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 Pregnancy-Associated Circulating MicroRNA predictors of infant birth outcomes are Determinants of Placental Maturation
AID  - 10.1101/409854
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 409854
4099  - http://biorxiv.org/content/early/2018/11/04/409854.short
4100  - http://biorxiv.org/content/early/2018/11/04/409854.full
AB  - We previously identified 11 miRNAs which were significantly elevated in blood plasma of pregnant mothers who subsequently gave birth to infants affected by prenatal alcohol exposure (PAE, Heavily Exposed Affected: HEa) compared to those with infants who were exposed but apparently unaffected (Heavily Exposed Unaffected: HEua) or unexposed (UE). These maternal HEamiRNAs were predicted to originate in part, as a paracrine placental signal to influence and coordinate placental epithelial-mesenchymal transition (EMT), a pathway essential for endometrial invasion and development. We now report that PAE inhibits expression of placental EMT pathway members in rodent and primate voluntary alcohol consumption models, with HEamiRNAs collectively mediating placental EMT inhibition. To directly investigate the interaction between HEamiRNAs and ethanol on placenta, we assessed their effects on human placental trophoblast cell lines. When administered together, HEamiRNAs retarded trophoblast cell cycle, significantly impaired expression of core EMT pathway members, and reduced invasiveness, pointing to their collective role in modulating placental growth and invasion deficits seen with PAE. HEamiRNAs additionally interfered with maturation-dependent intracellular calcium dynamics, while promoting syncytialization-dependent increases in placental hormone expression. Finally, a single systemic administration of the pooled murine-expressed HEamiRNA subpopulation, to pregnant mice, decreased fetal and placental growth and inhibited expression of EMT pathway mRNA transcripts in placenta. Taken together, our data suggests that, following PAE, HEamiRNAs interfere with placental development and may contribute 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.