Review: Endocrine disrupting chemicals and immune responses: a focus on bisphenol-A and its potential mechanisms.

Endocrine disrupting chemicals (EDCs) have become of concern for a variety f health issues. Due to their effects on the endocrine system they have been thoroughly examined with regards to sexual dysfunction, malformation, and cancers of reproductive origin. Bisphenol-A (BPA) is a widely studied EDC and has been characterized regarding its estrogenic effects on a variety of cell types. BPA also alters immune responses. In this review, we examine some of the documented effects of EDCs, with a focus on BPA that pertain to modulation of the immune system and various immune cell populations. We highlight the multiple actions of BPA on altering T cell subsets, B cell functions, and dendritic cell and macrophage biology. Finally, we consider that these immunological activities of BPA may be mediated through estrogen receptor signaling, arylhydrocarbon receptor, and the peroxisome proliferator-activated receptor family of nuclear receptors.

[1]  H. Jeong,et al.  Down-regulation of inducible nitric oxide synthase and tumor necrosis factor-α expression by bisphenol A via nuclear factor-κB inactivation in macrophages , 2003 .

[2]  C. Glass,et al.  Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells , 2010, Nature Reviews Immunology.

[3]  R. Zoeller,et al.  Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain. , 2005, Endocrinology.

[4]  G. Mor,et al.  Interaction of the Estrogen Receptors with the Fas Ligand Promoter in Human Monocytes1 , 2003, The Journal of Immunology.

[5]  S. Kovats,et al.  Understanding sex biases in immunity , 2005, Immunologic research.

[6]  S. Akira,et al.  Epigenetic control of macrophage polarization , 2011, European journal of immunology.

[7]  B. Bloodworth,et al.  Single laboratory validation of a method for the determination of Bisphenol A, Bisphenol A diglycidyl ether and its derivatives in canned foods by reversed-phase liquid chromatography. , 2006, Journal of chromatography. A.

[8]  J. Corton,et al.  Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor β. , 1998, Endocrinology.

[9]  Linda S Birnbaum,et al.  Cancer and developmental exposure to endocrine disruptors. , 2002, Environmental health perspectives.

[10]  K. Nakao,et al.  Thyroid hormone action is disrupted by bisphenol A as an antagonist. , 2002, The Journal of clinical endocrinology and metabolism.

[11]  Shu-Shen Liu,et al.  Immunotoxicity of bisphenol A to Carassius auratus lymphocytes and macrophages following in vitro exposure. , 2007, Journal of environmental sciences.

[12]  H. Takano,et al.  Effects of bisphenol A on antigen‐specific antibody production, proliferative responses of lymphoid cells, and TH1 and TH2 immune responses in mice , 2003, British journal of pharmacology.

[13]  Si-young Song,et al.  Efficient Induction of CCR9 on T Cells Requires Coactivation of Retinoic Acid Receptors and Retinoid X Receptors (RXRs): Exaggerated T Cell Homing to the Intestine by RXR Activation with Organotins , 2010, The Journal of Immunology.

[14]  D. Cha,et al.  Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[15]  Taku Sato,et al.  Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[16]  M. Veldhoen,et al.  External influences on the immune system via activation of the aryl hydrocarbon receptor. , 2011, Seminars in immunology.

[17]  A. Ballesteros-Gómez,et al.  Determination of bisphenols A and F and their diglycidyl ethers in wastewater and river water by coacervative extraction and liquid chromatography-fluorimetry. , 2007, Analytica chimica acta.

[18]  Yoshitomo Hamuro,et al.  Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA , 2008, Nature.

[19]  Laura N. Vandenberg,et al.  Human exposure to bisphenol A (BPA). , 2007, Reproductive toxicology.

[20]  B. Rubin,et al.  Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects , 2011, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  B. Staels,et al.  Activation of Proliferator-activated Receptors α and γ Induces Apoptosis of Human Monocyte-derived Macrophages* , 1998, The Journal of Biological Chemistry.

[22]  Kazuo Nakamura,et al.  Influence of Endocrine-disrupting Chemicals on the Immune System , 2010 .

[23]  Carlos Sonnenschein,et al.  Endocrine disruptors and reproductive health: The case of bisphenol-A , 2006, Molecular and Cellular Endocrinology.

[24]  J. Barnett,et al.  Evidence for a novel endocrine disruptor: the pesticide propanil requires the ovaries and steroid synthesis to enhance humoral immunity. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  H. Shinmoto,et al.  Mac1 Positive Cells Are Required for Enhancement of Splenocytes Proliferation Caused by Bisphenol A , 2004, Bioscience, biotechnology, and biochemistry.

[26]  C. Jan,et al.  Tumor necrosis factor-α activates estrogen signaling pathways in endometrial epithelial cells via estrogen receptor α , 2011, Molecular and Cellular Endocrinology.

