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DDT and its metabolites alter gene expression in human uterine cell lines through estrogen receptor-independent mechanisms.

By Daniel E Frigo, Matthew E Burow, Kamron A Mitchell, Tung-Chin Chiang and John A McLachlan

Abstract

Endocrine-disrupting organochlorines, such as the pesticide dichlorodiphenyltrichloroethane (DDT), bind to and activate estrogen receptors (ERs), thereby eliciting estrogen-like effects. Although ERs function predominantly through activation of transcription via estrogen-responsive elements, both ERs, alpha and ss, can interact with various transcription factors such as activator protein-1 (AP-1). Additionally, estrogens may regulate early signaling events, suggesting that the biological effects of environmental estrogens may not be mediated through classic ER (alpha and ss) activity alone. We hypothesized that known environmental estrogens, such as DDT and its metabolites, activate AP-1-mediated gene transactivation through both ER-dependent and ER-independent means. Using two Ishikawa human endometrial adenocarcinoma cell line variants that we confirmed to be estrogen responsive [Ishikawa(+)] and estrogen unresponsive [Ishikawa(-)], we generated stably transfected AP-1 luciferase cell lines to identify the role of an estrogen-responsive mechanism in AP-1-mediated gene expression by various stimuli. Our results demonstrate that DDT and dichlorodiphenyldichloroethane (DDD) were the most potent activators of AP-1 activity; 2,2-bis(p-chlorophenyl) acetic acid failed to activate. Although stimulated in both Ishikawa(+) and Ishikawa(-) cells by DDT and its congeners, AP-1 activation was more pronounced in the estrogen-unresponsive Ishikawa(-) cells. In addition, DDT, DDD, and dichlorodiphenyldichloroethylene (DDE) could also stimulate AP-1 activity in the estrogen-unresponsive human embryonic kidney 293 cells using a different promoter context. Thus, our data demonstrate that DDT and its metabolites activate the AP-1 transcription factor independent of ER (alpha or ss) status

Topics: Research Article
Year: 2002
OAI identifier: oai:pubmedcentral.nih.gov:1241112
Provided by: PubMed Central

