Dexamethasone Exposure Research Articles

Prenatal dexamethasone exposure and developmental programming of the ovary of the offspring: a structural study in the rat.

Overexposure to glucocorticoids during fetal development alters fetal organ growth and maturation patterns, which can result in adverse programming outcomes in adulthood. The aim of this study was to determine whether exposure to dexamethasone (Dx) during the fetal period programmed ovary development and function in infant (16-day-old) and peripubertal (38-day-old) female offspring. Pregnant Wistar rats were separated into control and Dx-treated (0.5mg kg-1) groups and were injected with Dx or an equivalent volume of vehicle on Days 16, 17 and 18 of gestation. Ovaries from 16- and 38-day-old female offspring were prepared for histological and stereological examination. The volume of the ovary and the number of primordial and primary follicles were significantly reduced in prenatally Dx-exposed infant and peripubertal female offspring compared with control offspring. The number of multilaminar follicles was decreased in infant female offspring. In peripubertal females, prenatal exposure to Dx increased the number of multilaminar and large follicles of all classes. Because vaginal opening did not occur up to Day 38 postpartum in the Dx-exposed offspring, the absence of ovulation and corpora lutea is confirmation that the onset of puberty had been delayed. We can conclude that overexposure to glucocorticoids early in life programs ovary development, which may affect fertility in adulthood.

H3K27 Acetylation of SF1 in PBMC: A Biomarker for Adrenal Insufficiency of Steroid Synthesis in Male Offspring Induced by Prenatal Dexamethasone Exposure

H3K27 Acetylation of SF1 in PBMC: A Biomarker for Adrenal Insufficiency of Steroid Synthesis in Male Offspring Induced by Prenatal Dexamethasone Exposure

Selection and Validation of the Optimal Panel of Reference Genes for RT-qPCR Analysis in the Developing Rat Cartilage.

Real-time fluorescence quantitative PCR (RT-qPCR) is widely used to detect gene expression levels, and selection of reference genes is crucial to the accuracy of RT-qPCR results. Minimum Information for Publication of RT-qPCR Experiments (MIQE) proposes that using the panel of reference genes for RT-qPCR is conducive to obtaining accurate experimental results. However, the selection of the panel of reference genes for RT-qPCR in rat developing cartilage has not been well documented. In this study, we selected eight reference genes commonly used in rat cartilage from literature (GAPDH, ACTB, 18S, GUSB, HPRT1, RPL4, RPL5, and SDHA) as candidates. Then, we screened out the optimal panel of reference genes in female and male rat cartilage of fetus (GD20), juvenile (PW6), and puberty (PW12) in physiology with stability analysis software of genes expression. Finally, we verified the reliability of the selected panel of reference genes with the rat model of intrauterine growth retardation (IUGR) induced by prenatal dexamethasone exposure (PDE). The results showed that the optimal panel of reference genes in cartilage at GD20, PW6, and PW12 in physiology was RPL4 + RPL5, which was consistent with the IUGR model, and there was no significant gender difference. Further, the results of standardizing the target genes showed that RPL4 + RPL5 performed smaller intragroup differences than other panels of reference genes or single reference genes. In conclusion, we found that the optimal panel of reference genes in female and male rat developing cartilage was RPL4 + RPL5, and there was no noticeable difference before and after birth.

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only

Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. ALL treatment using chemotherapy-only protocols. This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: β = 55.54; SE = 25.55; P = .03; right cerebellum: β = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: β = 82.71; SE = 31.04; P = .009; right cerebellum: β = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (β = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (β = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.

