Placental 11β-hydroxysteroid Dehydrogenase Type Research Articles

Early life corticosteroid overexposure: Epigenetic and fetal origins of adult diseases.

The relationship between events occurring during intrauterine development and later-life predisposition to long-term disease, has been described. The fetus responds to excess intrauterine exposure to high levels of corticosteroids, modifying their physiological development and stopping their growth. Fetal exposure to elevated levels of either endogenous (alterations in fetal hypothalamic-pituitary-adrenal axis) or synthetic corticosteroids, is one model of early-life adversity; to developing adult disease. At the molecular level, there are transcriptional changes in metabolic and growth pathways. Epigenetic mechanisms participate in transgenerational inheritance, not genomic. Exposures that change 11β-hydroxysteroid dehydrogenase type 2 enzyme methylation status in the placenta can result in transcriptional repression of the gene, causing the fetus to be exposed to higher levels of cortisol. More precise diagnosis and management of antenatal corticosteroids for preterm birth, would potentially decrease the risk of long-term adverse outcomes. More studies are needed to understand the potential roles of factors to alter fetal corticosteroid exposure. Long-term infant follow-up is required to determine whether methylation changes in placenta may represent useful biomarkers of later disease risk. This review, summarize recent advances in the programming of fetal effects of corticosteroid exposure, the role of corticosteroids in epigenetic gene regulation of placental 11β-hydroxysteroid dehydrogenase type 2 enzyme expression and transgenerational effects.

Maternal glucocorticoids do not directly mediate the effects of maternal social stress on the fetus.

Stress during pregnancy negatively affects the fetus and increases the risk for affective disorders in adulthood. Excess maternal glucocorticoids are thought to mediate fetal programming; however, whether they exert their effects directly or indirectly remains unclear. During pregnancy, protective mechanisms including maternal hypothalamic-pituitary-adrenal (HPA) axis hyporesponsiveness and placental 11β-hydroxysteroid dehydrogenase (11βHSD) type 2, which inactivates glucocorticoids, limit mother-to-fetus glucocorticoid transfer. However, whether repeated stress negatively impacts these mechanisms is not known. Pregnant rats were exposed to repeated social stress on gestational days (GD) 16-20 and several aspects of HPA axis and glucocorticoid regulation, including concentrations of glucocorticoids, gene expression for their receptors (Nr3c1, Nr3c2), receptor chaperones (Fkbp51, Fkbp52) and enzymes that control local glucocorticoid availability (Hsd11b1, Hsd11b2), were investigated in the maternal, placental and fetal compartments on GD20. The maternal HPA axis was activated following stress, though the primary driver was vasopressin, rather than corticotropin-releasing hormone. Despite the stress-induced increase in circulating corticosterone in the dams, only a modest increase was detected in the circulation of female fetuses, with no change in the fetal brain of either sex. Moreover, there was no change in the expression of genes that mediate glucocorticoid actions or modulate local concentrations in the fetal brain. In the placenta labyrinth zone, stress increased Hsd11b2 expression only in males and Fkbp51 expression only in females. Our results indicate that any role glucocorticoids play in fetal programming is likely indirect, perhaps through sex-dependent alterations in placental gene expression, rather than exerting effects via direct crossover into the fetal brain.

Mitochondria Targeted Antioxidant Significantly Alleviates Preeclampsia Caused by 11β-HSD2 Dysfunction via OPA1 and MtDNA Maintenance.

