General Research at the Fetal Treatment Center
Women & Infants Hospital is the recipient of a $9 million award from the Center of Biomedical Research Excellence (COBRE) to support emerging investigators in fetal, neonatal and perinatal biology. Investigators collaborate with leading scientists in their fields and utilize contemporary approaches in cell and molecular biology to address important issues in fetal development.
Recent studies have used proteomics to identify a biomarker in preeclampsia that allows for diagnosis as early as 10 to 12 weeks of pregnancy. Ongoing studies are directed at early intervention and treatment.
- Sera from preeclampsia patients elicit symptoms of human disease in mice and provide a basis for an in vitro predictive assay. Kalkunte S, Boij R, Norris W, Friedman J, Lai Z, Kurtis J, Lim KH, Padbury JF, Matthiesen L, Sharma S. Am J Pathol. 2010 177:2387-98.
- Novel approaches for mechanistic understanding and predicting preeclampsia. Kalkunte S, Lai Z, Norris WE, Pietras LA, Tewari N, Boij R, Neubeck S, Markert UR, Sharma S. J Reprod Immunol. 2009 83:134-8.
Numerous investigations have shown that antenatal environmental factors including diet, xenobiotics exposure, stress and lifestyle factors can alter fetal growth and, through programming, result in permanent biological and physiologic changes in the child. Research in fetal programming and many other related disciplines is now focusing on the paradigm that gene regulation occurs beyond the DNA sequence. Most of the acquired adverse effects related to intrauterine environment result in epigenetic alterations. The most thoroughly examined is DNA methylation.
We have demonstrated that the interaction between genes and environment can be captured in the placental epigenome, which exerts down-stream effects on fetal development. We have shown that the methylation profile of the placenta is more robust than any of a myriad of other tissues examined (1). We have evaluated the effect of the intrauterine environment on genome-wide placental DNA methylation and its association with birth weight (2), the association of methylation of repetitive elements in placental genomic DNA with fetal growth (3), the effects of the intrauterine environment on methylation of repetitive element DNA (4), changes in placental gene expression (5), and the effects of maternal smoking and birth weight on placental micro RNA expression (6-7).
The changes are part of the emerging paradigm that the placenta, at the interface between the fetus and the maternal and extrauterine environment, is not a passive player but an active mediator of fetal well-being. We believe the placental epigenome serves as an "integrated blue-print" of intrauterine life. The patterns of alteration in the placental epigenome serve to "tell the story" of events occurring during intrauterine life.
We are currently combining our expertise in the treatment of identical twin fetuses with TTTS and our experience with epigenetic research to identify phenomena that might affect one, but not the other twin later in life.
- Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Padbury JF, Bueno R, Sugarbaker DJ, Yeh R-F, Wiencke JK, Kelsey KT. Aging and environmental exposures are differentially associated with tissue-specific DNA methylation alterations. PLoS Genetics 5:e1000602, 2009.
- Banister CE, Koestler DC, Maccani MA, Padbury JF, Houseman EA, Marsit CJ. Infant growth restriction is associated with distinct patterns of DNA methylation in human placentas. Epigenetics 6:920-7, 2011.
- Wilhelm-Benartzi CS, Houseman EA, Maccani MA, Poage GM, Koestler DC, Langevin SM, Gagne L, Banister C, Padbury JF, Marsit CJ: In utero exposures, infant growth and DNA methylation of repetitive element and developmentally related genes in human placenta. Environ Health 2012 120:296-302.
- Marsit CJ, Lambertini L, Maccani M, Koestler D, Houseman EA, Gagne L, Padbury JF, Lester BM, Chen J: Placenta imprinted gene expression association of infant neurobehavioral. J Pediatrics 2011 (In Press).
- Ponder K, Salisbury A, McGonnigal BG, Laliberte A, Lester BM, Padbury JF: Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: Implications for fetal programming. Dev Psychobiol 53(7):711-23, 2011.
- Maccani MA, Avissar-Whiting M, Banister CE, McGonnigal B, Padbury JF, Marsit CJ. Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21, and miR-146a in the placenta. Epigenetics 5(7):583-9, 2010.
- Maccani MA, Padbury JF, Marsit CJ: miR-16 and miR-21 Expression in the placenta is associated with fetal growth. PLoS One 6(6):e21210, 2011.