[27]  K. Lim,et al.  Plant-originated glycoprotein (36 kDa) suppresses interleukin-4 and -10 in bisphenol A–stimulated primary cultured mouse lymphocytes , 2010, Drug and chemical toxicology.

[28]  Zhixian Gao,et al.  Influence of Bisphenol A on Developing Rat Estrogen Receptors and Some Cytokines in Rats: A Two-Generational Study , 2008, Journal of toxicology and environmental health. Part A.

[29]  C. Hung,et al.  Suppressive Effect on MDC and IP-10 Expression in Monocytes by Endocrine Disruptor Chemicals , 2010, Inflammation.

[30]  C. Sonnenschein,et al.  Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. , 2007, Reproductive toxicology.

[31]  E. Talbott,et al.  Associations of Serum Concentrations of Organochlorine Pesticides with Breast Cancer and Prostate Cancer in U.S. Adults , 2009, Environmental health perspectives.

[32]  H. Jeong,et al.  Down-regulation of inducible nitric oxide synthase and tumor necrosis factor-alpha expression by bisphenol A via nuclear factor-kappaB inactivation in macrophages. , 2003, Cancer letters.

[33]  S. Hwang,et al.  Enhanced interleukin‐4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen‐primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor‐AT and Ca2+ , 2003, Immunology.

[34]  Rosalind,et al.  Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. , 1996, Environmental health perspectives.

[35]  J. Rathmell,et al.  Metabolic pathways in T cell fate and function. , 2012, Trends in immunology.

[36]  T. Willson,et al.  Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis. , 2005, Journal of neuroimmunology.

[37]  A. Yamada,et al.  Transmaternal Exposure to Bisphenol A Modulates the Development of Oral Tolerance , 2007, Pediatric Research.

[38]  Y. Taketani,et al.  Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. , 2002, Human reproduction.

[39]  Huimin Yan,et al.  Exposure to Bisphenol A Prenatally or in Adulthood Promotes TH2 Cytokine Production Associated with Reduction of CD4+CD25+ Regulatory T Cells , 2008, Environmental health perspectives.

[40]  Dallas Jones,et al.  Nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in resting murine lymphocytes. The PPARalpha in T and B lymphocytes is both transactivation and transrepression competent. , 2002, The Journal of biological chemistry.

[41]  J. Youn,et al.  Evaluation of the immune response following exposure of mice to bisphenol A: Induction of th1 cytokine and prolactin by BPA exposure in the mouse spleen cells , 2002, Archives of pharmacal research.

[42]  D. Vethaak,et al.  Occurrence of bisphenol A in surface water and uptake in fish: evaluation of field measurements. , 2002, Chemosphere.

[43]  V. Fuster,et al.  Pioglitazone modulates vascular inflammation in atherosclerotic rabbits noninvasive assessment with FDG-PET-CT and dynamic contrast-enhanced MR imaging. , 2011, JACC. Cardiovascular imaging.

[44]  Yanfeng Wu,et al.  Rosiglitazone enhances the proliferation of neural progenitor cells and inhibits inflammation response after spinal cord injury , 2011, Neuroscience Letters.

[45]  Yongqing Hou,et al.  Activation of peroxisome proliferator-activated receptor-gamma potentiates pro-inflammatory cytokine production, and adrenal and somatotropic changes of weaned pigs after Escherichia coli lipopolysaccharide challenge. , 2009, Innate immunity.

[46]  Markus Frericks,et al.  Microarray analysis of the AHR system: tissue-specific flexibility in signal and target genes. , 2007, Toxicology and applied pharmacology.

[47]  Tanja Krüger,et al.  Plastic components affect the activation of the aryl hydrocarbon and the androgen receptor. , 2008, Toxicology.

[48]  Philippa Marrack,et al.  Genetic and hormonal factors in female-biased autoimmunity. , 2010, Autoimmunity reviews.

[49]  William Bourguet,et al.  Activation of RXR–PPAR heterodimers by organotin environmental endocrine disruptors , 2009, EMBO reports.

[50]  B. Staels,et al.  Therapeutic roles of peroxisome proliferator-activated receptor agonists. , 2005, Diabetes.

[51]  O. Abramsky,et al.  Activity of multiple sclerosis during pregnancy and puerperium , 1984, Annals of neurology.

[52]  I. Lutz,et al.  Bisphenol A induces feminization in Xenopus laevis tadpoles. , 2004, Environmental research.

[53]  L. Grumetto,et al.  Determination of bisphenol a and bisphenol B residues in canned peeled tomatoes by reversed-phase liquid chromatography. , 2008, Journal of agricultural and food chemistry.

[54]  A. Vandenbark,et al.  Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains1 , 2001, The Journal of Immunology.

