Effects of moderate drinking during pregnancy on placental gene expression

Abstract

Many children adversely affected by maternal drinking during pregnancy cannot be identified early in life using current diagnostic criteria for fetal alcohol spectrum disorder (FASD). We conducted a preliminary investigation to determine whether ethanol-induced alterations in placental gene expression may have some utility as a diagnostic indicator of maternal drinking during pregnancy and as a prognostic indicator of risk for adverse neurobehavioral outcomes in affected offspring. Pregnant Long-Evans rats voluntarily consumed either a 0 or 5% ethanol solution 4 h each day throughout gestation. Ethanol consumption produced a mean maternal daily intermittent peak serum ethanol concentration of 84 mg/dL. Placentas were harvested on gestational day 20 for gene expression studies. Microarray analysis of more than 28,000 genes revealed that the expression of 304 known genes was altered twofold or greater in placenta from ethanol-consuming dams compared with controls. About 76% of these genes were repressed in ethanol-exposed placentas. Gene expression changes involved proteins associated with central nervous system development; organ morphogenesis; immunological responses; endocrine function; ion homeostasis; and skeletal, cardiovascular, and cartilage development. To date, quantitative real-time polymerase chain reaction analysis has confirmed significant alterations in gene expression for 22 genes, including genes encoding for three calcium binding proteins, two matrix metalloproteinases, the cannabinoid 1, galanin 2 and toll-like receptor 4, iodothyronine deiodinase 2, 11-β hydroxysteroid dehydrogenase 2, placental growth factor, transforming growth factor alpha, gremlin 1, and epithelial growth factor (EGF)-containing extracellular matrix protein. These results suggest that the expression of a sufficiently large number of placental mRNAs is altered after moderate drinking during pregnancy to warrant more detailed investigation of the placenta as a biomarker system for maternal drinking during pregnancy and as an early indicator of FASD. Furthermore, these results provide new insights into novel mechanisms on how ethanol may directly or indirectly mediate its teratogenic effects through alterations in placental function during pregnancy.

Prenatal alcohol exposure and prenatal stress differentially alter glucocorticoid signaling in the placenta and fetal brain

“…However, data from previous studies on the effects of both PAE and PS on placental 11β-HSD2 mRNA levels have been somewhat inconsistent. Both decreased (Mairesse et al, 2007; Rosenberg et al, 2010; Liang et al, 2011; Pena et al, 2012) and increased (Clifton et al, 2006; Cuffe et al, 2012; Gardebjer et al, 2014) 11β-HSD2 expression levels have been reported in PAE and PS placentae and one study reported decreased levels in female, but increased levels in male placentae (Wilcoxon et al, 2003). In the present study, we found that placental 11β-HSD2 protein levels were higher in PAE, and unchanged in PS compared to C dams.…”

“…Of relevance, no studies, to our knowledge, have examined PAE or PS effects on placental 11β-HSD1, and reports on the effects of both PAE and PS on placental 11β-HSD2 mRNA levels have been somewhat inconsistent. Decreased 11β-HSD2 expression levels have been reported in PAE and PS placentae in some studies (Mairesse et al, 2007; Rosenberg et al, 2010; Liang et al, 2011; Pena et al, 2012). However, increased placental 11β-HSD2 expression levels were reported in mouse models of glucocorticoid exposure starting at mid-gestation, rat models of periconceptional alcohol exposure, and in pregnant women at term following inhaled glucocorticoid treatment (Clifton et al, 2006; Cuffe et al, 2012; Gardebjer et al, 2014).…”

Chronic Binge Alcohol Exposure During Pregnancy Impairs Rat Maternal Uterine Vascular Function

“…Although the focus of this study is on effects of alcohol maternal uterine vasodilation, a dose of 4.5 g/kg of alcohol administered to maternal rats till GD 20 is reported to produce significant loss of cerebellar and olfactory granule neurons in the offspring (Maier and West, 2001). Although FAS, an extreme form of the span of deficits produced by FASD is characterized by prenatal growth restriction (Sokol et al, 2003), low and moderate alcohol exposure levels may not lead to grossly observable growth deficits in humans (Henderson et al, 2007), rats (Rosenberg et al, 2010), and sheep (Ramadoss et al, 2007). However, it should be noted that it is possible that if the duration of alcohol exposure is longer than that utilized in this study (GD 7-17), or if a higher dose (6g/kg) that is utilized in many other FAS studies (Thomas et al, 2009, Thomas et al, 2010), gowth deficits are likely to be observed.…”

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

“…Clinical (21, 30, 52) and preclinical (4, 23, 33, 35, 46) studies have reported that fetal programming by alcohol results in HPA dysregulation, including both hyperresponsiveness to stressors and deficits in recovery to basal levels. While mechanisms mediating these adverse effects of alcohol are starting to be elucidated (23,55,59,60,71), the molecular pathology underlying fetal alcohol effects on the HPA axis is not fully understood.Accumulating evidence suggests that the interplay between environmental factors and epigenetic processes, such as DNA methylation and chromatin modifications, could play a role in mediating the adverse effects of PAE, including its effects on HPA regulation (20,22,38). Alcohol-induced alterations in one-carbon metabolism provide one potential link between alcohol exposure and epigenetic processes.…”

“…Clinical (21,30,52) and preclinical (4,23,33,35,46) studies have reported that fetal programming by alcohol results in HPA dysregulation, including both hyperresponsiveness to stressors and deficits in recovery to basal levels. While mechanisms mediating these adverse effects of alcohol are starting to be elucidated (23,55,59,60,71), the molecular pathology underlying fetal alcohol effects on the HPA axis is not fully understood.…”