Effects of alcohol, lithium, and homocysteine on nonmuscle myosin-II in the mouse placenta and human trophoblasts

Abstract

Mouse embryonic exposure to alcohol, lithium, and homocysteine results in intrauterine growth restriction (IUGR) and cardiac defects. Our present study focuses on the placental effects. Objectives We analyzed the hypothesis that expression of nonmuscle myosin (NMM)-II isoforms involved in cell motility, mechanosensing, and extracellular matrix assembly, are altered by the three factors in human trophoblast (HTR8/SVneo) cells in vitro and in the mouse placenta in vivo. Study Design After exposure during gastrulation to alcohol, homocysteine, or lithium, ultrasonography defined embryos exhibiting abnormal placental blood flow. Results NMM-IIA /NMM-IIB are differentially expressed in trophoblasts and in mouse placental vascular endothelial cells under pathological conditions. Misexpression of NMM-IIA/ NMM-IIB in the affected placentas continued stably to mid-gestation, but can be prevented by folate and myo-inositol supplementation. Conclusions It is concluded that folate and myo-inositol initiated early in mouse pregnancy can restore NMM-II expression, permit normal placentation/embryogenesis, and prevent IUGR induced by alcohol, lithium, and homocysteine.

The Heart-Placenta Axis in the First Month of Pregnancy: Induction and Prevention of Cardiovascular Birth Defects

“…For venous hemodynamics, we used the presence of flow reversal during atrial contraction (A wave) in the ductus venosus and the presence of umbilical venous pulsations. The abnormal echocardiographic patterns relating to myocardial and valve defects have been published [17, 18]. Our research indicates that the observed cardiac defects are preventable with folate supplementation that is initiated early after conception and at higher doses than presently available in periconceptional vitamins.…”

“…Two important pathways critical to placental development, implantation, and cardiac development during the same period of early development are canonical Wnt/ β -catenin signaling and pathways associated with folate metabolism [17–21]. If these pathways are altered, developmental anomalies ensue.…”

“…If one reads the literature provided to women upon learning of their pregnancy usually at 5 to 6 weeks after conception, pamphlets predominantly focus on neural development and the use of folate during pregnancy with targeting the second to third month of gestation. Possibly due to a lack of knowledge on effects of environmental exposures during early embryonic development, generally there is little discussion of adverse effects on cardiac outcomes, importance of planned pregnancy, and the use of folate before becoming pregnant and continuing until pregnancy is confirmed, so as to protect the earliest stages of embryonic development, specifically of the cardiovascular system [5, 18], placentation [29], and neurogenesis [30]. …”

“…Although human placentation differs from that of the rodent model, there is homology regarding trophoblast invasion and in the important regulatory elements [78]. We found that alcohol exposure as well as lithium and homocysteine did not affect cell proliferation, but rather trophoblast cell migration [17]. All three environmental exposures modulated placental nonmuscle-myosin-heavy-chain-(NMHC-) IIA and NMHC-IIB expression (Figure 4).…”

Maternal predictors of intrauterine growth restriction

“…Decreased DNA methylation has been reported in one of the differentially methylated regions of the Igf2 locus in prenatally alcohol-exposed mice. Finally, mouse embryonic exposure to alcohol, lithium and homocysteine results in IUGR and cardiac defects by alteration of expression of nonmuscle myosin-II isoforms involved in cell motility, mechanosensing and extracellular matrix assembly [55]. Furthermore, alterations of proteins with roles in cellular function, cell cycle, and the ubiquitin-proteasome pathway induced by alcohol have recently been demonstrated [54].…”