The developmental origins of adult disease hypothesis has gained strength as a powerful explanation for risk of some of the most prevalent and morbid human conditions. According to this theory, risk of disease in adulthood is initially induced by fetal responses to maternal conditions and exposures. Central to the developmental origins hypothesis is the concept of developmental plasticity which involves altered gene expression as a result of non-genomic modifications to DNA. Growing evidence supports the concept that developmental programming may occur from a window that spans periconception through postnatal life. Epidemiologic data supporting a relationship between assisted reproductive technologies, low birth-weight and rare conditions involving imprinted genes makes it plausible that additional exposures around the time of conception may also impact fetal growth. The full impact of impaired fetal growth may not be completely evident until years after birth when later developmental and reproductive milestones can be affected. We hypothesize that specific maternal exposures around the time of conception and in utero are associated with neonatal markers of metabolism, development and ovarian function. This study will measure several maternal exposures around conception and in utero that may impact developmental plasticity and post natal disease risk. Maternal levels of folate, vitamin B12, Vitamin D and the endocrine disrupting chemical Bisphenol-A will be measured. Cohorts of fertile women, infertile women seeking treatment will be recruited for study. At birth, neonatal weight and placental dimensions will be measured. Samples of cord blood from neonates will also be collected to measure biomarkers of metabolism (leptin, 1GF1, IFG2, Insulin, IGFBP3) and ovarian function (Anti-Mullerian Hormone). Results from this pilot study should help us design an appropriately powered clinical trial with the potential for the Reproductive Medicien Network to undertake.

Public Health Relevance

It is anticipated that results from the proposed pilot project could lead to larger scale investigations that would explore the impact of maternal exposures on developmental and reproductive outcomes in mechanistic detail. Such studies could make significant impact on clinical practice as and education of women attempting pregnancy in ways that could optimize fetal outcomes and minimize disease risk in adults.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L)
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University of Pennsylvania
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Mainigi, Monica A; Olalere, Devvora; Burd, Irina et al. (2014) Peri-implantation hormonal milieu: elucidating mechanisms of abnormal placentation and fetal growth. Biol Reprod 90:26
Ihara, Motomasa; Meyer-Ficca, Mirella L; Leu, N Adrian et al. (2014) Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression. PLoS Genet 10:e1004317
Butts, Samantha F; Owen, Carter; Mainigi, Monica et al. (2014) Assisted hatching and intracytoplasmic sperm injection are not associated with improved outcomes in assisted reproduction cycles for diminished ovarian reserve: an analysis of cycles in the United States from 2004 to 2011. Fertil Steril 102:1041-1047.e1
Butts, Samantha F; Guo, Wensheng; Cary, Mark S et al. (2013) Predicting the decline in human chorionic gonadotropin in a resolving pregnancy of unknown location. Obstet Gynecol 122:337-43
Bryant, Jessica M; Meyer-Ficca, Mirella L; Dang, Vanessa M et al. (2013) Separation of spermatogenic cell types using STA-PUT velocity sedimentation. J Vis Exp :
Meyer-Ficca, Mirella L; Lonchar, Julia D; Ihara, Motomasa et al. (2013) Alteration of poly(ADP-ribose) metabolism affects murine sperm nuclear architecture by impairing pericentric heterochromatin condensation. Chromosoma 122:319-35
de Waal, Eric; Yamazaki, Yukiko; Ingale, Puraskar et al. (2012) Primary epimutations introduced during intracytoplasmic sperm injection (ICSI) are corrected by germline-specific epigenetic reprogramming. Proc Natl Acad Sci U S A 109:4163-8
Abramowitz, Lara K; Bartolomei, Marisa S (2012) Genomic imprinting: recognition and marking of imprinted loci. Curr Opin Genet Dev 22:72-8