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Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity  [PDF]
Allison A. Appleton, David A. Armstrong, Corina Lesseur, Joyce Lee, James F. Padbury, Barry M. Lester, Carmen J. Marsit
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074691
Abstract: Background Prenatal socioeconomic adversity as an intrauterine exposure is associated with a range of perinatal outcomes although the explanatory mechanisms are not well understood. The development of the fetus can be shaped by the intrauterine environment through alterations in the function of the placenta. In the placenta, the HSD11B2 gene encodes the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol thereby protecting the developing fetus from this exposure. This gene is regulated by DNA methylation, and this methylation and the expression it controls has been shown to be susceptible to a variety of stressors from the maternal environment. The association of prenatal socioeconomic adversity and placental HSD11B2 methylation has not been examined. Following a developmental origins of disease framework, prenatal socioeconomic adversity may alter fetal response to the postnatal environment through functional epigenetic alterations in the placenta. Therefore, we hypothesized that prenatal socioeconomic adversity would be associated with less HSD11B2 methylation. Methods and Findings We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 444 healthy term newborn infants and several markers of prenatal socioeconomic adversity: maternal education, poverty, dwelling crowding, tobacco use and cumulative risk. We also examined whether such associations were sex-specific. We found that infants whose mothers experienced the greatest levels of socioeconomic adversity during pregnancy had the lowest extent of placental HSD11B2 methylation, particularly for males. Associations were maintained for maternal education when adjusting for confounders (p<0.05). Conclusions Patterns of HSD11B2 methylation suggest that environmental cues transmitted from the mother during gestation may program the developing fetus’s response to an adverse postnatal environment, potentially via less exposure to cortisol during development. Less methylation of placental HSD11B2 may therefore be adaptive and promote the effective management of stress associated with social adversity in a postnatal environment.
Epigenetic Effects of Prenatal Stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain  [PDF]
Catherine Jensen Pe?a, Catherine Monk, Frances A. Champagne
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039791
Abstract: Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14–20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain.
Human type 2 17beta-hydroxysteroid dehydrogenase mRNA and protein distribution in placental villi at mid and term pregnancy
Renée Drolet, Marc Simard, Julie Plante, Philippe Laberge, Yves Tremblay
Reproductive Biology and Endocrinology , 2007, DOI: 10.1186/1477-7827-5-30
Abstract: We obtained placentas from 10 to 26 6/7 weeks of pregnancy from women undergoing voluntary termination of pregnancy, term placentas were collected after normal spontaneous vaginal deliveries. We quantified 17beta-HSD2 mRNA levels in mid-gestation and term human placenta by RT-QPCR. We produced a new anti-17beta-HSD2 antibody to study its spatio-temporal expression by immunohistochemistry. We also compared steroid levels (testosterone, estrone and estradiol) and 17beta-HSD2 mRNA and protein levels between term placenta and endometrium.High 17beta-HSD2 mRNA and protein levels were found in both mid-gestation and term placentas. However, we showed that 17beta-HSD2 mRNA levels increase by 2.27 fold between mid-gestation and term. This period coincides with a transitional phase in the development of the villous vasculature. In mid-gestation placenta, high levels of 17beta-HSD2 were found in mesenchymal villi and immature intermediate villi, more precisely in endothelial cells of the stromal channel. At term, high levels of 17beta-HSD2 were found in the numerous sinusoidal capillaries of terminal villi. 17beta-HSD2 mRNA and protein levels in term placentas were respectively 25.4 fold and 30 to 60 fold higher than in the endometrium. Steroid levels were also significantly higher in term placenta than in the endometrium.The spatial and temporal expression of 17beta-HSD2 in the placenta during pregnancy and the comparison of 17beta-HSD2 expression and steroid levels between placental villi and endometrium are compatible with a role in the modulation of active and inactive forms of estrogens. Our observations strongly support the hypothesis that 17beta-HSD2 acts as a barrier decreasing estradiol secretion rates in the foetal circulation.During human pregnancy, the placenta produces and secretes high amounts of estradiol (E2) and estrone (E1) [1,2]. E2, the most potent form, participates in the development of some foetal organ systems. Indeed, late in gestation, E2 cooperates
Caffeine Reduces 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells through the Adenosine A2B Receptor  [PDF]
Saina Sharmin, Haiyan Guan, Andrew Scott Williams, Kaiping Yang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038082
Abstract: Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11β-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11β-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine) were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1) both caffeine and paraxanthine decreased placental 11β-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A2B receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11β-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11β-HSD2) abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11β-HSD2. Taken together, these findings reveal that placental 11β-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A2B receptor signaling in regulating placental 11β-HSD2, and consequently fetal development.
Lack of Renal 11 Beta-Hydroxysteroid Dehydrogenase Type 2 at Birth, a Targeted Temporal Window for Neonatal Glucocorticoid Action in Human and Mice  [PDF]
Laetitia Martinerie, Eric Pussard, Geri Meduri, Anne-Lise Delezoide, Pascal Boileau, Marc Lombès
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031949
Abstract: Background Glucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2). This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse. Methods Cortisol (F) and cortisone (E) concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity) and between plasma and urine in newborns (renal activity). Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species. Results We demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein. Conclusions We provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming.