We have previously demonstrated that placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) dysfunction contributes to PE pathogenesis. We sought to elucidate molecular mechanisms underlying 11β-HSD2 dysfunction-induced PE and to seek potential therapeutic targets using a 11β-HSD2 dysfunction-induced PE-like rat model as well as cultured extravillous trophoblasts (EVTs) since PE begins with impaired function of EVTs. In 11β-HSD2 dysfunction-induced PE-like rat model, we revealed that placental mitochondrial dysfunction occurred, which was associated with mitDNA instability and impaired mitochondrial dynamics, such as decreased optic atrophy 1 (OPA1) expression. MitoTEMPO treatment significantly alleviated the hallmark of PE-like features and improved mitDNA stability and mitochondrial dynamics in the placentas of rat PE-like model. In cultured human EVTs, we found that 11β-HSD2 dysfunction led to mitochondrial dysfunction and disrupted mtDNA stability. MitoTEMPO treatment improved impaired invasion and migration induced by 11β-HSD2 dysfunction in cultured EVTs. Further, we revealed that OPA1 was one of the key factors that mediated 11β-HSD2 dysfunction-induced excess ROS production, mitochondrial dysfunction and mtDNA reduction. Our data indicates that 11β-HSD2 dysfunction causes mitochondrial dysfunctions, which impairs trophoblast function and subsequently results in PE development. Our study immediately highlights that excess ROS is a potential therapeutic target for PE.

Maternal 11-Ketoandrostenedione Rises Through Normal Pregnancy and Is the Dominant 11-Oxygenated Androgen in Cord Blood.

Adrenal-derived 11-oxygenated androgens (11oAs) are known important contributors to human physiology and disease but have not been studied in pregnancy. We characterize 11oAs in normal human pregnancy and neonatal period and assess the ratios between 11oAs and compare with ratios of other steroids that undergo placental metabolism. Prospective cohort study, 2010-2018. Academic institution. Pairs of pregnant women and newborns (n = 120) were studied. Inclusion criteria were maternal age between 18 and 42 years old, spontaneous singleton pregnancies, and intention to deliver at University of Michigan. Maternal venous blood was collected during first trimester and at term. Neonatal cord blood was collected following delivery. Steroids were measured via liquid chromatography-tandem mass spectrometry. Levels of 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone, and 11-ketotestoterone (11KT) in maternal first trimester, maternal term, and neonatal cord blood were compared. 11OHA4-to-11KA4 ratios were correlated with cortisol-to-cortisone ratios. Dominant 11oAs in pregnancy and the cord blood are 11OHA4 and 11KA4, compared to 11OHA4 and 11KT in adult men and nonpregnant women. We found a rise in 11oA concentrations, particularly 11KA4, from first to third trimester. In cord blood, the concentration of 11KA4 exceeded those of both 11OHA4 and 11KT, reflecting placental 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and 17β-hydroxysteroid dehydrogenase (17βHSD2) activities, respectively. 11OHA4-to-11KA4 ratios are concordant with cortisol-to-cortisone ratios across all maternal and fetal compartments, reflecting placental 11βHSD2 activity. Placental 17βHSD2 activity defends the fetus against the androgen 11KT. Our normative values may be used in future studies of 11oAs in complicated pregnancies.

Biological Effects of Exposure to a Radiofrequency Electromagnetic Field on the Placental Barrier in Pregnant Rats.

The placenta protects the fetus against excessive stress‐associated maternal cortisol during pregnancy. We studied whether exposure to radiofrequency electromagnetic field (RF‐EMF) radiation during pregnancy can cause changes in dams and their placentas. Pregnant Sprague–Dawley rats were divided into cage‐control, sham‐exposed, and RF‐exposed groups. They were exposed to RF‐EMF signals at a whole‐body specific absorption rate of 4 W/kg for 8 h/day from gestational Day 1 to 19. Levels of cortisol in the blood, adrenal gland, and placenta were measured by enzyme‐linked immunosorbent assay. Levels of adrenocorticotropic hormone and corticotropin‐releasing hormone were monitored in maternal blood. Expression levels of placental 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2) messenger RNA (mRNA) were measured by reverse transcription polymerase chain reaction. Morphological changes in the placenta were analyzed using hematoxylin and eosin staining. Fetal parts of the placenta were measured using Zen 2.3 blue edition software. Maternal cortisol in circulating blood (RF: 230 ± 24.6 ng/ml and Sham: 156 ± 8.3 ng/ml) and the adrenal gland (RF: 58.3 ± 4.5 ng/ml and Sham: 30 ± 3.8 ng/ml) was significantly increased in the RF‐exposed group (P < 0.05). Placental cortisol was stably maintained, and the level of placental 11β‐HSD2 mRNA expression was not changed in the RF‐exposed group. RF‐EMF exposure during pregnancy caused a significant elevation of cortisol levels in circulating blood; however, no changes in the placental barrier were observed in pregnant rats. Bioelectromagnetics. © 2021 Bioelectromagnetics Society