EPID-08. PRE-SURGERY IMMUNE PROFILES OF ADULT GLIOMA PATIENTS

Abstract Changes in glioma patients’ immune profiles over the course of disease may predict outcomes. DNA based immunomethylomics quantifies blood immune cells based on cell specific DNA methylation signatures. To assess changes in immune profiles, we are longitudinally collecting blood samples from glioma patients pre-surgery and at other clinically relevant time points. Here we report patients’ pre-surgery immune profiles. All patients underwent biopsy or resection of a presumed new glioma or recurrent lower grade glioma. Blood DNA methylation was assessed with Illumina EPIC methylation arrays. Relative cell fractions of CD4, CD8, B-cells, natural killer cells, monocytes, and neutrophils, were estimated via our validated deconvolution algorithm. Total nucleated cell counts from Nexcelom cytometry were used to compute absolute cell counts. Other measures include total lymphocytes, CD4/CD8 ratio, neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio (LMR)). The first 125 participants includes 56 newly diagnosed glioblastomas (GBM), 28 newly diagnosed grade II-III gliomas, and 41 recurrent grade II-III gliomas. Median patient age is 49 years. 53 (43%) had recent dexamethasone exposure. In overall non-parametric analyses, most cell subsets, especially CD4, differed across grade, diagnosis group, WHO classification and dexamethasone exposure. In post-hoc pairwise analyses, immune profiles of IDH wildtype GBM patients who had taken dexamethasone differed from patients with GBM or grade II-III glioma who had not taken dexamethasone; they had clinically relevant and statistically significantly lower absolute CD4 counts, total white cell counts, and percent of total lymphocytes, and higher absolute neutrophil counts, NLR and LMR. However, some dexamethasone naïve GBM patients also had altered immune profiles. Comparisons of relative immune cell fractions with those from 454 non-glioma controls from the UCSF Adult Glioma Study showed that across grade and WHO classification, for the most part, immune profiles of glioma patients not exposed to dexamethasone did not differ from controls.

The optimal compound reference genes for qRT-PCR analysis in the developing rat long bones under physiological conditions and prenatal dexamethasone exposure model

Quantitative real-time polymerase chain reaction (qRT-PCR) is a powerful tool for evaluating gene expression, but its accuracy is affected by the stability of the reference genes used for normalization. The Minimum Information for Publication of Quantitative Real-time PCR Experiments (MIQE) guidelines indicated that it was important to use multiple stable reference genes as compound reference genes for acquiring optimal experimental results. In this study, the expression levels of eight candidate reference genes (SDHA, TBP, GAPDH, etc.) were detected by qRT-PCR in rat long bones at different developmental stages [gestation day (GD) 20, postnatal week (PW) 6 and PW12] under physiological conditions. Software geNorm, NormFinder, and BestKeeper were used to comprehensively evaluate the stability of the eight reference genes for screening out the most stable compound reference genes in each period. Additionally, the pathological model of prenatal dexamethasone exposure (PDE) was used to verify the stability and reliability of the selected compound reference genes. The result showed that two reference genes as compound reference genes for normalization were optimal. In the intrauterine period, SDHA and TBP could be selected as the compound reference genes, while YWHAZ and GAPDH could be selected at PW6 and PW12, and there was no significant gender difference in the selection of reference genes. The above compound reference genes remained stable in the PDE model and could make the statistical significance of the experimental results more remarkable. In conclusion, this study screened out the optimal compound reference genes in rat long bones before and after birth.

Antenatal Dexamethasone Exposure Impairs the High-Conductance Ca2+-Activated K+ Channels via Epigenetic Alteration at Gene Promoter in Male Offspring.

Antenatal exposure to glucocorticoids increases cardiovascular risks related to vascular dysfunctions in offspring, although underlying mechanisms are still unknown. As an important vascular mediator, high-conductance Ca2+-activated K+ channels (BK) plays an essential role in determining vascular tone. Long-term effects of antenatal glucocorticoids on BK in offspring are largely unknown. This study examined the effects and mechanisms of antenatal exposure to clinically relevant doses of glucocorticoids on vascular BK in offspring. Approach and Results: Pregnant Sprague-Dawley rats received synthetic glucocorticoids dexamethasone or vehicle during the last week of pregnancy. Vascular functions, cellular electrophysiology, target gene expression, and promoter methylation were examined in mesenteric arteries of male offspring (gestational day 21 [fetus] and postnatal day 120 [adult offspring]). Antenatal dexamethasone exposure impaired BK activators-mediated relaxation and reduced whole-cell BK currents in mesenteric arteries. Antenatal dexamethasone exposure did not alter Ca2+/voltage-sensitivity of BK but downregulated the expressions of BK α and β1 subunits in both fetal and adult mesenteric arteries. In addition, increased promoter methylations within BKα and BKβ1 were compatible with reduced expressions of the 2 genes. Our findings showed a profound and long-term impact of antenatal dexamethasone exposure on vascular BK via an altered epigenetic pattern from fetal stage to adulthood, advancing understanding of prolonged adverse effects and mechanisms of antenatal glucocorticoids exposure on vascular health in offspring.

