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

Wan-Yee Tang, Retha Newbold, Katerina Mardilovich, Wendy Jefferson, Robert Y S Cheng, Mario Medvedovic, Shuk Mei Ho

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5922-5931
Number of pages10
JournalEndocrinology
Volume149
Issue number12
DOIs
StatePublished - Dec 2008
Externally publishedYes

Fingerprint

HMGN Proteins
Diethylstilbestrol
Genistein
Uterus
CpG Islands
Puberty
Gene Expression
Epigenomics
Chromatin Assembly and Disassembly
Nucleosomes
Ovariectomy
Methylation
Genes
Carrier Proteins
Oils
Carcinogenesis
Adenocarcinoma
Hormones

ASJC Scopus subject areas

  • Endocrinology

Cite this

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. / Tang, Wan-Yee; Newbold, Retha; Mardilovich, Katerina; Jefferson, Wendy; Cheng, Robert Y S; Medvedovic, Mario; Ho, Shuk Mei.

In: Endocrinology, Vol. 149, No. 12, 12.2008, p. 5922-5931.

Research output: Contribution to journalArticle

Tang, Wan-Yee ; Newbold, Retha ; Mardilovich, Katerina ; Jefferson, Wendy ; Cheng, Robert Y S ; Medvedovic, Mario ; Ho, Shuk Mei. / 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. In: Endocrinology. 2008 ; Vol. 149, No. 12. pp. 5922-5931.
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abstract = "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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