Maternal stress, placental 11β-hydroxysteroid dehydrogenase type 2, and infant HPA axis development in humans: Psychosocial and physiological pathways

IntroductionPrenatal stress is known to influence fetal hypothalamic-pituitary-adrenal axis (HPA axis) development. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) is a central gene in this pathway, but little is known about what influences its functioning. We assess how maternal distress influences HSD11B2 functioning, and how HSD11B2 in turn, is associated with infant HPA axis development. MethodsData come from 24 mother-infant dyads on the Galápagos Islands. Using adjusted linear regression models, we assess the effects of maternal psychosocial (stress and depressive symptoms, measured by the Perceived Stress Scale and the Patient Health Questionnaire-8, respectively) and physiological (HPA axis dysregulation) distress during pregnancy on HSD11B2 methylation and expression and then test how these HSD11B2 measures influence infant HPA axis development. ResultsMaternal HPA axis dysregulation during pregnancy is associated with lower placental HSD11B2 expression, which is associated with an exaggerated cortisol reactivity in infants. Sex-specific analyses revealed that maternal depressive symptoms may influence the functioning of placental HSD11B2 differently in girls (n = 11, 46%) than in boys (n = 13, 54%), though the sample size was small. DiscussionThese results support a disrupted adaptive framework, in which the ability to upregulate HSD11B2 expression in response to acute stress diminishes as maternal stress becomes chronic. In this model, chronic stress may exhaust the protective mechanism of HSD11B2, leaving the infant vulnerable to high levels of maternal cortisol, which could injure the fetal HPA axis and disrupt long-term neurobehavioral and metabolic development. While larger studies will be needed to confirm these findings, this study offers exploratory results on the effects of maternal distress on both HSD11B2 methylation and expression and the effect of HSD11B2 on offspring HPA axis development.

Antenatal exposure to betamethasone induces placental 11β-hydroxysteroid dehydrogenase type 2 expression and the adult metabolic disorders in mice.

Antenatal overexposure to glucocorticoids causes fetal intrauterine growth restriction (IUGR) and adult metabolic disorders. 11β-hydroxysteroid dehydrogenase (11β-HSD) 1 and 2 are key enzymes for glucocorticoid metabolism, however, the detailed effects of antenatal overexposure to glucocorticoids on placental 11β-HSD1 and 2 expression and adult metabolic disorders remain obscure. Here, we report that, in placenta 11β-HSD1 is diffusely localized, whereas 11β-HSD2 is specifically expressed in labyrinthine layer. Exposure of pregnant dams to betamethasone significantly increases the expression of placental 11β-HSD2 but not 11β-HSD1, and decreases the weights of fetuses but not placentas. Antenatal exposure to betamethasone leads to either significant weight loss in the offspring younger than 10-week-old, or weight gain in those older than 14-week-old. Furthermore, antenatal exposure to betamethasone results in coexistence of various metabolic disorders in adult offspring, including hyperglycemia, glucose intolerance, low insulin secretory capacity and hyperlipidemia. The present study demonstrates that exposure of pregnant dams to betamethasone induces the expression of placental 11β-HSD2 but not 11β-HSD1, leads to fetal IUGR and causes adult metabolic disorders, providing evidence for fetal origins of adult diseases and the potential role of placental 11β-HSD2 in them.

