OBJECTIVE: To investigate the effects of excessive light exposure during gestation on intrauterine development and early growth of neonates in rats.
METHODS: Pregnant rats were randomly allocated to three groups: the constant light exposure group, non-light exposure group and control group. Blood samples were collected from the tail vein to analyze melatonin and cortisol levels. Weight, daily food and water consumption were recorded. Uterine weight, placental weight and placental diameter were measured on gestational day 19. Natural birth and neonate growth were also monitored. The expression of NR1D1(nuclear receptor subfamily 1 group D member 1) in offspring\'s SCN (suprachiasmatic nuclei), liver and adipose tissue was measured. Expression of NR1D1, MT1(melatonin 1 A receptor) and 11β-HSD2 (placental 11β-hydroxysteroid dehydrogenase type 2) in placenta was also measured. Finally, the expression of MT1 and 11β-HSD2 in NR1D1 siRNA transfected JEG-3 cells was evaluated.
RESULTS: There were no significant differences in maternal weight gain, pregnancy duration, uterine weight, placental body weight, placental diameter, fetal number among three groups. There were no significant differences in weights or lengths of offspring at birth. Compared to other two groups, constant light exposure group showed significantly more rapid growth of offspring in 21st day post-birth. The expression of NR1D1 in SCN, liver and adipose tissues of offspring was not significantly different among three groups. The maternal serum melatonin and cortisol levels of the constant light exposure group were lower and higher than other two groups, respectively. The expressions of NR1D1, MT1 and 11β-HSD2 were all decreased in placenta of the constant light exposure group. The expression of MT1 and 11β-HSD2 in JEG-3 cells were decreased after NR1D1 siRNA transfection.
CONCLUSIONS: Excessive light exposure during pregnancy results in elevated cortisol and reduced melatonin exposure to fetuses in uterus, potentially contributing to an accelerated early growth of offspring in rats.

Some halogenated bisphenol A (BPA) derivatives (tetrabromobisphenol A, TBBPA, and tetrachlorobisphenol A, TCBPA) are produced in a high volume and exist in PM2.5 after waste burning. 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) is a critical enzyme for placental function. However, whether halogenated bisphenols inhibit 11β-HSD2 and the mode of action remains unclear. The objective of this study was to investigate BPA derivatives on human and rat placental 11β-HSD2. The inhibitory strength on human 11β-HSD2 was TBBPA (IC50, 0.665 μM)>TCBPA (2.22 μM)>trichloro BPA (TrCBPA, 19.87 μM)>tetrabromobisphenol S (TBBPS, 36.76 μM)>monochloro BPA (MCBPA, 104.0 μM)>BPA (144.9 μM)>bisphenol S. All chemicals are mixed and competitive inhibitors. Rat 11β-HSD2 was less sensitive to BPA derivatives, with TBBPA (IC50, 96.63 μM)>TCBPA (99.69 μM)>TrCBPA (104.1 μM)>BPA (117.1 μM)>others. Docking analysis showed that BPA derivatives bind steroid active sites. Structure-activity relationship revealed that halogen atoms and LogP were inversely correlated with inhibitory strength on human 11β-HSD2, while LogS and polar desolvation energy were positively correlated with the inhibitory strength. In conclusion, halogenated BPA derivatives are mostly potent inhibitors on human 11β-HSD2 and there is structure-dependent inhibition.

Glucocorticoids (GCs) are an essential mediator hormone that can regulate animal growth, behavior, the phenotype of offspring, and so on, while GCs in poultry are predominantly corticosterones. The biological activity of GCs is mainly regulated by the intracellular metabolic enzymes, including 11β-hydroxysteroid dehydrogenases 1 (11β-HSD1), 11β-hydroxysteroid dehydrogenases 2 (11β-HSD2), and 20-hydroxysteroid dehydrogenase (20-HSD). To investigate the embryonic mechanisms of phenotypic differences between breeds, we compared the expression of corticosterone metabolic enzyme genes in the yolk-sac membrane and chorioallantoic membrane (CAM). We described the tissue distribution and ontogenic patterns of corticosterone metabolic enzymes during embryonic incubation between Tibetan and broiler chickens. Forty fertilized eggs from Tibetan and broiler chickens were incubated under hypoxic and normoxic conditions, respectively. Real-time fluorescence quantitative PCR was used to examine the expression of 11β-HSD1/2, and 20-HSD mRNA in embryonic tissues. The results showed that the expression levels of yolk-sac membrane mRNA of 11β-HSD2 and 20-HSD in Tibetan chickens on E14 (embryonic day of 14) were significantly lower than those of broiler chickens (P < 0.05), and these genes expression of CAM in Tibetan chickens were higher than those of broiler chickens (P < 0.05). In addition, the three genes in the yolk-sac membrane and CAM were followed by a down-regulation on E18 (embryonic day of 18). The 11β-HSD1 and 11β-HSD2 genes followed a similar tissue-specific pattern: the expression level was more abundantly in the liver, kidney, and intestine, with relatively lower abundance in the hypothalamus and muscle, and the expression level of 20-HSD genes in all tissues tested was higher. In the liver, 20-HSD of both Tibetan and broiler chickens showed different ontogeny development patterns, and hepatic mRNA expression of 20-HSD in broiler chickens was significantly higher than that of Tibetan chickens of the same age from E14 to E18 (P < 0.05). This study preliminarily revealed the expression levels of cortisol metabolic genes in different tissues during the development process of Tibetan and broiler chicken embryos. It provided essential information for in-depth research of the internal mechanism of maternal GCs programming on offspring.

Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11β-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.

Our previous study reported that prenatal caffeine exposure (PCE) could induce chondrodysplasia and increase the susceptibility to osteoarthritis in offspring rats. However, the potential mechanisms and initiating factors remain unknown. This study aims to investigate whether 11β-HSD2, a glucocorticoid-metabolizing enzyme, is involved in the susceptibility of osteoarthritis induced by PCE and to further explore its potential mechanisms and initiating factors. Firstly, we found that PCE reduced cartilage matrix synthesis (aggrecan/Col2a1 expression) in male adult offspring rats and exhibited an osteoarthritis phenotype following chronic stress, which was associated with persistently reduced H3K9ac and H3K27ac levels at the promoter of 11β-HSD2 as well as its expression in the cartilage from fetus to adulthood. The expression of 11β-HSD2, aggrecan and Col2a1 were all decreased by corticosterone in the fetal chondrocytes, while overexpression of 11β-HSD2 could partially alleviate the decrease of matrix synthesis induced by corticosterone in vitro. Furthermore, the glucocorticoid receptor (GR) activated by glucocorticoids directly bonded to the promoter region of 11β-HSD2 to inhibit its expression. Meanwhile, the activated GR reduced the H3K9ac and H3K27ac levels of 11β-HSD2 by recruiting HDAC4 and promoting GR-HDAC4 protein interaction to inhibit the 11β-HSD2 expression. Moreover, caffeine could reduce the expression of 11β-HSD2 by inhibiting the cAMP/PKA signaling pathway but without reducing the H3K9ac and H3K27ac levels of 11β-HSD2, thereby synergistically enhancing the corticosterone effect. In conclusion, the persistently reduced H3K9ac and H3K27ac levels of 11β-HSD2 from fetus to adulthood mediated the inhibition of cartilage matrix synthesis and the increased susceptibility to osteoarthritis. This epigenetic programming change in utero was induced by glucocorticoids with synergistic effect of caffeine.

Cadmium (Cd) exposure during pregnancy damages the placental glucocorticoid (GC) barrier, exposes the foetus to excess corticosterone (CORT) levels, and eventually inhibits foetal development. In addition, taurine (Tau) alleviates the toxicity of Cd on liver and kidney, but limited data are available on the role of Tau against the toxicity of heavy metals on female reproduction and fetal development. The present study was conducted to investigate the specific mechanism of Cd-induced placental GC barrier damage and the protective role of Tau. Pregnant rats were administered CdCl2 (1 mg/kg/day) and Tau (100, 200, or 300 mg/kg/day) by gavage from gestational day (GD) 0 to 19. The data showed that CdCl2 increased the foetal growth restriction (FGR) rate of the offspring, and the levels of CORT in the placental, maternal and foetal serum. Treatment with Tau significantly reversed the impact of Cd on both maternal and fetal parameters. Additionally, Tau can attenuate Cd-induced inhibition of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and specificity protein 1 (Sp1) in vivo and vitro. Furthermore, Sp1-siRNA alone reduced 11β-HSD2 levels and had a further inhibitory effect when the cells were treated with Cd simultaneously. Moreover, Cd suppressed cAMP/PKA signalling. Forskolin (adenylate cyclase agonist) pretreatment activated cAMP/PKA signalling and restored the Cd-induced downregulation of Sp1 and 11β-HSD2. Tau alleviated the Cd-induced decrease of Sp1 via activating cAMP/PKA signalling. Therefore, the results highlight that Tau protects against Cd-induced impairments in GC barrier damage by upregulating the cAMP/PKA/Sp1 pathway in placental trophoblasts.