A Novel 3-Hydroxysteroid Dehydrogenase That Regulates Reproductive Development and Longevity  [PDF]
Joshua Wollam,Daniel B. Magner,Lilia Magomedova,Elisabeth Rass,Yidong Shen,Veerle Rottiers,Bianca Habermann,Carolyn L. Cummins,Adam Antebi
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001305
Abstract: Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptor DAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics, mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis and characterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel 3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activity governing longevity in response to signals from the gonad. Our elucidation of C. elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans.
A Novel 3-Hydroxysteroid Dehydrogenase That Regulates Reproductive Development and Longevity  [PDF]
Joshua Wollam,Daniel B. Magner,Lilia Magomedova,Elisabeth Rass,Yidong Shen,Veerle Rottiers,Bianca Habermann,Carolyn L. Cummins,Adam Antebi
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001305
Abstract: Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptor DAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics, mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis and characterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel 3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activity governing longevity in response to signals from the gonad. Our elucidation of C. elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans.
Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase: A Review  [PDF]
Martin Kr?yer Rasmussen,Bo Ekstrand,Galia Zamaratskaia
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140917926
Abstract: This review focuses on the expression and regulation of 3β-hydroxysteroid dehydrogenase/Δ 5-Δ 4 isomerase (3β-HSD), with emphasis on the porcine version. 3β-HSD is often associated with steroidogenesis, but its function in the metabolism of both steroids and xenobiotics is more obscure. Based on currently available literature covering humans, rodents and pigs, this review provides an overview of the present knowledge concerning the regulatory mechanisms for 3β-HSD at all omic levels. The HSD isoenzymes are essential in steroid hormone metabolism, both in the synthesis and degradation of steroids. They display tissue-specific expression and factors influencing their activity, which therefore indicates their tissue-specific responses. 3β-HSD is involved in the synthesis of a number of natural steroid hormones, including progesterone and testosterone, and the hepatic degradation of the pheromone androstenone. In general, a number of signaling and regulatory pathways have been demonstrated to influence 3β-HSD transcription and activity, e.g., JAK-STAT, LH/hCG, ERα, AR, SF-1 and PPARα. The expression and enzymic activity of 3β-HSD are also influenced by external factors, such as dietary composition. Much of the research conducted on porcine 3β-HSD is motivated by its importance for the occurrence of the boar taint phenomenon that results from high concentrations of steroids such as androstenone. This topic is also examined in this review.
MDCK cells express serotonin-regulable 11?-hydroxysteroid dehydrogenase type 2
Zallocchi,Marisa L.; Damasco,Maria C.; Calvo,Juan C.; Lantos,Carlos P.; Matkovic',Laura B.;
Biocell , 2006,
Abstract: prior to this work, we found that adrenal as well as extra-adrenal factors activate the response of renal 11?-hydroxysteroid dehydrogenase 2 to stressful situations. these results -showing ways through which the organism hinders the pathological occupation of mineralocorticoid receptors by glucocorticoids leading to sodium retention and hypertension- prompted the present study on the nature of the above-mentioned extraadrenal factors. serotonin was chosen because of its properties as a widely distributed neurohormone, known to interact with glucocorticoids at many sites, also exhibiting increased levels and effects under stressful situations. we studied serotonin effects on 11b-hydroxysteroid dehydrogenase 2 activity in a cell line derived from distal nephron polarized-epithelium, employing 3h-corticosterone as substrate. the end-product, 3h-11-dehydrocorticosterone was separated from the substrate by hplc and quantified. serotonin stimulated 11?-hydroxysteroid dehydrogenase 2 activity only at 2nm and 25pm, the magnitude of the response depending also on substrate concentration. the stimulation was blocked by the specific inhibitors methiothepin and ketanserin. we postulate that the organism partially prevents renal mineralocorticoid receptor occupancy by glucocorticoids, circulating at enhanced levels under stressful situations, through serotonin-mediated catabolic regulation of the 11?- hydroxysteroid dehydrogenase 2 activity. given many, mostly positive, interactions between both hormones, this might eventually pave the way to studies on a new regulatory axis.
MDCK cells express serotonin-regulable 11 -hydroxysteroid dehydrogenase type 2  [cached]
Marisa L. Zallocchi,Maria C. Damasco,Juan C. Calvo,Carlos P. Lantos
Biocell , 2006,
Abstract: Prior to this work, we found that adrenal as well as extra-adrenal factors activate the response of renal 11 -hydroxysteroid dehydrogenase 2 to stressful situations. These results -showing ways through which the organism hinders the pathological occupation of mineralocorticoid receptors by glucocorticoids leading to sodium retention and hypertension- prompted the present study on the nature of the above-mentioned extraadrenal factors. Serotonin was chosen because of its properties as a widely distributed neurohormone, known to interact with glucocorticoids at many sites, also exhibiting increased levels and effects under stressful situations. We studied serotonin effects on 11b-hydroxysteroid dehydrogenase 2 activity in a cell line derived from distal nephron polarized-epithelium, employing 3H-corticosterone as substrate. The end-product, 3H-11-dehydrocorticosterone was separated from the substrate by HPLC and quantified. Serotonin stimulated 11 -hydroxysteroid dehydrogenase 2 activity only at 2nM and 25pM, the magnitude of the response depending also on substrate concentration. The stimulation was blocked by the specific inhibitors methiothepin and ketanserin. We postulate that the organism partially prevents renal mineralocorticoid receptor occupancy by glucocorticoids, circulating at enhanced levels under stressful situations, through serotonin-mediated catabolic regulation of the 11 - hydroxysteroid dehydrogenase 2 activity. Given many, mostly positive, interactions between both hormones, this might eventually pave the way to studies on a new regulatory axis.
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