Impact of maternal obesity on placental transcriptome and morphology associated with fetal growth restriction in mice

Abstract

Background In utero exposure to obesity is consistently associated with increased risk of metabolic disease, obesity and cardiovascular dysfunction in later life despite the divergence of birth weight outcomes. The placenta plays a critical role in offspring development and long-term health, as it mediates the crosstalk between the maternal and fetal environments. However, its phenotypic and molecular modifications in the context of maternal obesity associated with fetal growth restriction (FGR) remain poorly understood.Methods Using a mouse model of maternal diet-induced obesity, we investigated changes in the placental transcriptome through RNA sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) at embryonic day (E) 19. The most differentially expressed genes (FDR < 0.05) were validated by Quantitative real-time PCR (qPCR) in male and female placentae at E19. The expression of these targets and related genes was also determined by qPCR at E13 to examine whether the observed alterations had an earlier onset at mid-gestation. Structural analyses were performed using immunofluorescent staining against Ki67 and CD31 to investigate phenotypic outcomes at both timepoints. Results RNA-seq and IPA analyses revealed differential expression of transcripts and pathway interactions related to placental vascular development and tissue morphology in obese placentae at term, including downregulation of Muc15, Cnn1, and Acta2. Pdgfb, which is implicated in labyrinthine layer development, was downregulated in obese placentae at E13. This was consistent with the morphological evidence of reduced labyrinth zone (LZ) size, as well as lower fetal weight at both timepoints irrespective of offspring sex. Conclusions Maternal obesity results in abnormal placental LZ development and impaired vascularization, which may mediate the observed FGR through reduced transfer of nutrients across the placenta.

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“…Maternal obesity during pregnancy is associated with an increased risk of both small and large for gestational age babies [ 35 ]. Consistent with previous studies in the model [ 16 , 36 , 37 ], we observed growth restriction followed by catch-up growth in offspring exposed to maternal obesity. The combination of low birth weight and accelerated postnatal growth is associated with long-term adverse effects on offspring cardiometabolic health in human studies [ 38 , 39 , 40 , 41 ] and animal models [ 42 , 43 ].…”

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“…Mechanistic insight into how reduced labyrinthine area might occur comes from recent transcriptomic analyses from our laboratory showing downregulation of transcripts involved in labyrinthine development in placentas from obese dams (De Barros Mucci et al . 2020). We observed a strong correlation between reduced labyrinthine area, increased placental impedance (as measured by the PPI; Gudmundsson et al .…”