Maternal Circulating MicroRNAs Control the Placental Response to Alcohol
bioRxiv(2019)
摘要
We previously identified 11 miRNAs which were significantly elevated in the plasma of mothers whose infants were affected by maternal alcohol consumption (Heavily Exposed Affected: HEa) compared to infants who were apparently unaffected by alcohol exposure (Heavily Exposed Unaffected: HEua) or unexposed (UE) controls. These HEa miRNAs were predicted to influence epithelial-mesenchymal transition (EMT), a pathway which is essential for fetal and placental growth and maturation. We now report that prenatal alcohol exposure (PAE) inhibits expression of placental EMT pathway members in rodent and non-human primate voluntary alcohol consumption models. Furthermore, in non-human primates, HEa miRNAs mediated effects of PAE on EMT pathway inhibition. To directly investigate the interaction between HEa miRNAs and ethanol on placenta, we assessed their effects on the cytotrophoblastic BeWO and extravillous/invasive HTR8 human trophoblast cell lines. When administered together, but not separately, HEa miRNAs retarded the cell cycle, significantly impaired expression of core EMT pathway members, and reduced the invasiveness of trophoblasts, pointing to their collective role in modulating the placental growth and invasion deficits seen in PAE. HEa miRNAs additionally interfered with maturation-dependent calcium dynamics, while promoting syncytialization-dependent increases in placental hormone expression. Finally, a single systemic administration of HEa miRNAs, together, to pregnant mice, resulted in decreased fetal and placental growth. Taken together, our data suggests that, following PAE, HEa miRNAs interfere with placental development and disrupt the EMT pathway, thereby contributing to the pathology of Fetal Alcohol Spectrum Disorders.
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关键词
microRNA,placenta,EMT,trophoblast,fetal growth restriction
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