Maternal circulating miRNAs that predict infant FASD outcomes influence placental maturation

Area of Science:

• Reproductive biology
• Developmental biology
• Molecular biology

Background:

• Pregnancy complications like prenatal alcohol exposure (PAE) can cause placental insufficiency and fetal growth restriction.
• The precise mechanisms linking PAE to these outcomes remain unclear.
• Previously identified gestationally elevated maternal circulating microRNAs (HEa-miRNAs) predicted infant growth deficits after PAE.

Purpose of the Study:

• To investigate if HEa-miRNAs contribute to PAE pathology by inhibiting trophoblast epithelial-mesenchymal transition (EMT), a key pathway in placental development.
• To determine if HEa-miRNAs mediate placental EMT inhibition and affect trophoblast function.

Main Methods:

• Examined PAE effects on placental pro-EMT pathway members in rodents and primates.
• Assessed the collective and individual effects of HEa-miRNAs on cultured trophoblast proliferation, EMT, cell stress, and endocrine maturation.
• Administered pooled murine HEa-miRNAs to pregnant mice to evaluate impacts on placental and fetal growth and pro-EMT transcript expression.

Main Results:

• PAE inhibits placental pro-EMT pathway members in both rodents and primates.
• HEa-miRNAs collectively, but not individually, mediate placental EMT inhibition.
• In cultured trophoblasts, HEa-miRNAs inhibited proliferation and EMT, induced cell stress, and caused aberrant endocrine maturation.
• Administration of pooled HEa-miRNAs in mice reduced placental and fetal growth and inhibited placental pro-EMT transcripts.

Conclusions:

• HEa-miRNAs collectively interfere with placental development, contributing to PAE pathology.
• These findings suggest HEa-miRNAs may also play a role in other causes of fetal growth restriction.
• The study elucidates a novel mechanism by which PAE impacts placental function and fetal development.