Texas Medical Center
Greathouse, Kristen L.
XENOESTROGEN-SPECIFIC MECHANISMS OF DEVELOPMENTAL REPROGRAMMING CORRELATE WITH GENE EXPRESSION AND TUMOR DEVELOPMENT.
Degree: PhD, 2010, Texas Medical Center
Environmental exposures during sensitive windows of development can reprogram
normal physiological responses and alter disease susceptibility later in life in a process
known as developmental reprogramming. We have shown that neonatal exposure to
the xenoestrogen diethylstilbestrol (DES) can developmentally reprogram the
reproductive tract in genetically susceptible Eker rats giving rise to complete
penetrance of uterine leiomyoma. Based on this, we hypothesized that xenoestrogens,
including genistein (GEN) and bisphenol A (BPA), reprogram estrogen-responsive
gene expression in the myometrium and promote the development of uterine
leiomyoma. We proposed the mechanism that is responsible for the developmental
reprogramming of gene expression was through estrogen (E2)/ xenoestrogen inducedrapid
ER signaling, which modifies the histone methyltransferase Enhancer of Zeste
homolog 2 (EZH2) via activation of the PI3K/AKT pathway. We further hypothesized
that there is a xenostrogen-specific effect on this pathway altering patterns of histone
modification, DNA methylation and gene expression. In addition to our novel finding
that E2/DES-induced phosphorylation of EZH2 by AKT reduces the levels of
H3K27me3 in vitro and in vivo, this work demonstrates in vivo that a brief neonatal
exposure to GEN, in contrast to BPA, activates the PI3K/AKT pathway to regulate
EZH2 and decreases H3K27me3 levels in the neonatal uterus. Given that H3K27me3
is a repressive mark that has been shown to result in DNA methylation and gene
silencing we investigated the methylation of developmentally reprogrammed genes. In
support of this evidence, we show that neonatal DES exposure in comparison to VEH,
leads to hypomethylation of the promoter of a developmentally reprogrammed gene,
Gria2, that become hyper-responsive to estrogen in the adult myometrium indicating
that DES exposure alter gene expression via chromatin remodeling and loss of DNA
methylation. In the adult uterus, GEN and BPA exposure developmentally
reprogrammed expression of estrogen-responsive genes in a manner opposite of one
another, correlating with our previous data. Furthermore, the ability of GEN and BPA
to developmental reprogram gene expression correlated with tumor incidence and
multiplicity. These data show that xenoestrogens have unique effects on the activation
of non-genomic signaling in the developing uterus that promotes epigenetic and
genetic alterations, which are predictive of developmental reprogramming and
correlate with their ability to modulate hormone-dependent tumor development.
Advisors/Committee Members: Cheryl L. Walker, Ph.D., David Johnson, Ph.D., Stephen Hursting, Ph.D., M.P.H..
Subjects/Keywords: Xenoestrogens; developmental reprogramming; uterine leiomyoma; epigenetics; non-genomic signaling; estrogen receptor; Cancer Biology; Developmental Biology; Molecular Biology; Other Pharmacology, Toxicology and Environmental Health
to Zotero / EndNote / Reference
APA (6th Edition):
Greathouse, K. L. (2010). XENOESTROGEN-SPECIFIC MECHANISMS OF DEVELOPMENTAL REPROGRAMMING CORRELATE WITH GENE EXPRESSION AND TUMOR DEVELOPMENT. (Doctoral Dissertation). Texas Medical Center. Retrieved from http://digitalcommons.library.tmc.edu/utgsbs_dissertations/51
Chicago Manual of Style (16th Edition):
Greathouse, Kristen L. “XENOESTROGEN-SPECIFIC MECHANISMS OF DEVELOPMENTAL REPROGRAMMING CORRELATE WITH GENE EXPRESSION AND TUMOR DEVELOPMENT.” 2010. Doctoral Dissertation, Texas Medical Center. Accessed December 13, 2018.
MLA Handbook (7th Edition):
Greathouse, Kristen L. “XENOESTROGEN-SPECIFIC MECHANISMS OF DEVELOPMENTAL REPROGRAMMING CORRELATE WITH GENE EXPRESSION AND TUMOR DEVELOPMENT.” 2010. Web. 13 Dec 2018.
Greathouse KL. XENOESTROGEN-SPECIFIC MECHANISMS OF DEVELOPMENTAL REPROGRAMMING CORRELATE WITH GENE EXPRESSION AND TUMOR DEVELOPMENT. [Internet] [Doctoral dissertation]. Texas Medical Center; 2010. [cited 2018 Dec 13].
Available from: http://digitalcommons.library.tmc.edu/utgsbs_dissertations/51.
Council of Science Editors:
Greathouse KL. XENOESTROGEN-SPECIFIC MECHANISMS OF DEVELOPMENTAL REPROGRAMMING CORRELATE WITH GENE EXPRESSION AND TUMOR DEVELOPMENT. [Doctoral Dissertation]. Texas Medical Center; 2010. Available from: http://digitalcommons.library.tmc.edu/utgsbs_dissertations/51