Sexually dimorphic patterns in maternal circulating microRNAs in pregnancies complicated by fetal growth restriction

ABSTRACT:

Background

Current methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented as are sex-specific differences in gene and protein expression in the placenta. Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that may also be informative of underlying pathology. We hypothesised that FGR would be associated with an altered miRNA profile and would differ depending on fetal sex.

Methods

miRNA expression profiles were assessed in maternal serum (> 36 weeks’ gestation) from women delivering a severely FGR infant (defined as an individualised birthweight centile (IBC) < 3rd) and matched control participants (AGA; IBC = 20–80th), using miRNA arrays. qPCR was performed using specific miRNA primers in an expanded cohort of patients with IBC < 5th (n = 15 males, n = 16 females/group). Maternal serum human placental lactogen (hPL) was used as a proxy to determine if serum miRNAs were related to placental dysfunction. In silico analyses were performed to predict the potential functions of altered miRNAs.

Results

Initial analyses revealed 11 miRNAs were altered in maternal serum from FGR pregnancies. In silico analyses revealed all 11 altered miRNAs were located in a network of genes that regulate placental function. Subsequent analysis demonstrated four miRNAs showed sexually dimorphic patterns. miR-28-5p was reduced in FGR pregnancies (p < 0.01) only when there was a female offspring and miR-301a-3p was only reduced in FGR pregnancies with a male fetus (p < 0.05). miR-454-3p was decreased in FGR pregnancies (p < 0.05) regardless of fetal sex but was only positively correlated to hPL when the fetus was female. Conversely, miR-29c-3p was correlated to maternal hPL only when the fetus was male. Target genes for sexually dimorphic miRNAs reveal potential functional roles in the placenta including angiogenesis, placental growth, nutrient transport and apoptosis.

Conclusions

These studies have identified sexually dimorphic patterns for miRNAs in maternal serum in FGR. These miRNAs may have potential as non-invasive biomarkers for FGR and associated placental dysfunction. Further studies to determine if these miRNAs have potential functional roles in the placenta may provide greater understanding of the pathogenesis of placental dysfunction and the differing susceptibility of male and female fetuses to adverse in utero conditions.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13293-021-00405-z. Highlights Detection and treatment of pregnancies at high risk of fetal growth restriction (FGR) and stillbirth remains a major obstetric challenge; circulating maternal serum microRNAs (miRNAs) offer potential as novel biomarkers. Unbiased analysis of serum miRNAs in women in late pregnancy identified a specific profile of circulating miRNAs in women with a growth-restricted infant. Some altered miRNAs (miR-28-5p, miR-301a-3p) showed sexually dimorphic expression in FGR pregnancies and others a fetal-sex dependent association to a hormonal marker of placental dysfunction (miR-454-3p, miR-29c-3p). miR-301a-3p and miR-28-5p could potentially be used to predict FGR specifically in pregnancies with a male or female baby, respectively, however larger cohort studies are required. Further investigations of these miRNAs and their relationship to placental dysfunction will lead to a better understanding of the pathophysiology of FGR and why there is differing susceptibility of male and female fetuses to FGR and stillbirth.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13293-021-00405-z.

SUBMITTER: Baker B 

PROVIDER: S-EPMC8597318 | biostudies-literature |

REPOSITORIES: biostudies-literature