Urban habitats present animals with persistent disturbances and acute stressors not present in rural habitats or present at significantly lower levels. Differences in the glucocorticoid stress response could underlie colonization of these novel habitats. Despite urban habitats characterization as more stressful, previous comparisons of urban and rural birds have failed to find consistent differences in baseline and stress induced glucocorticoid levels. Another aspect of glucocorticoid regulation that could underlie an animal\'s ability to inhabit novel habitats, but has yet to be well examined, is more efficient termination of the glucocorticoid stress response which would allow birds in urban habitats to recover more quickly after a disturbance. The glucocorticoid stress response is terminated by negative feedback achieved primarily through their binding of receptors in the hippocampus and hypothalamus and subsequent decreased synthesis and release from the adrenals. We investigated if male song sparrows (Melospiza melodia) in urban habitats show more efficient termination of the glucocorticoid stress response than their rural counterparts using two approaches. First, we measured glucocorticoid receptor, mineralocorticoid receptor and 11β-HSD2 (an enzyme that inactivates corticosterone) mRNA expression in negative feedback targets of the brain (the hippocampus and hypothalamus) as a proxy measure of sensitivity to negative feedback. Second, we measured plasma corticosterone levels after standardized restraint and again following a challenge with the synthetic glucocorticoid, dexamethasone, as a means of assessing how quickly birds decreased glucocorticoid synthesis and release. Though there were no differences in the hypothalamus of urban and rural song sparrows, urban birds had lower glucocorticoid receptor and 11β-HSD2 mRNA expression in the hippocampus. Further, urban and rural birds had similar reductions in corticosterone following the dexamethasone challenge, suggesting that they do not differ in how quickly they decrease glucocorticoid synthesis and release. Thus, urban and rural song sparrows display similar termination of the glucocorticoid stress response even though urban birds have decreased hippocampal glucocorticoid receptor and 11β-HSD2 abundance.

Myocardial fibrosis (MF) is one of the leading causes of end-stage heart disease. Many studies have confirmed that inflammation caused by aldosterone may play an important role in the process of MF. A selective 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme inhibitor can reduce the inactivation of cortisol, allowing cortisol to compete for mineralocorticoid receptors. This study investigated the protective effect of a novel selective 11βHSD2 inhibitor (WZ51) on MF and described its underlying mechanism. The administration of WZ51 in rats with MF significantly alleviated myocardial injury, accompanied by a decrease in lactate dehydrogenase and the creatine kinase myocardial band. Furthermore, WZ51 significantly inhibited the development of MF and increased the protein level of 11β-HSD2. The results of this study demonstrate that 11β-HSD2 plays an important pathological role in MF. Thus, WZ51 may be a potential therapeutic agent for the treatment of this condition.

Placental 11β-HSD2 has been a focus of research for understanding potential fetal programming associated with maternal emotional disorders. This study examined the pathway from antenatal mental health via placental 11β-HSD2 mRNA to cortisol regulation in the infant offspring. This study reports on data obtained from 236 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS). At term, placental tissue was collected within 30 min of birth from 52 participants meeting current criteria for a depressive disorder, and 184 control participants. Depressive disorders were diagnosed using the SCID-IV. In addition, antidepressant use, depressive and anxiety symptoms were measured in early and late pregnancy. Placental 11β-HSD2 mRNA expression was measured using qRT-PCR. Infant salivary cortisol samples were taken at 12 months of age. Women on antidepressant medication and with higher trait anxiety had higher placental 11β-HSD2 expression compared to women not taking medication. Furthermore, the offspring of women taking an antidepressant and who also had a current depressive disorder and high trait anxiety had high cortisol reactivity at 12 months of age and this was mediated through 11β-HSD2 mRNA expression. In contrast, offspring of women not taking antidepressant medication with depressive disorder and high anxiety there was low cortisol reactivity observed. Our findings suggest that the relationship between maternal antenatal depression and anxiety and infant cortisol reactivity is mediated through placental 11β-HSD2 mRNA expression. Furthermore, the direction differed for women taking antidepressants, where infant cortisol reactivity was high whereas when compared to those with unmedicated depression and anxiety, where infant cortisol reactivity was low.

Preeclampsia, a major human pregnancy-specific disorder, leads to maternal and fetal morbidity and mortality. Here we reported that 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an enzyme that degrades active glucocorticoids, is one of the key factors that contributes to preeclampsia development. In the pregnant rat model, we firstly confirmed that administration of 11β-HSD2 inhibitor carbenoxolone (CBX) subcutaneously or by placenta-targeted delivery system could lead to a decrease in placental 11β-HSD2 expression and activity and an increase in corticosterone level in placenta and maternal circulation. Then, we showed that subcutaneous administration and placenta-targeted delivery of CBX resulted in the hallmark of preeclampsia-like features including hypertension, proteinuria, renal damages as well as elevated circulatory soluble fms-like tyrosine kinase 1 (sFlt1) and increased sFlt1/placental growth factor (PlGF) ratio in pregnant rats. These animals displayed decreased trophoblast invasion in uterus, impaired spiral artery remodeling, and reduced placental blood flow. Preeclampsia-like features could also be induced by administration of dexamethasone in pregnant rats. In the cultured human trophoblast models, we found that cortisol only inhibited migration and invasion of the extravillous trophoblasts with 11β-HSD2 knockdown, and promoted sFlt1 release in the cultured syncytiotrophoblasts with 11β-HSD2 knockdown. Furthermore, we elucidated that cortisol stimulated a disintegrin and metalloprotease (ADAM)17 expression in placentas, thereby promoting sFlt1 release in placenta. Collectively, our study provided the evidence that placental 11β-HSD2 dysfunction plays a key role in the development of preeclampsia and immediately identified innovative target to counteract preeclampsia.