Exposure of the developing fetus to harmful chemicals, such as xenoestrogens, heavy metals, alcohol, and cigarette smoke, is associated with poor fetal and developmental outcomes. The overarching hypothesis of this work is that environment-associated differential expression of placental miRNA has consequences for the growth and development of the placenta and fetus and plays a role in fetal programming. In 25 human placentas, qRT-PCR revealed that miR-16, miR-21, and miR-146a were significantly downregulated in cigarette smoke-exposed placentas (n=17) compared to controls (n=8), and TCL-1 cells exposed to both nicotine and benzo(a)pyrene exhibited significant, downregulation of miR-146a. In an independent, population-based birth cohort, 107 human placenta samples were examined for the expression of 6 miRNA expressed in the placenta and previously shown to regulate cell growth and development pathways ? miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182 ? and were investigated for associations of fetal growth and miRNA expression. The expression of miR-16 and miR-21 was markedly reduced in infants with the lowest birthweights (p<0.05). Logistic regression models suggested that low expression of miR-16 in the placenta predicts an over 4-fold increased odds of small for gestational age (SGA) status (p=0.009). Moreover, having both low miR-16 and low miR-21 expression in the placenta predicts a greater increase in odds for SGA than having just low miR-16 or miR-21 expression (p<0.02), suggesting an additive effect of both of these miRNA. Placental cell lines transfected to overexpress miRNA of interest were utilized to analyze changes in cell viability, growth, proliferation, migration, and invasion, as well as to empirically validate miRNA targets predicted using in silico bioninformatic approaches. Overexpression of miR-21 in 3A cells resulted in a trend to increased cell migration. TCL-1 cells overexpressing miR-21 exhibited a 50% reduction in protein levels of PTEN (p<0.05), and 3A cells overexpressing miR-146a exhibited a 25% reduction in STAT-1 protein levels (p<0.05). Taken collectively, this work further elucidates the association of placental miRNA expression with in utero exposures and fetal growth and seeks to better understand how an adverse intrauterine environment acts through epigenetic mechanisms to alter infant and child health.
Maccani, Matthew A.,
"Exposure and Fetal Growth-Associated miRNA Alterations in the Human Placenta"
(2011).
Pathobiology Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0SB440T
