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Persistent Hypomethylation in the Promoter of Nucleosomal Binding Protein 1 (Nsbp1) Correlates with Overexpression of Nsbp1 in Mouse Uteri Neonatally Exposed to Diethylstilbestrol or Genistein

Department of Environmental Health (W.-Y.T., M.M., S.-M.H.), Center for Environmental Genetics (S.-M.H., M.M.), and Cancer Center (S.-M.H.), University of Cincinnati Medical School, Cincinnati, Ohio 45267; Division of Urology (W.-Y.T., K.M., R.Y.S.C., S.-M.H.), Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts 01605; and Laboratory of Molecular Toxicology (R.N., W.J.), National Institute of Environmental Health Sciences, National Institutes of Health/Department of Health and Human Services, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Shuk-Mei Ho, Department of Environmental Health, Kettering Complex, Room 128, 3223 Eden Avenue, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, Ohio 45267–0056. E-mail: shuk-mei.ho{at}uc.edu.

Neonatal exposure of CD-1 mice to diethylstilbestrol (DES) or genistein (GEN) induces uterine adenocarcinoma in aging animals. Uterine carcinogenesis in this model is ovarian dependent because its evolution is blocked by prepubertal ovariectomy. This study seeks to discover novel uterine genes whose expression is altered by such early endocrine disruption via an epigenetic mechanism. Neonatal mice were treated with 1 or 1000 µg/kg DES, 50 mg/kg GEN, or oil (control) on d 1–5. One group of treated mice was killed before puberty on d 19. Others were ovariectomized or left intact, and killed at 6 and 18 months of age. Methylation-sensitive restriction fingerprinting was performed to identify differentially methylated sequences associated with neonatal exposure to DES/GEN. Among 14 candidates, nucleosomal binding protein 1 (Nsbp1), the gene for a nucleosome-core-particle binding protein, was selected for further study because of its central role in chromatin remodeling. In uteri of immature control mice, Nsbp1 promoter CpG island (CGI) was minimally methylated. Once control mice reached puberty, the Nsbp1 CGI became hypermethylated, and gene expression declined further. In contrast, in neonatal DES/GEN-treated mice, the Nsbp1 CGI stayed anomalously hypomethylated, and the gene exhibited persistent overexpression throughout life. However, if neonatal DES/GEN-treated mice were ovariectomized before puberty, the CGI remained minimally to moderately methylated, and gene expression was subdued except in the group treated with 1000 µg/kg DES. Thus, the life reprogramming of uterine Nsbp1 expression by neonatal DES/GEN exposure appears to be mediated by an epigenetic mechanism that interacts with ovarian hormones in adulthood.

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