Selection and identification of the panel of reference genes for quantitative real-time PCR normalization in rat testis at different development periods

BackgroundIn quantitative real-time PCR (qRT-PCR), the expression levels of various adult reference genes may be unstable at different developmental periods and tissues, and will lead to inaccurate detected results. This study aimed to select and identify the optimal panel of reference genes in rat testis at different development periods. MethodsWe detected mRNA expression levels of five common rat testicular reference genes (GAPDH, β-actin, 18s, RPS16 and RPL19) by qRT-PCR at different developmental periods (fetus, infancy, and adolescence), selected optimal panel of reference genes by combining with stability algorithms, and verified their tissue specificity. Lastly, we observed their mRNA expression alterations under pathological conditions to evaluate the stability and accuracy, and verify testicular dysplasia model. ResultsBased on comprehensive analysis, the best panel of reference genes of testis were GAPDH+β-actin (at fetus) and GAPDH+RPL19 (at infancy and adolescent). Meanwhile, the best panel of reference genes of fetal testis was consistent with placenta and fetal hippocampus but different from fetal liver and kidney. Furthermore, in prenatal dexamethasone exposure (PDE) model, the results were consistent with those under physiological conditions, and the testicular steroidogenesis acute regulatory protein (StAR) was most obviously decreased when using the best panel of reference genes. ConclusionIn this study, rat testicular GAPDH+β-actin for fetuses and GAPDH+RPL19 for infants and adolescents are recommended to be the optimal panel of reference genes. Respectively. The selected panel of reference genes was still stable under PDE condition. This study provided technical and theoretical supports for researches on testicular development toxicology.

Lentivirus-delivered ACE siRNA rescues the impaired peak bone mass accumulation caused by prenatal dexamethasone exposure in male offspring rats.

Angiotensin I converting enzyme (ACE) is a major component of the renin-angiotensin system (RAS). Our previous study demonstrated that activated bone RAS was associated with low peak bone mass induced by prenatal dexamethasone exposure (PDE) in male offspring rats. However, we did not determine whether the inhibition of ACE expression could rescue PDE-induced low peak bone mass. In the present study, we treated pregnant Wistar rats with dexamethasone (0.2mg/kg.d) on gestational days 9-20 and obtained eight weeks old male offspring rats. Some of the offspring rats from the PDE group were injected lentivirus delivered-ACE siRNA (LV-ACE siRNA) through the intra-bone marrow for 4weeks. We found that the intra-bone marrow injection of LV-ACE siRNA rescued the impaired peak bone mass accumulation caused by PDE in male offspring rats. Moreover, LV-ACE siRNA ameliorated PDE-induced inhibition of osteogenesis and alleviated PDE-induced RAS activation in the bone tissues in vivo. Our in vitro findings further confirmed that LV-ACE siRNA reversed the suppressed osteogenic differentiation caused by dexamethasone, which can be attributed to alleviated RAS activation. In conclusion, LV-ACE siRNA rescued impaired peak bone mass accumulation caused by PDE through alleviation of local bone RAS activation in male offspring rats.

Effect of cumulative dexamethasone dose in preterm infants on neurodevelopmental and growth outcomes: a Western Australia experience

ObjectiveComparing the long-term neurodevelopmental and growth outcomes of lower and higher cumulative dexamethasone exposure in preterm infants ventilated for a minimum cumulative duration of 7 days.DesignA retrospective cohort medical chart...

Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mouse offspring

BackgroundPrenatal dexamethasone exposure (PDE) induces low birth weight and retardation of fetal bone development which are associated with lower peak bone mass in adult offspring. Here we evaluated whether and how PDE affects postnatal long bone growth in mouse offspring.MethodsPregnant mice were injected subcutaneously with dexamethasone (1.2 mg/kg/day) every morning from gestational days (GD) 12–14. Femurs and tibias of 2-, 4-, 6-, and 12-week-old female offspring were harvested for histological, immunofluorescence, flow cytometric analysis, or microcomputed tomography (μCT) measurement.ResultsPDE leads to impaired bone remodeling as well as decreased bone mass in the long bone of female mouse offspring. During postnatal bone growth, significant decrease of CD45−CD29+CD105+Sca-1+ bone marrow mesenchymal stem cells (BMSCs) and CD45−Nestin+ cells, loss of type H vessels, and increment of cellular senescence were found in metaphysis of long bone in mouse offspring after PDE. We further show that eliminating the excessive senescent cells with dasatinib (5 mg/kg/day) and quercetin (50 mg/kg/day) during GD 12–14 rescues the above toxic effect of PDE on the postnatal long bone growth in female mouse offspring.ConclusionCellular senescence mediates the toxic effect of PDE on postnatal long bone growth in mouse offspring, and inhibition of cellular senescence may be proposed for treating the retardation of bone growth caused by PDE.

The combination of hprt and gapdh is the best compound reference genes in the fetal rat hippocampus.

Hippocampus, as an important organ of central memory storage and spatial orientation, has been studied increasingly in recent years. The expression of reference genes in the hippocampus of adult rats, which are commonly used in the quantitative real-time polymerase chain reaction (qRT-PCR), is unstable in the fetal hippocampus and may not be suitable for the fetal period. Therefore, this study intends to screen and determine the optimal compound reference genes in the fetal rat hippocampus. Based on the literature, we selected five housekeeping genes (HKGs), including glyceraldehyde 3-phosphate dehydrogenase (gapdh), actin beta (β-actin), hypoxanthine phosphoribosyltransferase (hprt), 18s ribosomal RNA (18s rRNA), and cyclophilin B (cypB). We analyzed the expression of them under physiological conditions in the fetal rat hippocampus using BestKeeper, GeNorm, and NormFinder, to select the most stable compound reference genes. Furthermore, to verify the stability of the compound reference genes, we analyzed the expression of reference genes in the fetal rat hippocampus under the pathological model of prenatal dexamethasone exposure (PDE). Finally, we evaluated the accuracy of compound reference genes through detecting the expression of fetal rat hippocampal brain-derived neurotrophic factor (BDNF) under PDE model. This study determined that the combination of gapdh and hprt was the most stable and suitable compound reference genes in the fetal rat hippocampus. There was no significant difference between male and female fetal rats. We provided the support of accurate and reliable reference genes for the further study of diseases related to the fetal hippocampus.

Ryanodine receptor 1 mediated dexamethasone-induced chondrodysplasia in fetal rats

BackgroundOsteoarthritis is caused by cartilage dysplasia and has fetal origin. Prenatal dexamethasone exposure (PDE) induced chondrodysplasia in fetal rats by inhibiting transforming growth factor β (TGFβ) signaling. This study aimed to determine the effect of dexamethasone on fetal cartilage development and illustrate the underlying molecular mechanism. MethodsDexamethasone (0.2 mg/kg.d) was injected subcutaneously every morning in pregnant rats from gestational day (GD) 9 to GD21. Harvested fetal femurs and tibias at GD21 for immunofluorescence and gene expression analysis. Fetal chondrocytes were treated with dexamethasone (100, 250 and 500 nM), endoplasmic reticulum stress (ERS) inhibitor, and ryanodine receptor 1 (RYR1) antagonist for subsequent analyses. ResultsIn vivo, prenatal dexamethasone exposure (PDE) decreased the total length of the fetal cartilage, the proportion of the proliferation area and the cell density and matrix content in fetal articular cartilage. Moreover, PDE increased RYR1 expression and intracellular calcium levels and elevated the expression of ERS-related genes, while downregulated the TGFβ signaling pathway and extracellular matrix (ECM) synthesis in fetal chondrocytes. In vitro, we verified dexamethasone significantly decreased ECM synthesis through activating RYR 1 mediated-ERS. ConclusionsPDE inhibited TGFβ signaling pathway and matrix synthesis through RYR1 / intracellular calcium mediated ERS, which ultimately led to fetal dysplasia. This study confirmed the molecular mechanism of ERS involved in the developmental toxicity of dexamethasone and suggested that RYR1 may be an early intervention target for fetal-derived adult osteoarthritis.