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Citations

  1. (2000). 1,1,1-trichloro-2,2-bis (pchlorophenyl)-ethane (DDT) and reduced bone mineral density.
  2. (1994). A C-terminal domain in FosB, absent in FosB/SF and Fra-1, which is able to interact with the TATA binding protein, is required for altered cell growth.
  3. A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology
  4. (2000). Ability of xeno- and phytoestrogens to modulate expression of estrogen-sensitive genes in rat uterus: estrogenicity profiles and uterotropic activity.
  5. (1998). Activation of c-Neu tyrosine kinase by o,p´-DDT and beta-HCH in cell-free and intact cell preparations from MCF-7 human breast cancer cells.
  6. (2000). Activation of estrogen receptor-alpha by the heavy metal cadmium.
  7. (1338). Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-dependent transcriptional events in carcinogenesis. Free Radic Biol Med
  8. (1997). Additive estrogenic activities of a binary mixture of 2´,4´,6´-trichloroand 2´,3´,4´,5´-tetrachloro-4-biphenylol.
  9. (1998). Altered biologic activities of commercial polychlorinated biphenyl mixtures after microbial reductive dechlorination. Environ Health Perspect 106(suppl 6):1409–1418
  10. (2001). An Introduction to Insecticides. Minneapolis, MN:University of Minnesota Press,
  11. (1999). AP-1: one switch for many signals.
  12. (2001). Association of DDT with spontaneous abortion: a case-control study.
  13. (1992). Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines.
  14. (1999). Avantaggiati ML. p300 and CBP: partners for life and death.
  15. (1993). Blood levels of organochlorine residues and risk of breast cancer.
  16. (1999). c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms.
  17. (2000). Cadmium-mediated oxidative stress in alveolar epithelial cells induces the expression of gamma-glutamylcysteine synthetase catalytic subunit and glutathione S-transferase alpha and pi isoforms: potential role of activator protein-1.
  18. (2000). Cancer mortality and environmental exposure to DDE in the United States. Environ Health Perspect
  19. (2001). Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-alpha knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors.
  20. (2000). Cell signaling by receptor tyrosine kinases.
  21. (1995). Cellular pattern of c-fos induction by estradiol in the immature rat uterus.
  22. (1994). Characterization of a mitogen-response unit in the mouse lactoferrin gene promoter.
  23. (1997). Chiral pesticides in soils of the Fraser Valley, British Columbia.
  24. (1997). Comparative in vitro and in vivo protein kinase C activation by selected pesticides and transition metal salts.
  25. (2000). Comparison of transcriptional synergy of estrogen receptors alpha and beta from multiple tandem estrogen response elements.
  26. (1998). Concentrations and enantiomeric ratios of organochlorine pesticides in soils from the U.S. corn belt.
  27. (1999). Correlation between the activation of Neu tyrosine kinase and promotion of foci formation induced by selected organochlorine compounds in the MCF-7 model system.
  28. (1992). Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor.
  29. (2000). Cross-talk between phosphatidylinositol 3-kinase and sphingomyelinase pathways as a mechanism for cell survival/death decisions.
  30. (1997). DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells.
  31. (1994). Developmental abnormalities of the gonad and abnormal sex hormone concentrations in juvenile alligators from contaminated and control lakes in Florida. Environ Health Perspect
  32. (2000). Differences in protein kinase C and estrogen receptor alpha, beta expression and signaling correlate with apoptotic sensitivity of MCF-7 breast cancer cell variants.
  33. (2001). Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogenresponsive elements.
  34. (1997). Differential effects of aroclors and DDT on growth factor gene expression and receptor tyrosine kinase activity in human breast epithelial cells.
  35. (2000). Differential estrogen receptor binding of estrogenic substances: a species comparison.
  36. (1997). Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites.
  37. (1998). Differential spatiotemporal regulation of lactoferrin and progesterone receptor genes in the mouse uterus by primary estrogen, catechol estrogen, and xenoestrogen.
  38. (1999). Effects of environmental estrogens on tumor necrosis factor alpha-mediated apoptosis in MCF-7 cells.
  39. (1995). Effects of sex hormones on oncogene expression in the vagina and on development of sexual dimorphism of the pelvis and anococcygeus muscle in the mouse. Environ Health Perspect 103(suppl 7):79–82
  40. (2001). Endocrine disruption in sexual differentiation and puberty. What do pseudohermaphroditic polar bears have to do with the practice of pediatrics?
  41. (1998). Endocrine disruption in wildlife: a critical review of the evidence. Crit Rev Toxicol
  42. (2000). Endocrine disruptors: present issues, future directions.
  43. (1993). Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-pdioxin. Fundam Appl Toxicol
  44. (1997). Environmental estrogen stimulation of growth and estrogen receptor function in preneoplastic and cancerous human breast cell lines.
  45. (1998). Environmental estrogenic pollutants induce acute vascular relaxation by inhibiting L-type Ca2+ channels in smooth muscle cells.
  46. (2000). Environmental factors in infertility.
  47. (2001). Estrogen receptor alpha mediated induction of the transforming growth factor alpha gene by estradiol and 4-hydroxytamoxifen in MDA-MB-231 breast cancer cells.
  48. (2000). Estrogen receptor pathways to AP-1.
  49. (2001). Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1.
  50. (2001). Estrogen receptors alpha and beta exhibit different estradiol and estrogen response element binding in the presence of nonspecific DNA.
  51. (2000). Estrogen receptors: how do they control reproductive and nonreproductive functions?
