Abnormal growth and morphogenesis of placenta at term is linked to adverse fetal development after perigestational alcohol consumption up to early gestation in mouse

Abstract

Background: Gestation alcohol consumption produces fetal growth restriction and malformations by affecting the embryo-fetal development. Recently a relationship between abnormal placentation and fetal malformation and intrauterine growth retardation has been suggested. However, the effects of perigestational alcohol ingestion up to early pregnancy on the placenta at term and its association with fetal abnormalities are little known. Methods: In female mice, ethanol 10% in water was administered for 15 days previous and up to days 4 (D4), 8 (D8), or 10 (D10) of gestation (TF), and gestation continues without ethanol exposure. Control females (CF) received ethanol-free water. At day 18, feto-placental units and implantation sites were studied.Results: TF had increased resorptions and only fetuses from D8-TF and D10-TF had significantly increased weights versus CF. D4 and D10-TFplacentas had significantly reduced weights. All TF had increased junctional zone (JZ) and reduced labyrinth (Lab) areas (PAS-histology and morphometry) compared with CF. Fetuses with mainly with craniofacial abnormalities and skeletal defects (Alizarin red staining), significantly increase; while the fetal bone density (alizarin color intensity, ImageJ) was reduced in D4, D8 and D10-TF versus CF. Although all TF-placentas were histo-structural affected, TF-abnormal fetuses had the most severe placental anomalies, with junctional abundant glycogenic cells into the labyrinth, disorganized labyrinthine vascularization with signs of leukocyte infiltrates and feto-maternal blood mix. Conclusions: Perigestational alcohol consumption up to early gestation induces at term fetal growth alterations, dysmorphology and defective skeleton, linked to deficient growth and abnormal morphogenesis of placenta, highlighting insight into the prenatal etiology of FASD.

Involvement of metalloproteinase and nitric oxide synthase/nitric oxide mechanisms in early decidual angiogenesis–vascularization of normal and experimental pathological mouse placenta related to maternal alcohol exposure

“…Placental hemodynamics and adaptations require extensive structural and functional modifications in the maternal blood vessels of the placenta. In normal pregnancy, remodeling of maternal vessels needs secretion of MMPs by trophoblast and decidual stromal cells to mediate proteolysis and degradation, vascular and matrix remodeling, and angiogenesis ( Staun-Ram et al, 2004 ; Gualdoni et al, 2022 ; Rusidzé et al, 2023 ). Through their proteolytic activity, MMPs may mediate detachment of pericytes from the vessels, release ECM-bound angiogenic growth factors, expose cryptic proangiogenic integrin-binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell–cell adhesions ( Rundhaug, 2005 ).…”

“…However, at present, little evidence suggests that perigestational alcohol consumption (PAC) up to early gestation induces abnormal placentation and leads to deficient growth and vasculopathy of the placenta at term. Reduced growth and malformed embryos ( Gualdoni et al, 2021 ) or abnormal fetuses at term ( Gualdoni et al, 2022a ), induced by perigestational alcohol exposure up to organogenesis, were associated with altered placental indexes. Some studies in animal models explain the PAC-induced effects on the placenta by alterations in trophoblastic development and functionality ( Gårdebjer et al, 2014 ; Kalisch-Smith and Moritz, 2017 ; Kalisch-Smith et al, 2019 ).…”

“…Some studies in animal models explain the PAC-induced effects on the placenta by alterations in trophoblastic development and functionality ( Gårdebjer et al, 2014 ; Kalisch-Smith and Moritz, 2017 ; Kalisch-Smith et al, 2019 ). Also, we recently showed, in a mouse model, that PAC up to peri-implantation or organogenesis disrupts the development of trophoblasts and induces deficient vascularization of the labyrinth ( Perez-Tito et al, 2014 ; Gualdoni et al, 2021 ), leading to abnormal placenta later ( Gualdoni et al, 2022a ). However, early alterations in decidual angiogenesis during the trophoblast-independent phase may contribute primarily to insufficient maternal vascular development in the placenta at term.…”

“…In this context, periconceptional alcohol exposure in the highly susceptible peri-implantatory and early organogenic periods may be affected and can lead to placentopathy at term ( Gualdoni et al, 2022b ). In view of these periods of consumption, we established a mouse model of perigestational alcohol consumption starting before pregnancy and continuing up to early gestation (mouse gestational days (GD) 4, 5, 7, 8, and 10) to study the embryo development ( Cebral et al, 2007 ; 2011 ; Coll et al, 2011 ; 2017 ; Perez-Tito et al, 2014 ; Gualdoni et al, 2022a ). We have shown that moderate oral ethanol intake for 2 weeks before pregnancy and up to peri-implantational stages affect embryo differentiation and growth and leads to retardation during implantation ( Pérez-Tito et al, 2014 ).…”