Search
Close
Search
Advanced Search
Search Menu
AI Discovery Assistant

The placenta is essential for fetal development and nutrient exchange in mammalian pregnancy, and placental malformation can lead to grave complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) of the fetus. PE occurs in approximately 7% of pregnancies in the United States and can lead to maternal and fetal mortality. Studies have identified increased serum testosterone in PE patients, increased placental expression of androgen receptor, and decreased placental aromatase activity. Treatment of pregnant ewes with testosterone propionate during gestational days 60 to 90 (a well-established model of prenatal androgenization) leads to abnormal developmental programming, including IUGR, polycystic ovarian syndrome in female offspring, and decreased fertility in male offspring. While many of these could be contributed to direct effects on the developing fetus, we hypothesize that prenatal androgenization leads to epigenetic changes and perturbed placental development and differentiation, which in turn leads to abnormal fetal programming. Starting on gestational day 60, pregnant ewes were injected IM biweekly with 100 mg testosterone propionate (treated) or 2 mL cottonseed oil (control). On gestational day 90, 5 placentomes closest to the umbilicus were collected and characterized for each fetus. For all control pregnancies, only type A placentomes were present closest to the umbilicus while a range from type A to D, with increasing fetal cotyledon overgrowth, were present in treated pregnancies. Results demonstrate a decrease in global DNA methylation in placentomes in treated (n=6) compared to control ewes (n=4) according to ELISA (p=0.023). In accordance, real time qPCR analysis revealed a 3.3 fold increase in DNMT3a mRNA levels in type D placentomes in treated compared to control placentomes (p=0.032). DNMT3b mRNA levels also were increased (1.7 fold) in caruncles from type A treated compared to controls (p=0.023). There was a 7.3 fold increase in ESR2 mRNA levels (p=0.047) in type D placentomes (composed primarily of cotyledon tissues) from treated compared to cotyledons in controls, and a 6.2 fold increase in the imprinted gene H19 in type A cotyledons from treated compared to controls (p=0.026). In summary, results indicate that prenatal androgenization leads to changes in placentome morphology and a decrease in global DNA methylation. Furthermore, accompanying changes in a number of transcripts were observed, including the DNA methyltransferases DNMT3a and DNMT3b. The observed increase in ESR2 mRNA levels suggests a mechanism for the increased proliferation in cotyledon tissue in the prenatal androgenized ewes. Future work will confirm gene specific changes in methylation using chromatin immunoprecipitation, as well as changes at the protein level. Finally, these results indicate that prenatal androgenization leads to epigenetic changes that result in perturbed placental development and function, and can provide new insight into other placental defects. This project is supported by USDA-NIFA-National Institute of Food and Agriculture Grant #2010-38420-20397 National Needs Graduate Fellowship Program.

Copyright 2012 by The Society for the Study of Reproduction.
Issue Section:
8/13/2012
You do not currently have access to this article.
Download all slides