title: Sustained reprogramming of the estrogen response after chronic exposure to endocrine disruptors.
abstract: The pervasive nature of estrogenic industrial and dietary compounds is a growing health concern linked to cancer, obesity, and neurological disorders. Prior analyses of endocrine disruptor action have focused primarily on the short-term consequences of exposure. However, these studies are unlikely to reflect the consequences of constant exposures common to industrialized countries. Here we examined the global effects of long-term endocrine disruption on gene transcription and estrogen signaling. Estrogen-dependent breast cancer cell lines were chronically treated with physiologically relevant levels of bisphenol A or genistein for more than 70 passages. Microarray analysis demonstrated global reprogramming of the transcriptome when compared with a similarly cultured control cell line. Estrogen-responsive targets showed diminished expression in both the presence and absence of estrogen. Estrogen receptor recruitment, H3K4 monomethylation, and deoxyribonuclease accessibility were reduced at nearby response elements. Based on these observations, we investigated the potential of long-term endocrine disruptor exposure to initiate persistent transcriptional reprogramming. Culture of chronically exposed cell lines in the absence of the endocrine disruptors did not reverse many of the signaling defects that accumulated during treatment. Taken together, these data demonstrate that chronic exposure to endocrine disrupting compounds can permanently alter physiological hormone signaling.
authors.affiliation: Department of Molecular Genetics (A.R.P., A.S., K.E.W., C.J.B.), The Ohio State University, Center for Biostatistics (X.M.), Ohio State University Wexner Medical Center, and The Arthur G. James Comprehensive Cancer Center (A.R.P., A.S., C.J.B.), Columbus, Ohio 43210; and Laboratory of Molecular Carcinogenesis (T.K.A.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Patterson
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.forename: Ali
authors.initials: A
authors.lastname: Shapiro
authors.forename: Karen E
authors.initials: KE
authors.lastname: Wernke
authors.forename: Trevor K
authors.initials: TK
authors.lastname: Archer
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Burd
mesh_terms: D045744:Cell Line, Tumor; D051776:Early Growth Response Protein 3 / Q000235:genetics; D052244:Endocrine Disruptors / Q000633:toxicity*; D044127:Epigenesis, Genetic / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056426:Genetic Loci; D006801:Humans; D008024:Ligands; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C079945:EGR3 protein, human; D052244:Endocrine Disruptors; D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen; D051776:Early Growth Response Protein 3