  52. (2000). Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF.
  53. (1999). Estrogen-induced activation of mitogenactivated protein kinase requires mobilization of intracellular calcium.
  54. (1998). Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation.
  55. (2000). Estrogenic and antiestrogenic activities of flavonoid phytochemicals through estrogen receptor binding-dependent and -independent mechanisms.
  56. (1998). Estrogenic regulation of clusterin mRNA in normal and malignant endometrial tissue.
  57. (1997). Estrogenic responses in estrogen receptor-alpha deficient mice reveal a distinct estrogen signaling pathway.
  58. (1998). Fos family members induce cell cycle entry by activating cyclin D1.
  59. (1998). Germ cell cancer and disorders of spermatogenesis: an environmental connection?
  60. (1998). Heptachlor and the mitogenactivated protein kinase module in human lymphocytes.
  61. (1993). Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain.
  62. (1996). Identification of environmental chemicals with estrogenic activity using a combination of in vitro assays.
  63. (2001). Increased ErbB-2 tyrosine kinase activity, MAPK phosphorylation, and cell proliferation in the prostate cancer cell line LNCaP following treatment by select pesticides.
  64. (1998). Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.
  65. Interactions of chlorinated hydrocarbons with steroid hormones. Fed Proc
  66. (2000). Isolation and molecular characterization of the 5´-upstream region of the human TRAIL gene.
  67. (2000). Ligand-independent activation of the androgen receptor in prostate cancer by growth factors and cytokines.
  68. (1998). Long-term DDT pollution in tropical soils: effect of DDT and degradation products on soil microbial activities leading to soil fertility.
  69. (1999). Methoxychlor stimulates estrogen-responsive messenger ribonucleic acids in mouse uterus through a non-estrogen receptor (non-ER) alpha and non-ER beta mechanism.
  70. (1994). Multiple elements within the 5´ distal enhancer of the mouse heme oxygenase-1 gene mediate induction by heavy metals.
  71. (2000). Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta.
  72. (1995). Organochlorine compounds in relation to breast cancer, endometrial cancer, and endometriosis: an assessment of the biological and epidemiological evidence. Crit Rev Toxicol
  73. (1997). Organochlorine exposure and risk for breast cancer.
  74. (1996). Peptide growth factor crosstalk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol.
  75. (2001). Phosphatidylinositol 3-kinase/AKTmediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance.
  76. (2001). Phytochemical glyceollins, isolated from soy, mediate antihormonal effects through estrogen receptor alpha and beta.
  77. (1995). Phytoestrogens are partial estrogen agonists in the adult male mouse. Environ Health Perspect 103(suppl 7):123–127
  78. (1999). Plasma steroid concentrations and male phallus size in juvenile alligators from seven Florida lakes.
  79. (1999). Polychlorinated biphenyls and chlorinated pesticides in bird eggs from Calabria (southern Italy). Ecotoxicol Environ Saf
  80. (1996). Promoter-specific activation of mouse lactoferrin gene by epidermal growth factor involves two adjacent regulatory elements.
  81. (2001). Rapid actions of plasma membrane estrogen receptors.
  82. (1995). Regulation of c-fos expression by convulsants and hexachlorocyclohexane isomers in primary cultures of cortical neurons.
  83. (2000). Relative binding affinity does not predict biological response to xenoestrogens in rat endometrial adenocarcinoma cells.
  84. (1995). Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells.
  85. (1986). Residues of chlorinated hydrocarbons in tissues of raptors in Florida.
  86. (1999). Sex reversal effects of environmentally relevant xenobiotic concentrations on the redeared slider turtle, a species with temperature-dependent sex determination.
  87. (2000). Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor.
  88. (2001). Statistics for Organochlorine Compounds in Whole Fish,
  89. (1997). Steroid effects at the membrane level on oxytocin systems.
  90. (2001). Stretch-mediated activation of selective MAPK subtypes and potentiation of AP-1 binding in human osteoblastic cells.
  91. (1999). SUM-159PT cells: a novel estrogen independent human breast cancer model system.
  92. (2000). The carcinogen Cd(2+) activates InsP(3)-mediated Ca(2+) release through a specific metal ion receptor in Xenopus oocyte.
  93. (1999). The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens.
  94. (1999). The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions.
  95. (1998). The oestrogen receptor regulates NFkappaB and AP-1 activity in a cell-specific manner.
  96. (1992). The PAR1 (YAP1/SNQ3) gene of Saccharomyces cerevisiae, a c-jun homologue, is involved in oxygen metabolism.
  97. (1981). Toone CK. DDT-induced feminization of gull embryos.
  98. (1992). Toxicological Profile for 4,4´-DDT, 4,4´-DDE, 4,4´-DDD. Atlanta, GA:Agency for Toxic Substances and Disease Registry,
  99. (1998). Transcription activation by the human estrogen receptor subtype beta (ER beta) studied with ER beta and ER alpha receptor chimeras.
  100. (1999). Transcriptional regulation of Fas gene expression by GA-binding protein and AP-1 in T cell antigen receptor.CD3 complex-stimulated T cells.
  101. (2000). Uncoupling of apoptosis and Jun/AP-1 activity in human promonocytic cells treated with DNA-damaging and stress-inducing agents.
  102. (2002). What are the implications of the interaction Articles • DDT and its metabolites induce AP-1 activity Environmental Health Perspectives •
  103. (1999). Will we be taught ethics by our clones? The mutations of the living, from endocrine disruptors to genetics. Baillieres Best Pract Res Clin Obstet Gynaecol
  104. (1997). Xenoestrogens and estrogen receptor action. In:

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