Sex-specific and lasting effects of a single course of antenatal betamethasone treatment on human placental 11β-HSD2

IntroductionWe have previously shown that even a single course of antenatal betamethasone (BET) as an inductor for lung maturity reduces birth weight and head circumference. Moreover, animal studies link BET administration to alterations of the hypothalamic-pituitary-adrenal-gland-axis (HPA). The unhindered development of the fetal HPA axis is dependent on the function and activity of 11β-hydroxysteroiddehydrogenase type 2 (11β-HSD2), a transplacental cortisol barrier. Therefore, we investigated the effects of BET on this transplacental barrier and fetal growth. MethodsPregnant women treated with a single course of BET between 23 + 5 to 34 + 0 weeks of gestation were compared to gestational-age-matched controls. Placental size and neonatal anthropometrics were taken. Cortisol and ACTH levels were measured in maternal and umbilical cord blood samples. Placental 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1) protein levels and 11β-HSD2 protein and activity levels were determined. Parameters were analyzed independent of sex, and in subgroups divided by gender and gestational age. ResultsIn term born females, BET administration was associated with reduced head circumference and decreased 11β-HSD2 protein levels and enzyme activity. Males treated with BET, especially those born prematurely, showed increased 11β-HSD2 protein levels. ConclusionA single course of BET alters placental glucocorticoid metabolism in a sex-specific manner. Decreased 11β-HSD2 levels in term born females may lead to an increased placental transfer of maternal cortisol and therefore result in a reduced head circumference and a higher risk for altered stress response in adulthood. Further research is needed to conclude the significance of increased 11β-HSD2 levels in males.

NAChRs-ERK1/2-Egr-1 signaling participates in the developmental toxicity of nicotine by epigenetically down-regulating placental 11β-HSD2

Impaired placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity which inactivates maternal glucocorticoids is associated with poor fetal growth and a higher risk of chronic diseases in adulthood. This study aimed to elucidate the epigenetically regulatory mechanism of nicotine on placental 11β-HSD2 expression. Pregnant Wistar rats were administered 1.0 mg/kg nicotine subcutaneously twice a day from gestational day 9 to 20. The results showed that prenatal nicotine exposure increased corticosterone levels in the placenta and fetal serum, disrupted placental morphology and endocrine function, and reduced fetal bodyweight. Meanwhile, histone modification abnormalities (decreased acetylation and increased di-methylation of histone 3 Lysine 9) on the HSD11B2 promoter and lower-expression of 11β-HSD2 were observed. Furthermore, the expression of nicotinic acetylcholine receptor (nAChR) α4/β2, the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and Ets-like protein-1 (Elk-1), and the expression of early growth response-1 (Egr-1) were increased in the nicotine groups. In human BeWo cells, nicotine decreased 11β-HSD2 expression, increased nAChRα9 expression, and activated ERK1/2/Elk-1/Egr-1 signaling in the concentration (0.1–10 μM)-dependent manner. Antagonism of nAChRs, inhibition of ERK1/2 and Egr-1 knockdown by siRNA were able to block/abrogate the effects of nicotine on histone modification and expression of 11β-HSD2. Taken together, nicotine can impair placental structure and function, and induce fetal developmental toxicity. The underlying mechanism involves histone modifications and down-regulation of 11β-HSD2 through nAChRs/ERK1/2/Elk-1/Egr-1 signaling, which increases active glucocorticoids levels in the placenta and fetus, and eventually inhibits the fetal development.

A maternal high-fat, high-sucrose diet has sex-specific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice.

Maternal overnutrition and obesity during pregnancy can have long-term effects on offspring physiology and behaviour. These developmental programming effects may be mediated by fetal exposure to glucocorticoids, which is regulated in part by placental 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2. We tested whether a maternal high-fat, high-sucrose diet would alter expression of placental 11β-HSD1 and 2, thereby increasing fetal exposure to maternal glucocorticoids, with downstream effects on offspring physiology and behaviour. C57BL/6J mice were fed a high-fat, high-sucrose (HFHS) diet or a nutrient-matched low-fat, no-sucrose control diet prior to and during pregnancy and lactation. At day 17 of gestation, HFHS dams had ~20% lower circulating corticosterone levels than controls. Furthermore, there was a significant interaction between maternal diet and fetal sex for circulating corticosterone levels in the fetuses, whereby HFHS males tended to have higher corticosterone than control males, with no effect in female fetuses. However, placental 11β-HSD1 or 11β-HSD2 expression did not differ between diets or show an interaction between diet and sex. To assess potential long-term consequences of this sex-specific effect on fetal corticosterone, we studied locomotor activity and metabolic traits in adult offspring. Despite a sex-specific effect of maternal diet on fetal glucocorticoids, there was little evidence of sex-specific effects on offspring physiology or behaviour, although HFHS offspring of both sexes had higher circulating corticosterone at 9 weeks of age. Our results suggest the existence of as yet unknown mechanisms that mitigate the effects of altered glucocorticoid exposure early in development, making offspring resilient to the potentially negative effects of a HFHS maternal diet.