Reducing dexamethasone antiemetic prophylaxis during the COVID-19 pandemic: recommendations from Ontario, Canada.

PurposePeople with cancer face an elevated risk of infection and severe sequelae from COVID-19. Dexamethasone is commonly used for antiemetic prophylaxis with systemic therapy for cancer. However, dexamethasone is associated with increased risk of viral and respiratory infections, and causes lymphopenia, which is associated with worse outcomes during COVID-19 infections. Our purpose was to minimize dexamethasone exposure during antiemetic prophylaxis for systemic therapy for solid tumors during the COVID-19 pandemic, while maintaining control of nausea and emesis.MethodsWe convened an expert panel to systematically review the literature and formulate consensus recommendations.ResultsNo studies considered the impact of dexamethasone-based antiemetic regimens on the risk and severity of COVID-19 infection. Expert consensus recommended modifications to the 2019 Cancer Care Ontario Antiemetic Recommendations.ConclusionClinicians should prescribe the minimally effective dose of dexamethasone for antiemetic prophylaxis. Single-day dexamethasone dosing is recommended over multi-day dosing for regimens with high emetogenic risk excluding high-dose cisplatin, preferably in combination with palonosetron, netupitant, and olanzapine. For regimens with low emetogenic risk, 5-HT3 antagonists are recommended over dexamethasone.

Dexamethasone increases renal free fatty acids and xanthine oxidase activity in female rats: could there be any gestational impact?

Dexamethasone (DEX) is used for various conditions in female and even during pregnancy. We tested the hypothesis that DEX exposure in female rats would lead to renal free fatty acid (FFA) accumulation with elevated xanthine oxidase (XO) activity that would be aggravated by pregnancy. Twenty-four female rats (n = 6/group) were randomly assigned to non-pregnant (NPR), DEX-exposed non-pregnant (NPR + DEX), pregnant (PRE) and DEX-exposed pregnant (PRE + DEX), respectively. NPR and PRE rats received vehicle (po) while NPR + DEX and PRE + DEX groups received DEX (0.2 mg/kg; po), between gestational days 14 and 19. Data showed that DEX exposure caused increased plasma creatinine, urea, renal FFA accumulation, lipid peroxidation, aminotranferases, depressed glutathione, increased activity of XO, and elevated uric acid in both pregnant and non-pregnant rats. The findings of this study indicate that DEX exposure would cause renal FFA accumulation and glutathione depletion that are accompanied by increased activity of XO/uric acid independently of gestation. The study also implies that DEX-induced renal damage could be worsened by gestation.

The effects, underlying mechanism and interactions of dexamethasone exposure during pregnancy on maternal bile acid metabolism

As important members in steroids related signal pathways, bile acids are very important in regulating substance metabolism and immune homeostasis. However, bile acids are highly cytotoxic, and the excessive accumulation can induce several abnormalities such as cholestatic liver injury. It is known that the bile acid metabolism alters during pregnancy and mostly will not result in pathologies. However, the effect of dexamethasone exposure during pregnancy on bile acid metabolism is still unknown. In this study, pregnant Wistar rats were subcutaneously administered dexamethasone (0.2 mg/kg.d) or saline from gestation day 9–21, while virgin rats were given the same treatment for 13 days. We found that, physiological pregnancy or dexamethasone exposure during non-pregnancy did not affect maternal serum TBA level and liver function. Nevertheless, dexamethasone exposure during pregnancy increased serum TBA level and accompanied with liver injury. Furthermore, we discovered that the conservation of bile acid homeostasis under pregnancy or dexamethasone exposure was maintained through compensatory pathways. However, dexamethasone exposure during pregnancy tipped the balance of liver bile acid homeostasis by increasing classical synthesis and decreasing efflux and uptake. In addition, dexamethasone exposure during pregnancy also increased serum estrogen level and nuclear receptors mRNA expression levels. Finally, two-way ANOVA analysis showed that dexamethasone exposure during pregnancy could induce or facilitate maternal cholestasis and liver injury by up-regulating ERα and CYP7A1 expression. This study confirmed that dexamethasone exposure during pregnancy was related to maternal intrahepatic cholestasis of pregnancy and should be carefully monitored in clinical settings.

