Gene expression changes in immune response pathways following oral administration of tetrabromobisphenol A (TBBPA) in female Wistar Han rats.

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant used globally at high volumes, primarily in the epoxy resin of circuit boards. It has been detected in the environment and in humans. The National Toxicology Program found that chronic oral TBBPA treatment of 250mg/kg and higher caused an increased incidence of uterine lesions in female Wistar Han rats. The present laboratory has previously reported changes in gene expression associated with estrogen homeostasis in liver and uterine tissue of adult female Wistar Han rats after five days of gavage with 250mg/kg of TBBPA. Microarray analysis of tissue from these same TBBPA-treated rats was performed to detect additional pathways perturbed by TBBPA. Microarray analysis of uterine tissue detected downregulation of genes in pathways of the immune response following TBBPA treatment. These results, along with validation of associated gene expression changes using droplet digital PCR, are reported here. Our findings suggest mechanisms that may be related to estrogen-mediated immunosuppression.

[1]  M. Whalen,et al.  Tetrabromobisphenol A decreases cell-surface proteins involved in human natural killer (NK) cell–dependent target cell lysis , 2011, Journal of immunotoxicology.

[2]  Timo Hamers,et al.  In vitro profiling of the endocrine-disrupting potency of brominated flame retardants. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[3]  K. Straif,et al.  Carcinogenicity of some industrial chemicals. , 2016, The Lancet Oncology.

[4]  C. D. de Wit,et al.  Brominated flame retardants in the Arctic environment--trends and new candidates. , 2010, The Science of the total environment.

[5]  K. Nakayama,et al.  Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface. , 2007, Cancer research.

[6]  Jeff Mellen,et al.  High-Throughput Droplet Digital PCR System for Absolute Quantitation of DNA Copy Number , 2011, Analytical chemistry.

[7]  I. Meerts,et al.  Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[8]  T. Taniguchi,et al.  Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses , 2014, eLife.

[9]  L. Birnbaum,et al.  Mimicking of Estradiol Binding by Flame Retardants and Their Metabolites: A Crystallographic Analysis , 2013, Environmental health perspectives.

[10]  T. Furuno,et al.  Role of cathepsin E in decidual macrophage of patients with recurrent miscarriage. , 2014, Molecular human reproduction.

[11]  Ǻ. Bergman,et al.  An overview of commercially used brominated flame retardants, their applications, their use patterns in different countries/regions and possible modes of release. , 2003, Environment international.

[12]  Wout Slob,et al.  Endocrine effects of tetrabromobisphenol-A (TBBPA) in Wistar rats as tested in a one-generation reproduction study and a subacute toxicity study. , 2008, Toxicology.

[13]  R. Holmdahl,et al.  Estrogen-mediated immunosuppression in autoimmune diseases , 1998, Inflammation Research.

[14]  M. Whalen,et al.  Tetrabromobisphenol A has immunosuppressive effects on human natural killer cells , 2009, Journal of immunotoxicology.

[15]  Whitten Wk.  Modification of the oestrous cycle of the mouse by external stimuli associated with the male; changes in the oestrous cycle determined by vaginal smears. , 1958 .

[16]  C. Hubscher,et al.  A quantitative method for assessing stages of the rat estrous cycle , 2005, Biotechnic & histochemistry : official publication of the Biological Stain Commission.

[17]  Satoru Takahashi,et al.  Repression of cathepsin E expression increases the risk of mammary carcinogenesis and links to poor prognosis in breast cancer. , 2014, Carcinogenesis.

[18]  Adrian Covaci,et al.  After the PBDE Phase-Out: A Broad Suite of Flame Retardants in Repeat House Dust Samples from California , 2012, Environmental science & technology.

[19]  J. Arunakaran,et al.  Interaction of estradiol, progesterone and corticosterone on uterine connective tissue degrading enzymes. , 1998, Endocrine research.

[20]  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.

[21]  G. Tiegs,et al.  The flame retardants tetrabromobisphenol A and tetrabromobisphenol A-bisallylether suppress the induction of interleukin-2 receptor alpha chain (CD25) in murine splenocytes. , 2003, Toxicology.

[22]  Y. van Kooyk,et al.  Recognition of tumor glycans by antigen-presenting cells. , 2006, Current opinion in immunology.

[23]  M. Dourson,et al.  A reproductive, developmental and neurobehavioral study following oral exposure of tetrabromobisphenol A on Sprague-Dawley rats. , 2015, Toxicology.

[24]  S. Bilbo,et al.  The immune system and developmental programming of brain and behavior , 2012, Frontiers in Neuroendocrinology.

[25]  S. Elmore,et al.  Environmental Chemical Exposure May Contribute to Uterine Cancer Development , 2015, Toxicologic pathology.

[26]  Akihiko Hirose,et al.  Effects of tetrabromobisphenol A, a brominated flame retardant, on the immune response to respiratory syncytial virus infection in mice. , 2010, International immunopharmacology.

[27]  W. Utian,et al.  Myometrial oxytocin receptors levels in the pregnant rat are higher in distal than in proximal portions of the horn and correlate with disparate oxytocin responsive myometrial contractility in these segments. , 1990, Endocrinology.

[28]  P. Bizargity,et al.  Dendritic cells: a family portrait at mid‐gestation , 2009, Immunology.

[29]  D. Morgan,et al.  Tetrabromobisphenol A activates the hepatic interferon pathway in rats. , 2017, Toxicology letters.

[30]  Benjamin J. Hindson,et al.  Evaluation of a Droplet Digital Polymerase Chain Reaction Format for DNA Copy Number Quantification , 2011, Analytical chemistry.

[31]  Mohamed Abou-Elwafa Abdallah,et al.  Analytical and environmental aspects of the flame retardant tetrabromobisphenol-A and its derivatives. , 2009, Journal of chromatography. A.

[32]  R. Elble,et al.  Loss of CLCA4 Promotes Epithelial-to-Mesenchymal Transition in Breast Cancer Cells , 2013, PloS one.

[33]  W. Whitten.  Modification of the oestrous cycle of the mouse by external stimuli associated with the male. , 1956, The Journal of endocrinology.

[34]  L. Birnbaum,et al.  Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A. , 2016, Toxicology and applied pharmacology.