Invited Commentary: An Ingenious Approach to Examining the Relationship Between Maternal Stress and Offspring Health?

The potentially deleterious effects on offspring health of excess maternal stress in pregnancy are important to understand-both whether observed associations are causal and through what mechanisms their effects may exert an influence. In this issue of the Journal, Räikkönen et al. (Am J Epidemiol. 2012;000(0):000-000) provide an ingenious test of a potential pathway through which maternal stress may influence offspring development. Licorice consumption is known to disrupt the ability of the placental enzyme 11β-hydroxysteroid dehydrogenase type 2 to inactivate cortisol before it reaches the fetus, leading to higher levels of cortisol exposure. Higher levels of cortisol exposure are also hypothesized to underlie the mechanism through which maternal stress may disrupt fetal development. Thus licorice consumption may serve, in some ways, to mimic maternal stress. The authors report associations between heavy licorice consumption during pregnancy and a wide range of offspring outcomes, including changes in pubertal timing, intelligence quotient, and mental health. In our view, these results should be considered preliminary; more work needs to be completed to determine the relationship of prenatal licorice consumption to these outcomes. Nonetheless, these intriguing and suggestive results demonstrate that this line of work should be given high priority, and they set the stage for additional research moving forward.

Maternal Licorice Consumption During Pregnancy and Pubertal, Cognitive, and Psychiatric Outcomes in Children.

Earlier puberty, especially in girls, is associated with physical and mental disorders. Prenatal glucocorticoid exposure influences the timing of puberty in animal models, but the human relevance of those findings is unknown. We studied whether voluntary consumption of licorice, which contains glycyrrhizin (a potent inhibitor of placental 11β-hydroxysteroid dehydrogenase type 2, the "barrier" to maternal glucocorticoids), by pregnant women was associated with pubertal maturation (height, weight, body mass index for age, difference between current and expected adult height, Tanner staging, score on the Pubertal Development Scale), neuroendocrine function (diurnal salivary cortisol, dexamethasone suppression), cognition (neuropsychological tests), and psychiatric problems (as measured by the Child Behavior Checklist) in their offspring. The children were born in 1998 in Helsinki, Finland, and examined during 2009-2011 (mean age=12.5 (standard deviation (SD), 0.4) years; n=378). Girls exposed to high maternal glycyrrhizin consumption (≥500mg/week) were taller (mean difference (MD)=0.4 SD, 95% confidence interval (CI): 0.1, 0.8), were heavier (MD =0.6 SD, 95% CI: 0.2, 1.9), and had higher body mass index for age (MD = 0.6 SD, 95% CI: 0.2, 0.9). They were also 0.5 standard deviations (95% CI: 0.2, 0.8) closer to adult height and reported more advanced pubertal development (P<0.04). Girls and boys exposed to high maternal glycyrrhizin consumption scored 7 (95% CI: 3.1, 11.2) points lower on tests of intelligence quotient, had poorer memory (P<0.04), and had 3.3-fold (95% CI: 1.4, 7.7) higher odds of attention deficit/hyperactivity disorder problems compared with children whose mothers consumed little to no glycyrrhizin (≤249mg/week). No differences in cortisol levels were found. Licorice consumption during pregnancy may be associated with harm for the developing offspring.