[55]  D. Zalko,et al.  Peroxisome Proliferator-Activated Receptor γ Is a Target for Halogenated Analogs of Bisphenol A , 2011, Environmental health perspectives.

[56]  G. Gilkeson,et al.  Estrogen Receptors in Immunity and Autoimmunity , 2011, Clinical reviews in allergy & immunology.

[57]  C. Sonnenschein,et al.  Environmental causes of cancer: endocrine disruptors as carcinogens , 2010, Nature Reviews Endocrinology.

[58]  Y. Terauchi,et al.  Peroxisome proliferator-activated receptor-gamma haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis. , 2001, The Journal of clinical investigation.

[59]  新野 正明.  Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-γ , 2003 .

[60]  Anne Marie Vinggaard,et al.  Endocrine-Disrupting Potential of Bisphenol A, Bisphenol A Dimethacrylate, 4-n-Nonylphenol, and 4-n-Octylphenol in Vitro: New Data and a Brief Review , 2007, Environmental health perspectives.

[61]  W. Paul,et al.  Memory CD4+ T Cells: fate determination, positive feedback and plasticity , 2012, Cellular and Molecular Life Sciences.

[62]  M. Emborg,et al.  The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys , 2011, Journal of Neuroinflammation.

[63]  B. Shepherd,et al.  Effects of endocrine disrupters on the expression of growth hormone and prolactin mRNA in the rainbow trout pituitary. , 2006, General and comparative endocrinology.

[64]  D. Snow,et al.  Agrichemicals in nebraska, USA, watersheds: Occurrence and endocrine effects , 2009, Environmental toxicology and chemistry.

[65]  R J Walter,et al.  Steroid sex hormones regulate the release of tumor necrosis factor by macrophages. , 1995, Cellular immunology.

[66]  A. Scott,et al.  17beta-estradiol alters the activity of conventional and IFN-producing killer dendritic cells. , 2008, Journal of immunology.

[67]  O. Tsutsumi,et al.  Serum bisphenol a concentrations showed gender differences, possibly linked to androgen levels. , 2002, Biochemical and biophysical research communications.

[68]  Yutaka Osuga,et al.  Differential Interactions of Bisphenol A and17β-estradiol with Estrogen Receptor α (ERα) and ERβ , 1999 .

[69]  R. Henderson,et al.  Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. , 2005, Immunology letters.

[70]  K. Clark,et al.  Exposure analysis of bisphenol A in surface water systems in North America and Europe. , 2009, Environmental science & technology.

[71]  Scott M Belcher,et al.  Assessment of bisphenol A released from reusable plastic, aluminium and stainless steel water bottles. , 2011, Chemosphere.

[72]  H. Sone,et al.  Xenoestrogens down-regulate aryl-hydrocarbon receptor nuclear translocator 2 mRNA expression in human breast cancer cells via an estrogen receptor alpha-dependent mechanism. , 2011, Toxicology letters.

[73]  H. Taylor,et al.  In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer , 2010, Hormones & cancer.

[74]  Hong Wang,et al.  Transient neonatal estrogen exposure to estrogen-deficient mice (aromatase knockout) reduces prostate weight and induces inflammation in late life. , 2006, The American journal of pathology.

[75]  H. Weiner,et al.  Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor , 2008, Nature.

[76]  A. Soto,et al.  Bisphenol A: Perinatal exposure and body weight , 2009, Molecular and Cellular Endocrinology.

[77]  Yuhong Yang,et al.  Regulation of Immune Responses and Autoimmune Encephalomyelitis by PPARs , 2010, PPAR research.

[78]  M. Muroi,et al.  Effect of endocrine disrupting chemicals on lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production by mouse macrophages. , 2004, Biological & pharmaceutical bulletin.

[79]  Bruce Blumberg,et al.  Endocrine disrupting chemicals and disease susceptibility , 2011, The Journal of Steroid Biochemistry and Molecular Biology.

[80]  T. Klonisch,et al.  Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction. , 2005, Reproduction.

[81]  K. Korach,et al.  Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice , 2008, Genes and Immunity.

[82]  B Staels,et al.  Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. , 2001, European journal of immunology.

[83]  Zijian Wang,et al.  Acute and early life stage toxicity of industrial effluent on Japanese medaka (Oryzias latipes). , 2006, Science of the Total Environment.

[84]  M. Veldhoen,et al.  The aryl hydrocarbon receptor: fine-tuning the immune-response. , 2010, Current opinion in immunology.

[85]  Taisen Iguchi,et al.  An ecological assessment of bisphenol-A: evidence from comparative biology. , 2007, Reproductive toxicology.

