Characterization of placental endocrine function and fetal brain development in a mouse model of small for gestational age

Abstract

Conditions such as small for gestational age (SGA), which is defined as birthweight less than 10th percentile for gestational age can predispose to neurodevelopmental abnormalities compared to babies with normal birthweight. Fetal growth and birthweight depend on placental function, as this organ transports substrates to the developing fetus and it acts as a source of endocrine factors, including steroids and prolactins that are required for fetal development and pregnancy maintenance. To advance our knowledge on the aetiology of fetal growth disorders, the vast majority of the research has been focused on studying the transport function of the placenta, leaving practically unexplored the contribution of placental hormones in the regulation of fetal growth. Here, using mice and natural variability in fetal growth within the litter, we compared fetuses that fell on or below the 10th percentile (classified as SGA) with those that had adequate weight for their gestational age (AGA). In particular, we compared placental endocrine metabolism and hormone production, as well as fetal brain weight and expression of developmental, growth and metabolic genes between SGA and AGA fetuses. We found that compared to AGA fetuses, SGA fetuses had lower placental efficiency and reduced capacity for placental production of hormones (e.g. steroidogenic gene Cyp17a1, prolactin Prl3a1, and pregnancy-specific glycoproteins Psg21). Brain weight was reduced in SGA fetuses, although this was proportional to the reduction in overall fetal size. The expression of glucose transporter 3 (Slc2a3) was reduced despite the abundance of AKT, FOXO and ERK proteins were similar. Developmental (Sv2b and Gabrg1) and microglia genes (Ier3), as well as the pregnancy-specific glycoprotein receptor (Cd9) were lower in the brain of SGA versus AGA fetuses. In this mouse model of SGA, our results therefore demonstrate that placental endocrine dysfunction is associated with changes in fetal growth and fetal brain development.

Maternal gutBifidobacterium brevemodifies fetal brain metabolism in germ-free mice

“…Fetal brain RNA was extracted with RNeasy plus Mini Kits (Qiagen) as previously described (Lopez-Tello and Sferruzzi-Perri, 2023). Reverse transcription was performed using the cDNA reverse transcription kit (Applied Biosystems) following manufacturer’s instructions.…”

“…Brain protein extraction and Western blotting were performed as previously described (Lopez-Tello and Sferruzzi-Perri, 2023). Briefly, brain samples were lysed with radioimmunoprecipitation assay (RIPA) lysis buffer (R0278-50M, Sigma Aldrich) supplemented with protease inhibitor cocktail mix (11836170001, Roche), 1mM β-glycerophosphate (G-9891, Sigma Aldrich) and 1mM sodium orthovanadate (S65089891, Sigma Aldrich).…”

Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring

“…Animal experiments have shown that the dysregulation of hormones secreted by the placenta during pregnancy may alter insulin signaling and adversely affect fetal growth[ 11 , 48 ]. A number of studies have shown that the level of human placental lactogen (HPL) in GDM patients increases during the third trimester of pregnancy, and the expression levels of HPL in mothers and umbilical cord blood are closely related to placental weight and birth weight[ 49 , 50 ].…”

“…Previous studies have shown that metabolic abnormalities in GDM patients could damage the structure, morphology and functions of the placenta and lead to pathological changes, affecting the energy conversion between the mother and the fetus, and affecting fetal development[ 8 ]. In recent years, an increasing number of studies have shown that the placenta is associated with diseases such as obesity in offspring[ 9 ], cardiovascular diseases[ 10 ] and impaired neurodevelopment[ 11 ], implying the importance of the placenta during fetal development.…”