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

Abstract

Adverse intrauterine environments increase vulnerability to chronic diseases across the lifespan. The hypothalamic-pituitary-adrenal (HPA) axis, which integrates multiple neuronal signals and ultimately controls the response to stressors, may provide a final common pathway linking early adversity and adult disease. Both prenatal alcohol exposure (PAE) and prenatal stress (PS) induce a hyperresponsive HPA phenotype in adulthood. As glucocorticoids are pivotal for the normal development of many fetal tissues including the brain, we used animal models of PAE and PS to investigate possible mechanisms underlying fetal programming of glucocorticoid signaling in the placenta and fetal brain at gestation day (GD) 21. We found that both PAE and PS dams had higher corticosterone levels than control dams. However, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme levels were increased in PAE and unchanged in PS placentae, although there were no differences in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) levels. Moreover, only PAE fetuses showed decreased body weight and increased placental weight, and hence a lower fetal/placental weight ratio, a marker of placenta efficiency, compared to all other prenatal groups. Importantly, PAE and PS differentially altered corticosteroid receptor levels in placentae and brains. In the PS condition, maternal corticosterone was negatively correlated with both 11β-HSD1 and mineralocorticoid receptor (MR) proteins levels in male and female placentae, whereas in the PAE condition, there were trends for a positive correlation between maternal corticosterone and 11β-HSD1, regardless of sex, and a negative correlation between maternal alcohol intake and MR in male placentae. In fetal brains, sexually dimorphic changes in MR and glucocorticoid receptor (GR) levels, and the MR/GR ratio seen in C fetuses were absent in PAE and PS fetuses. In addition, PS but not PAE female fetuses had higher MR and lower GR expression levels in certain limbic areas compared to C female fetuses. Thus the similar adult HPA hyperresponsive phenotype in PAE and PS animals likely occurs through differential effects on glucocorticoid signaling in the placenta and fetal brain.

Effects of prenatal stress on anxiety‐ and depressive‐like behaviours are sex‐specific in prepubertal rats

“…In parallel, limbic brain areas that regulate the foetal HPA axis also develop, such as the hippocampus and the amygdala . The mineralocorticoid receptor (MR) and GR are expressed in these limbic areas in the last third of pregnancy, when the prenatal stress was applied in the present study. Another consequence of overexposure of the foetal brain to maternal corticosterone is an increased activity of negative‐feedback control of the foetal HPA axis to counter the effects of higher levels of maternal corticosterone.…”

Assessing the Independent and Joint Effects of Unmedicated Prenatal Depressive Symptoms and Alcohol Consumption in Pregnancy and Infant Neurodevelopmental Outcomes

“…However, the authors found no interaction on either measure between the exposures (Staples et al, 2013). Both exposures are hypothesized to alter maternal and fetal HPA functioning, although they do not appear to share the same mechanisms (Lan et al, 2015; Lee and Rivier, 1992). Using adrenalectomized rats, Lee and Rivier demonstrated that corticosterone, which appears to mediate HPA changes in the offspring from prenatal stressors (including depression), does not mediate the changes in HPA function resulting from PAE (Lee and Rivier, 1992).…”

First trimester alcohol exposure alters placental perfusion and fetal oxygen availability affecting fetal growth and development in a non-human primate model

“…Due to the fact that many pregnancies are unplanned or unrecognized until mid- to late-first trimester 2–4 , this NHP model is relevant for studying the outcomes of pregnancies at risk for fetal alcohol spectrum disorder due to alcohol consumption prior to pregnancy recognition. Compared with other animal models studying the effects of fetal alcohol exposure, the NHP is advantageous due to its similar physiology to humans 19 , including the rates of absorption and metabolism of ethanol 19 , the ability to train animals to voluntarily drink alcohol (hence avoiding confounds associated with inducing maternal stress) 31 , and similarities in fetal development, particularly with regard to gestational timing 17–18 . Significant findings of decreased fetal oxygen availability, weight, and abnormal brain development were observed in ethanol-exposed pregnancies at mid-gestation.…”