic isoflavones present in soybeans and soy products. On average, infants fed soy-based formula consume 6.0-11.9 mg of isoflavones͞kg per day (3, 4), an order of magnitude greater than adults eating high-soy diets. Total plasma levels of isoflavones and genistein in soy-fed infants range from 2.0 to 6.6 and 1.5 to 4.4 mol͞liter, respectively (3), 10-fold greater than levels in Japanese adults whose diets have historically included soy, and 200-fold greater than plasma levels in infants fed cow's milk formula or human breast milk (3, 5). Levels of the free genistein aglycone as a percent of total genistein are higher in rat pups than in adults (6), but have not been measured in human infants. If a similar phenomenon occurs in humans, relative levels of the biologically active free aglycones may be even greater than the 10-fold difference documented in total (free ϩ conjugated) serum isoflavone and genistein levels in...

The role of environmental estrogens and autoimmunity

“…Due to its unique effect on the immune system, genistein has been used in the treatment of collagen-induced arthritis, an animal model for RA: mice receiving genistein prior to immunization with collagen showed less frequent and less severe arthritis than controls [91]. The in vivo findings have been confirmed by in vitro experiments: genistein inhibited lymphocyte proliferation response induced by mitogen or alloantigen [89]. In NK cells stimulated with antibodies against CD43, it has been shown to inhibit the secretion of chemokines as RANTES and macrophage inflammatory protein (MIP)-1.…”

“…Nowadays genistein is used as antineoplastic agent: it has been shown to stop G2 phase of cellular cycle. In animal models, genistein induced dose-dependent reduction in thymic weight, reduced the number of peripheral CD4+ and CD8+ cells, suppressed antigen-specific immune response [89] and decreased levels of IFN-γ protein [90]. Due to its unique effect on the immune system, genistein has been used in the treatment of collagen-induced arthritis, an animal model for RA: mice receiving genistein prior to immunization with collagen showed less frequent and less severe arthritis than controls [91].…”

Influence of Dietary Soy Phytoestrogens on Cytokine Production and Immunoglobulin in Ovariectomized Rats

“…Genistein (5 mg/d for 21 d) intravenously injected into ovariectomized female mice resulted in an 80% reduction of thymic weight, while genistein injection at 2 mg/d for only 7 d led to a 70% decrease in thymic weight [16]. Genistein reduced the numbers of peripheral CD4+ and CD8+ T cells and this reduction might come from thymic atrophy [17].…”

Fitoestrogênios: posicionamento do Departamento de Endocrinologia Feminina da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM)

“…Quando se suspendeu o uso da ipriflavona, algumas mulheres normalizaram sua taxa, outras demoraram alguns meses e outras não normalizaram. Estudo publicado este ano (132), sobre alterações imunológicas no timo induzidas por genisteína, mostrou que a injeção de genisteína em doses equivalentes às das formulas infantis de soja a ratas ooforectomizadas adultas provocou diminuição dose-dependente do peso do timo em até 80%, via mecanismos mediados pelo RE ou não. A genisteína duplicou a apoptose e causou diminuição na percentagem relativa dos timócitos CD4(+)/CD8(-), acompanhada de diminuição das células esplênicas CD4(+)CD8(-) e linfocitopenia sistêmica.…”