Prenatal maternal distress affects atopic dermatitis in offspring mediated by oxidative stress

Recent evidence suggests that prenatal maternal distress increases the risk of allergic diseases in offspring. However, the effect of prenatal maternal depression and anxiety on atopic dermatitis (AD) risk remains poorly understood. We investigated whether prenatal maternal distress is associated with AD risk in offspring and whether the mechanism is mediated by reactive oxygen species. Two general population-based birth cohorts formed the study. One cohort (Cohort for Childhood Origin of Asthma and Allergic Diseases [COCOA]) consisted of 973 mother-baby dyads, and the other (Panel Study on Korean Children [PSKC]) consisted of 1531 mother-baby dyads. The association between prenatal distress and AD was assessed by using Cox proportional hazards and logistic regression models. In COCOA placental 11β-hydroxysteroid dehydrogenase type 2 and glutathione levels and serum IgE levels in 1-year-old children were measured. In COCOA and PSKC AD occurred in 30.6% (lifetime prevalence) and 11.6% (1year prevalence) of offspring, respectively. Prenatal maternal distress increased the risk of AD in offspring, both in COCOA (hazard ratio for depression, 1.31 [95% CI, 1.02-1.69]; hazard ratio for anxiety, 1.41 [95% CI, 1.06-1.89]) and PSKC (odds ratio for distress, 1.85 [95% CI, 1.06-3.25]). In COCOA both prenatal maternal depression and anxiety scores were positively related to the predicted probability of AD (P<.001 in both). Prenatal distress decreased placental glutathione to glutathione disulfideratios (P=.037) and, especially in those who later had AD, decreased placental 11β-hydroxysteroid dehydrogenase type 2 levels (P=.010) and increased IgE levels at 1year of age (P=.005). Prenatal maternal depression and anxiety promote risk of AD in offspring. Maternal distress increases the predicted probability of AD. The mechanism might involve chronic stress, abnormal steroid levels, and reactive oxygen species.

Nutritional marginal zinc deficiency disrupts placental 11β-hydroxysteroid dehydrogenase type 2 modulation.

This paper investigated if marginal zinc nutrition during gestation could affect fetal exposure to glucocorticoids as a consequence of a deregulation of placental 11βHSD2 expression. Placenta 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) plays a central role as a barrier protecting the fetus from the deleterious effects of excess maternal glucocorticoids. Rats were fed control (25 μg zinc per g diet) or marginal (10 μg zinc per g diet, MZD) zinc diets from day 0 through day 19 (GD19) of gestation. At GD19, corticosterone concentration in plasma, placenta, and amniotic fluid was similar in both groups. However, protein and mRNA levels of placenta 11βHSD2 were significantly higher (25% and 58%, respectively) in MZD dams than in controls. The main signaling cascades modulating 11βHSD2 expression were assessed. In MZD placentas the activation of ERK1/2 and of the downstream transcription factor Egr-1 was low, while p38 phosphorylation and SP-1-DNA binding were low compared to the controls. These results point to a central role of ERK1/Egr-1 in the regulation of 11βHSD2 expression under the conditions of limited zinc availability. In summary, results show that an increase in placenta 11βHSD2 expression occurs as a consequence of gestational marginal zinc nutrition. This seems to be due to a low tissue zinc-associated deregulation of ERK1/2 rather than to exposure to high maternal glucocorticoid exposure. The deleterious effects on brain development caused by diet-induced marginal zinc deficiency in rats do not seem to be due to fetal exposure to excess glucocorticoids.

