Abstract

Background: One of the major adverse effects of maternal ethanol consumption is intrauterine growth restriction (IUGR). Previous studies demonstrated that ethanol-induced IUGR is mediated by impaired placentation. Chronic gestational ethanol exposure reduces trophoblastic cell motility and invasiveness through inhibition of insulin/IGF signaling leading to impaired vascular transformation at the implantation site. Furthermore, ethanol reduces the number of secondary giant cells that mediate vascular invasion in rat placenta. However, the degree to which ethanol inhibits progenitor cell survival and differentiation is not known.

Study Design: To determine the effects of ethanol exposure on trophoblastic cell resilience, pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 8.2% (v/v) ethanol. The diets were initiated at different embryonic days (E) corresponding to stem cell activation (E6), appearance of secondary trophoblast giant cells (E10), accumulation of glycogen cells (E14), and prior to (E15) and after (E16) trophoblast invasion of the implantation site. Pups were harvested on E19 to evaluate growth parameters. Placental tissue was used for histological, immunohistochemical, and molecular studies.

Results: Severity of fetal growth impairment correlated with early ethanol exposures (E6, E10). Vascular transformation was inhibited by ethanol with more profound effects in earlier exposure groups. Correspondingly, invasive trophoblastic cells and their precursor secondary giant cells were reduced in ethanol groups and degree of reduction was increased by earlier exposures. The mRNA expression levels of genes encoding stem cell, trophoblast giant cell, and invasive trophoblast were significantly reduced by ethanol in accordance with timing of their activity.

Conclusion: Gestational ethanol exposure impairs placentation by reducing progenitor cells and compromising trophoblast invasion.

Keywords: Fetal alcohol spectrum disorder; Placenta; Trophoblast differentiation; IUGR; Development