Developmental diethylstilbestrol exposure alters genetic pathways of uterine cytodifferentiation.
The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2-/- uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.
Huang
Wei-Wei
WW
Tulane/Xavier Center for Bioenvironmental Research, Tulane University Medical Center, New Orleans, Louisiana 70112, USA.
Yin
Yan
Y
Bi
Qun
Q
Chiang
Tung-Chin
TC
Garner
Neysa
N
Vuoristo
Jussi
J
McLachlan
John A
JA
Ma
Liang
L
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004054:Diethylstilbestrol / Q000009:adverse effects*; D004848:Epithelium / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000009:adverse effects*; D005260:Female; D018398:Homeodomain Proteins; D017403:In Situ Hybridization; D007246:Infertility; D007633:Keratins / Q000378:metabolism; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation; D014599:Uterus / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D051153:Wnt Proteins; D000071818:Wnt-5a Protein
D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004968:Estrogens, Non-Steroidal; D018398:Homeodomain Proteins; C084119:MSX2 protein; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C490508:Wnt7a protein, mouse; D007633:Keratins; D004054:Diethylstilbestrol; D012260:Ribonucleases; D000469:Alkaline Phosphatase