Effects of Xenoestrogens on T Lymphocytes: Modulation of bcl-2, p53, and Apoptosis

Kenneth Ndebele,Robert W Mcmurray,Paul B Tchounwou

doi:10.3390/i4020045

Abstract

Endogenous estrogens have significant immunomodulatory effects characterized as suppression of cell mediated immunity and stimulation of humoral immunity. Xenoestrogens are environmental estrogens that have endocrine impact, acting as estrogen agonists and antagonists but whose immune effects are not well characterized. Using CD4+ Jurkat T cells as a model, the effects of representative xenoestrogens on T proliferation, cell cycle, and apoptosis were examined. Coumestrol (CM), a phytoestrogen, and tetrachlorodioxin (TCDD) in concentrations of 10-4 to 10-6M significantly inhibited Jurkat T cell lymphoproliferation, whereas bisphenol A (BPA) and DDT had minimal effect, but did antagonize 17-β-estrtadiol induced effects. Xenoestrogens, especially CM, produced accumulation of Jurkat T cells in G2/M phase, and subsequently induced apoptosis, particularly CM (% apoptotic cells = 30 ± 12 vs. control = 5 ± 2). These changes were associated with DNA fragmentation. BPA and DDT also induced DNA fragmentation but not significant DNA hypoploidy. Xenoestrogen – CM, BPA, DDT, and TCDD - exposure suppressed bcl-2 protein and mRNA transcript levels but augmented p53 protein and mRNA transcripts. Human purified peripheral blood lymphocytes responded with similar significant cell cycle changes (G0/G1 exodus and G2/M accumulation) for CM, BPA, and DDT exposure. These preliminary data, taken together, suggest that xenoestrogens have direct, compound-specific T lymphocyte effects that enhance our understanding of environmental modulation of immune and autoimmune responses.

Highlights

Endogenous estrogens, especially 17-β-estradiol, have significant immunoendocrine impact on cellmediated and humoral immune and autoimmune responses [1,2,3,4,5]
Representative xenoestrogens include compounds such as coumestrol, a phytoestrogen found in high levels in legumes that acts as an estrogen agonist
T cells were activated with phorbol-myristate acetate (PMA) and plate-bound anti-CD3 at optimal concentrations as previously described [40]. 17-β-estradiol and TCDD were used as representative controls of endogenous and environmental estrogen compounds unless otherwise indicated

Summary

Introduction

Endogenous estrogens, especially 17-β-estradiol, have significant immunoendocrine impact on cellmediated and humoral immune and autoimmune responses [1,2,3,4,5]. Derived from plant or industrial synthesis, environmental xenobiotics with potential estrogenic or hormonal activities are known as xenoestrogens or ecohormones. These compounds are ubiquitous, exhibit bioaccumulation, and act as estrogen agonists or antagonists, disrupting normal endocrine axes [6,7,8,9,10,11,12,13,14,15]. DDT (o,p–dichlorodiphenyltrichloroethane), a synthetic organochlorine pesticide, has weak estrogenic agonist activity (as well as androgen antagonist activity) [21] and has been associated with immunosuppression in murine models [22,23,24] and modulation of cell cycle and apoptosis [25,26,27], but its effects on T lymphocyte biology is less well defined. TCDD (tetrachlorodibenzo-p-dioxin), a polychlorinated biphenyl dioxin, has been widely studied with variably results, having both estrogen agonist and antagonist activity [6,14,21], modulation of cell cycle proteins [28,29], induction of thymic involution [30], and modulation of cytokine expression [31,32]

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Conclusion