title: Exposure to diethylstilbestrol during pregnancy modulates microRNA expression profile in mothers and fetuses reflecting oncogenic and immunological changes.
abstract: Prenatal exposure to diethylstilbestrol (DES) is known to cause an increased susceptibility to a wide array of clinical disorders in humans. Previous studies from our laboratory demonstrated that prenatal exposure to DES induces thymic atrophy and apoptosis in the thymus. In the current study, we investigated if such effects on the thymus result from alterations in the expression of microRNA (miR). To that end, pregnant C57BL/6 mice who were exposed to DES and miR profiles in thymocytes of both the mother and fetuses on postnatal day 3 (gestation day 17) were studied. Of the 609 mouse miRs examined, we noted 59 altered miRs that were common for both mothers and fetuses, whereas 107 altered miRs were specific to mothers only and 101 altered miRs were specific to fetuses only. Upon further analyses in the fetuses, we observed that DES-mediated changes in miR expression may regulate genes involved in important functions, such as apoptosis, autophagy, toxicity, and cancer. Of the miRs that showed decreased expression following DES treatment, miR-18b and miR-23a were found to possess complementary sequences and binding affinity for 3' untranslated regions of the Fas ligand (FasL) and Fas, respectively. Transfection studies confirmed that DES-mediated downregulation of miR-18b and miR-23a led to increased FasL and Fas expression. These data demonstrated that prenatal DES exposure can cause alterations in miRs, leading to changes in the gene expression, specifically, miR-mediated increased expression in FasL and Fas causing apoptosis and thymic atrophy.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (N.P.S., I.K.A., M.M., U.P.S., P.N., M.N.) and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (J.Z.).
authors.forename: Narendra P
authors.initials: NP
authors.lastname: Singh
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (N.P.S., I.K.A., M.M., U.P.S., P.N., M.N.) and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (J.Z.).
authors.forename: Ikbal K
authors.initials: IK
authors.lastname: Abbas
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (N.P.S., I.K.A., M.M., U.P.S., P.N., M.N.) and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (J.Z.).
authors.forename: Martine
authors.initials: M
authors.lastname: Menard
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (N.P.S., I.K.A., M.M., U.P.S., P.N., M.N.) and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (J.Z.).
authors.forename: Udai P
authors.initials: UP
authors.lastname: Singh
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (N.P.S., I.K.A., M.M., U.P.S., P.N., M.N.) and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (J.Z.).
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (N.P.S., I.K.A., M.M., U.P.S., P.N., M.N.) and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (J.Z.).
authors.forename: Prakash
authors.initials: P
authors.lastname: Nagarkatti
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (N.P.S., I.K.A., M.M., U.P.S., P.N., M.N.) and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (J.Z.) mnagark@uscmed.sc.edu.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D020413:3' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D004054:Diethylstilbestrol / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D053222:Fas Ligand Protein / Q000235:genetics; D005260:Female; D005333:Fetus / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009035:Mothers; D009369:Neoplasms / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D060168:Thymocytes / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects* / Q000235:genetics; D019014:fas Receptor / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D035683:MicroRNAs; D019014:fas Receptor; D004054:Diethylstilbestrol