[86]  Kyung-Chul Choi,et al.  Effects of 17beta-estradiol and xenoestrogens on mouse embryonic stem cells. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[87]  D. Choubey,et al.  Mutually Positive Regulatory Feedback Loop between Interferons and Estrogen Receptor-α in Mice: Implications for Sex Bias in Autoimmunity , 2010, PloS one.

[88]  H. Takano,et al.  Prenatal exposure to bisphenol A up‐regulates immune responses, including T helper 1 and T helper 2 responses, in mice , 2004, Immunology.

[89]  M. Petri,et al.  Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. , 2010, Arthritis and rheumatism.

[90]  Justin G Teeguarden,et al.  Twenty-four hour human urine and serum profiles of bisphenol a during high-dietary exposure. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[91]  Philippe Gosset,et al.  Peroxisome proliferator‐activated receptor γ  activators affect the maturation of human monocyte‐derived dendritic cells , 2001 .

[92]  S H Snyder,et al.  Nitric oxide in the nervous system. , 1995, Annual review of pharmacology and toxicology.

[93]  J. Rajasingh,et al.  PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. , 2005, Journal of neuroimmunology.

[94]  P. Lalonde,et al.  Migration of bisphenol A from plastic baby bottles, baby bottle liners and reusable polycarbonate drinking bottles , 2009, Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment.

[95]  Ichiro Manabe,et al.  Chronic inflammation links cardiovascular, metabolic and renal diseases. , 2011, Circulation journal : official journal of the Japanese Circulation Society.

[96]  F. Huang,et al.  The upregulation of tumour necrosis factor-α and surface antigens expression on macrophages by bisphenol A-glycidyl-methacrylate. , 2012, International endodontic journal.

[97]  B. Le Bizec,et al.  Exposure assessment of French women and their newborns to tetrabromobisphenol-A: occurrence measurements in maternal adipose tissue, serum, breast milk and cord serum. , 2008, Chemosphere.

[98]  D. Feldman,et al.  Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. , 1993, Endocrinology.

[99]  J. Rajasingh,et al.  PPARγ antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis , 2005, Journal of Neuroimmunology.

[100]  T. Willson,et al.  Protective effects of a peroxisome proliferator-activated receptor-β/δ agonist in experimental autoimmune encephalomyelitis , 2005, Journal of Neuroimmunology.

[101]  P. Chambon,et al.  Estradiol enhances primary antigen‐specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor α expression in hematopoietic cells , 2003, European journal of immunology.

[102]  Yongmin Tang,et al.  OCT4 pseudogenes present in human leukemia cells , 2012, Clinical and Experimental Medicine.

[103]  T. Midoro-Horiuti,et al.  Maternal Bisphenol A Exposure Promotes the Development of Experimental Asthma in Mouse Pups , 2009, Environmental health perspectives.

[104]  N. Olea,et al.  In vitro effect of the resin component bisphenol A on substrate adherence capacity of macrophages. , 1999, Journal of endodontics.

[105]  T. Akaike,et al.  Suppression of NO production and 8-nitroguanosine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: involvement of estrogen receptor-dependent or -independent pathways. , 2008, Nitric oxide : biology and chemistry.

[106]  Catherine M. Sawai,et al.  Effect of bisphenol A on murine immune function: modulation of interferon-gamma, IgG2a, and disease symptoms in NZB X NZW F1 mice. , 2003, Environmental health perspectives.

[107]  G. Tsokos,et al.  Pathogenesis of human systemic lupus erythematosus: recent advances. , 2010, Trends in molecular medicine.

[108]  T. Hünig,et al.  Molecular and cellular mechanisms of T Cell development , 2004, Cellular and Molecular Life Sciences CMLS.

[109]  M. Denison,et al.  Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound. , 2008, Blood.

[110]  J. Corton,et al.  Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. , 1998, Endocrinology.

[111]  M. Marino,et al.  Bisphenol A impairs estradiol‐induced protective effects against DLD‐1 colon cancer cell growth , 2010, IUBMB life.

[112]  M. Currás-Collazo.  Nitric Oxide Signaling as a Common Target of Organohalogens and Other Neuroendocrine Disruptors , 2011, Journal of toxicology and environmental health. Part B, Critical reviews.

[113]  H. Shinmoto,et al.  Orally Administered Bisphenol A Disturbed Antigen Specific Immunoresponses in the Naïve Condition , 2007, Bioscience, biotechnology, and biochemistry.

[114]  S. Senju,et al.  Bisphenol A in combination with TNF-α selectively induces Th2 cell-promoting dendritic cells in vitro with an estrogen-like activity , 2010, Cellular and Molecular Immunology.

[115]  M. Pyo,et al.  Bisphenol A-induced downregulation of murine macrophage activities in vitro and ex vivo. , 2005, Environmental toxicology and pharmacology.