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Disruption of estrogen-sensitive, estrogen receptor (ER)–dependent events during development of the porcine uterus between birth (postnatal day = PND 0) and PND 14 affects patterns of uterine morphoregulatory gene expression in the neonate and alters the developmental trajectory of uterine tissues with lasting consequences for reproductive success. Uterine capacity for conceptus support is reduced in pregnant adult gilts exposed to estradiol valerate (EV) for 14 days from birth. Effects of such uterine developmental disruption were reflected dramatically in neonatally EV-exposed adult gilts on pregnancy day 12 (PxD 12), in which a proteomic analysis revealed quantitative changes in relative expression patterns for 300 different endometrial proteins and peptides. Objectives of this study were to determine effects of EV exposure from birth through PND 13 on patterns of change in neonatal uterine and adult endometrial expression of genes implicated in the regulation of critical, estrogensensitive uterine organizational events during early neonatal life. Targeted transcripts included the morphoregulatory genes Hoxa10 and Wnt7a, the relaxin receptor, LGR7, and ER alpha, both recognized to mediate uterine growth and endometrial development in the pig, and the matrix metalloproteinases (MMP)-2 and MMP-9. Gilts (n=4–6/neonatal and adult groups) were treated daily with EV (50μg/kg BW/day, i.m.) or corn oil (CO) vehicle alone from PND 0 to PND 13. Uteri were obtained from CO- and EV-treated neonates on PND 14 and from adult gilts in both groups on PxD 12. Targeted transcripts were quantified using real-time RT-PCR with pig-specific primers and total RNA isolated from individual uteri (neonates) or endometrial samples (adults). In neonates on PND 14, results indicated that EV exposure from birth reduced (p<0.001) levels of Wnt7a mRNA and increased (p<0.05) levels of Hoxa10, LGR7 and MMP-9 mRNA. Treatment with EV did not affect ER alpha or MMP-2 transcript levels on PND 14. In adults on PxD 12, transient neonatal EV exposure reduced (p<0.05) endometrial levels of Wnt7a and MMP-9 mRNA, and increased (p<0.05) levels of LGR7 mRNA. Endometrial Hoxa10, ER alpha and MMP-2 mRNA levels on PxD 12 were unaffected by neonatal EV treatment. These quantitative data complement and extend earlier in situ hybridization analyses indicating that EV exposure from birth affects expression of neonatal uterine epithelial Wnt7a negatively, and stromal Hoxa10 and LGR7 positively, without affecting endometrial ER alpha expression. Data also provide the first evidence that estrogen-sensitive developmental programming of porcine uterine tissues between birth and PND 14 may involve MMP-9. Results support the hypothesis that transient estrogen-induced disruption of porcine uterine development from birth will be reflected by alterations in adult endometrial gene expression patterns during early pregnancy. Persistent dysregulation of endometrial Wnt7a, MMP-9 and LGR7 expression in adult gilts on PxD 12 indicates that EV-exposure from birth not only alters the neonatal uterine developmental program acutely but affects the developmental trajectory of endometrial tissues and, ultimately, endometrial function in adulthood. Further, results indicate that Wnt7a, MMP-9 and LGR7 may be useful as molecular markers of neonatal estrogen exposure in the adult porcine uterus. (Support USDA-NRI 2003-35203-13572 and NSF EPS-0447675) (platform)

© 2007 Society for the Study of Reproduction, Inc.
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