Placental 11β-Hydroxysteroid dehydrogenase type 2 expression: Correlations with birth weight and placental metal concentrations

IntroductionInfants born below 2500 g are classified as low birth weight. Excess in utero exposure to cortisol has been linked to restricted fetal growth. Placental production of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol before passage into the fetus. The present study tested the hypothesis that placental 11β-HSD2 expression is positively correlated with an individualized birth weight centile and raw birth weight, and examines the relationship between metal concentrations in placental tissue and 11β-HSD2 expression. MethodsPlacentae from 191 births were collected and samples preserved to maintain mRNA profile. Placental 11β-HSD2 expression was measured via qRT-PCR. Addition samples were collected from placental tissues and uniformly dried in order to quantify 18 metals via ICP-MS (n = 160). ResultsA significant, positive correlation between 11β-HSD2 expression and individualized birth weight centile (p = 0.0321) and birth weight (p = 0.0243) was found. Additionally, maternal age and gestational age were positivity correlated with each other (p = 0.0321). Birth weight was significantly different with race, marital status, education and maternal tobacco use. Four metals (Co, Mn, Ni, Zn) demonstrated significant positive correlations (p < 0.05) with 11β-HSD2 expression. Sex specific differences were found; Co, Cu, Fe, Zn, and Ni were positively correlated with 11β-HSD2 expression in males only, no significant correlations were found in the female only sample. ConclusionThese data indicate that the growth potential of a fetus is related to the 11β-HSD2 expression in the placenta, and that 11β-HSD2 expression is related to the trace metals status of the mother.

Stress exposure during pregnancy affects placental 11β-hydroxysteroid dehydrogenase type 2 and maternal immune repertoire

as in the 1st trimester trophoblast cell line HTR-8/SVneo. Isolated blood monocytes where cultured and differentiated in the presence of IL-34 for six days. When analyzed with flow cytometry, they showed high expression of CD14, CD163 (scavenger receptor), CD206 (mannose receptor) and CD209 (DC-SIGN), markers expressed on decidual macrophages. Taken together, our results show that IL-34 is produced both by placental and decidual cells and is able to induce macrophages with a phenotype resembling that of decidual macrophages. The findings suggest a role for IL-34 in the regulation of decidual macrophages during early pregnancy.

HPA Axis Function During the Perinatal Period in Patients with Affective Disorders

Abnormal function of the hypothalamic–pituitary–adrenal (HPA) axis along with the sympathetic-adrenalmedullary (SAM) axis represents the hallmark pathological findings in non-pregnant and pregnant women exhibiting major depressive disorder (MDD). Perinatal depression is highly prevalent, with an estimated prevalence exceeding 10% in most high-income countries. Pregnant women experience more stressful life events than non-pregnant women. Pregnant women with MDD show higher baseline levels of cortisol, increased levels of proinflammatory cytokines, and higher levels of hypothalamic-pituitary peptide hormones, catecholamines, and low dehydroepiandrosterone (DHEA) levels in plasma compared to those without MDD. During pregnancy the innate immune system and placental factors play crucial roles in the development of the conceptus to its full term. These factors when altered may generate a persistent dysfunction of the HPA axis that could lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11β-hydroxysteroid dehydrogenase Type 2 (11β-HSD-2). Epigenetic modifications (DNA methylation) of gene enhancers of the glucocorticoid receptor (GR) in addition to the corticotrophin-releasing hormone (CRH) and arginine-vasopressin (AVP) among other brain and placental molecules, may significantly contribute to the expression of depression during pregnancy. Pregnant women exhibiting affective disorders have a higher risk of generating preterm babies with high rates of morbidity and mortality and negative outcomes in child development compared to pregnant women without these disorders. Affective disorders in pregnant women should be taken seriously, and therapies focused in reducing or at most preventing the deleterious effects induced by stressors should be implemented to promote the welfare of both mother and baby. The goal of this paper is to describe the modulatory role of distinct paracrine and endocrine mediators including epigenetics of hormone receptors that drive the abnormal activity of the HPA axis in perinatal depression.

Hypothalamic-pituitary-adrenal axis function during perinatal depression.

Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis is an important pathological finding in pregnant women exhibiting major depressive disorder. They show high levels of cortisol pro-inflammatory cytokines, hypothalamic-pituitary peptide hormones and catecholamines, along with low dehydroepiandrosterone levels in plasma. During pregnancy, the TH2 balance together with the immune system and placental factors play crucial roles in the development of the fetal allograft to full term. These factors, when altered, may generate a persistent dysfunction of the HPA axis that may lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11β-hydroxysteroid dehydrogenase type 2. Epigenetic modifications also may contribute to the dysregulation of the HPA axis. Affective disorders in pregnant women should be taken seriously, and therapies focused on preventing the deleterious effects of stressors should be implemented to promote the welfare of both mother and baby.

