title: Altered expression of histone deacetylases, inflammatory cytokines and contractile-associated factors in uterine myometrium of Long Evans rats gestationally exposed to benzo[a]pyrene.
abstract: Etiology of preterm birth (PTB) is multifactorial; therefore, decreasing the incidence of PTB is a major challenge in the field of obstetrics. Epidemiological studies have reported an association between toxicants and PTB. However, there are no studies on the role of benzo[a]pyrene (BaP), an environmental toxicant, in the incidence of PTB. We first assessed the effects of BaP (150 and 300 µg kg(-1) body weight) dosed via gavage from day 14 to 17 of pregnancy on gestation length in Long Evans rats. We further assessed the histopathology of the uterus, expression of inflammatory cytokines, contractile-associated factors, histone deacetylases (HDACs) and NFқB-p65 in myometrium collected on day 22 postpartum versus vehicle-treated controls. In our study, rats exposed to BaP delivered prematurely (P < 0.05) compared to control. Hematoxylin and eosin staining of uterus showed squamous metaplasia, glandular and stromal hyperplasia in BaP-exposed rats versus control. The concentrations of BaP metabolites measured by high-pressure liquid chromatography were higher in uterine myometrium of BaP-exposed rats while they were undetectable in controls. Quantitative real-time polymerase chain reaction showed significant increases in mRNA expression of interleukin-1β and -8, tumor necrosis factor-α, connexin 43, cyclo-oxygenase-2 and prostaglandin F2α receptor as compared to controls (P < 0.05). Western blot analysis revealed that BaP exposure caused decreases in class I HDACs 1 and 3 and increases in class II HDAC 5, cyclo-oxygenase-2 and nuclear translocation of NFκB-p65 relative to controls. Our results suggest that gestational exposure to BaP increases incidence of PTB through epigenetic changes that causes increases in the expression of contractile-associated factors through the NFκB pathway. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Laknaur
authors.affiliation: Center for Women's Health Research, Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, TN, USA.
authors.forename: Terri-Lee
authors.initials: TL
authors.lastname: Foster
authors.affiliation: Center for Women's Health Research, Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, TN, USA.
authors.forename: Lesley E
authors.initials: LE
authors.lastname: Bobb
authors.affiliation: Department of Biochemistry & Cancer Biology, Meharry Medical College, Nashville, TN, USA.
authors.forename: Aramandla
authors.initials: A
authors.lastname: Ramesh
authors.affiliation: Center for Women's Health Research, Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, TN, USA.
authors.forename: Gwinnett M
authors.initials: GM
authors.lastname: Ladson
authors.affiliation: Division of Environmental Health Sciences, College of Public Health and Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Darryl B
authors.initials: DB
authors.lastname: Hood
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Hendy
authors.affiliation: Center for Women's Health Research, Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, TN, USA.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Thota
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D016207:Cytokines / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009215:Myometrium / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D047928:Premature Birth / Q000209:etiology; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011897:Random Allocation; D020318:Rats, Long-Evans; D014018:Tissue Distribution; D066007:Toxicokinetics; D051996:Transcription Factor RelA / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D002274:Carcinogens, Environmental; D016207:Cytokines; D007527:Isoenzymes; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D001564:Benzo(a)pyrene; D006655:Histone Deacetylases
keywords: Benzo(a)pyrene; Environmental toxicant; Histone deacetylases; NFқB; Preterm birth; Rats; Uterine myometrium; connexin 43, Cox2; inflammatory cytokines