PT  - JOURNAL ARTICLE
AU  - Alexander M. Tseng
AU  - Amanda H. Mahnke
AU  - Alan B. Wells
AU  - Nihal A. Salem
AU  - Andrea M. Allan
AU  - Victoria H.J. Roberts
AU  - Natali Newman
AU  - Nicole A.R. Walter
AU  - Christopher D. Kroenke
AU  - Kathleen A. Grant
AU  - Lisa K. Akison
AU  - Karen M. Moritz
AU  - Christina D. Chambers
AU  - Rajesh C. Miranda
AU  - CIFASD
TI  - Maternal Circulating MicroRNAs Control the Placental Response to Alcohol
AID  - 10.1101/409854
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 409854
4099  - http://biorxiv.org/content/early/2018/09/06/409854.short
4100  - http://biorxiv.org/content/early/2018/09/06/409854.full
AB  - 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 HEamiRNAs 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, HEamiRNAs mediated effects of PAE on EMT pathway inhibition. To directly investigate the interaction between HEamiRNAs 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, HEamiRNAs 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. HEamiRNAs additionally interfered with maturation-dependent calcium dynamics, while promoting syncytialization-dependent increases in placental hormone expression. Finally, a single systemic administration of HEamiRNAs, together, to pregnant mice, resulted in decreased fetal and placental growth. Taken together, our data suggests that, following PAE, HEamiRNAs interfere with placental development and disrupt the EMT pathway, thereby contributing to the pathology of Fetal Alcohol Spectrum Disorders.This research was supported by grants from the NIH, P50 AA022534 (AMA), U01 AA014835 and the Office of Dietary Supplements (CDC), R24 AA019431 (KAG), R01 AA021981 (CDK), R01 AA024659 (RCM), F31 AA026505 (AMT) and support from National Health and Medical Research Council of Australia (KMM). We thank CIFASD for intellectual support and Megan S. Pope and Tenley E. Lehman for their assistance in conducting cell culture and animal studies. Data on human subjects is deposited at CIFASD.org, in accordance with NIH data repository guidelines.