The acute autonomic stress response and amniotic fluid glucocorticoids in second-trimester pregnant women.

The maternal autonomic nervous system (ANS) has received little attention in the investigation of biological mechanisms linking prenatal stress to fetal cortisol (F) excess. In vitro, norepinephrine and epinephrine inhibit placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which protects the fetus from F overexposure by inactivating it to cortisone (E). Here, we investigated the acute ANS stress response to an amniocentesis and its association with amniotic fluid F, E, and E/(E + F) as a marker of fetoplacental 11β-HSD2 activity. An aliquot of amniotic fluid was obtained from 34 healthy, second-trimester pregnant women undergoing amniocentesis. Repeated assessment of mood states served to examine the psychological stress response to amniocentesis. Saliva samples were collected to measure stress-induced changes in salivary α-amylase concentrations in response to amniocentesis. Cardiac parameters were measured continuously. Undergoing amniocentesis induced significant psychological and autonomic alterations. Low-frequency (LF)/high-frequency (HF) baseline, suggested to reflect sympathovagal balance, was negatively correlated with amniotic E/(E + F) (r=-0.53, p = .002) and positively with F (r = 0.62, p < .001). In contrast, a stronger acute LF/HF response was positively associated with E/(E + F) (r = 0.44, p = .012) and negatively with F (r=-0.40, p = .025). These findings suggest that the maternal ANS is involved in the regulation of the fetoplacental barrier to stress. Allostatic processes may have been initiated to counterbalance acute stress effects. In contrast, higher LF/HF baseline values, possibly indicative of chronic stress exposure, may have inhibited 11β-HSD2 activity in the fetoplacental unit. These results parallel animal findings of up-regulated placental 11β-HSD2 in response to acute stress but impairment under chronic stress.

Reduced Expression of 11β-Hydroxysteroid Dehydrogenase Type 2 in Preeclamptic Placentas Is Associated With Decreased PPARγ but Increased PPARα Expression

Placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is reduced in pregnancies complicated with preeclampsia (PE). Peroxisome proliferator-activated receptors β/δ (PPARβ/δ) have been shown to suppress 11β-HSD2 expression in human placental cells. Our objectives were to investigate whether the reduced 11β-HSD2 expression is associated with the changes in PPARs in PE placentas, and whether PPARα and PPARγ affect 11β-HSD2 expression in placental cells. PPARα and PPARβ/δ mRNA and protein expression was increased, whereas PPARγ mRNA and protein expression was decreased in PE placentas. 11β-HSD2 protein expression was inversely correlated with PPARβ/δ in normal placentas but correlated positively with PPARγ and inversely to PPARα in PE placentas. In cultured placental cells, PPARα agonist inhibited, whereas PPARγ agonist stimulated, 11β-HSD2 mRNA and protein expression and activity in a dose-dependent manner. Knockdown of retinoid X nuclear receptor α (RXRα) resulted in a loss of PPARγ effect but not PPARα effect on11β-HSD2. The PPARα effect remained, but the PPARγ effect was lost in the presence of the translational inhibitor cycloheximide. PPARγ agonist dose-dependently stimulated specificity protein 1 (Sp-1) protein expression. Inhibition or knockdown of Sp-1 resulted in a loss of the effects of PPARα and PPARγ. The Sp-1 protein level was not correlated with 11β-HSD2 and PPARs in normal placentas, whereas Sp-1 expression was correlated with 11β-HSD2, PPARγ, and PPARβ/δ in PE placentas. Our data indicate that 11β-HSD2 expression can be modulated by PPARα and PPARγ in placental trophoblasts through Sp-1. Decreased 11β-HSD2 expression in PE placenta might be associated with decreased PPARγ but increased PPARα expression.