First-Trimester Prenatal Dexamethasone Treatment Is Associated With Alterations in Brain Structure at Adult Age.

ContextPrenatal treatment of human disease is rare. Dexamethasone (DEX) is used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in an affected female fetus. The safety and long-term consequences of prenatal DEX exposure on the brain are largely unknown.ObjectiveWe investigate whether first-trimester prenatal DEX treatment is associated with alterations in brain structure at adult age, and if these alterations are associated with DNA methylation, mood, and cognitive abilities.Design, Setting, and ParticipantsT1-weighted and diffusion-weighted imaging scans, from a single research institute, are compared between 19 (9 women) first-trimester DEX-treated individuals, at risk of CAH but not having CAH, and 43 (26 women) controls (age range, 16.0-26.4 years).ResultsDEX-treated participants showed bilateral enlargement of the amygdala, increased surface area and volume of the left superior frontal gyrus, and widespread increased radial, mean, and axial diffusivity of white matter, in particular in the superior longitudinal fasciculi and corticospinal tracts. In the DEX-treated group, increased mean and radial diffusivity correlated with increased methylation of the promotor region of the FKBP5 gene. There were no group differences in cognition or in scales assessing depression or anxiety, and the relationship between brain structure and cognition did not differ between DEX-treated and controls.ConclusionsFirst-trimester prenatal DEX treatment is associated with structural alterations of the brain at adult age, with an accompanying change in gene methylation. The findings add to the safety concerns of prenatal DEX treatment in the context of CAH.

Intrauterine RAS programming alteration-mediated susceptibility and heritability of temporal lobe epilepsy in male offspring rats induced by prenatal dexamethasone exposure.

Partial temporal lobe epilepsy (TLE) has an intrauterine developmental origin. This study was aimed at elucidating the heritable effects and programming mechanism of TLE in offspring rats induced by prenatal dexamethasone exposure (PDE). Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2mg/kgday) from gestational day9 to 20. The F1 and F2 generations of male offspring were administered lithium pilocarpine (LiPC) for electroencephalography and video monitoring in epilepsy or behavioral tests. Results showed that the PDE + LiPC group exhibited TLE susceptibility, which continued throughout F2 generation. Expression of hippocampal glucocorticoid receptor (GR), CCAAT enhancer-binding protein α (C/EBPα), intrauterine renin-angiotensin system (RAS) classical pathway related genes, the H3K27ac level in angiotensin-converting enzyme (ACE) promoter, as well as high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) were increased, but glutamate dehydrogenase (GLUD) 1/2 expression were decreased, accompanied by increased glutamate levels in PDE fetal and adult rats, as well as in F1 and F2 offspring of the PDE + LiPC group. These consistent changes were also observed by treating the H19-7 fetal hippocampal cell line with dexamethasone and were reversed by GR inhibitor (RU486) and ACE inhibitor (enalaprilat). Our results confirmed that PDE-induced H3K27ac enrichment in the ACE promoter and enhanced the RAS classic pathway via activating GR-C/EBPα-p300 in utero, which caused changes of the HMGB1 pathway and glutamate excitatory damage. Intrauterine programming mediated by abnormal histone modification of hippocampal ACE could continue to adulthood and even F2 generation, which induced the heritability of TLE in male offspring rats.

Influence of prenatal exposure to dexamethasone on neurodevelopmental behaviour

Abstract Introduction Early life stress, such as prenatal exposure to exogenous glucocorticoids (GC), can have a negative impact on brain development. Dexamethasone (DEX) is a synthetic GC used in preterm pregnancies to promote lung maturation. However, prenatal exposure to DEX induces an anxious-like behaviour in male and female offspring at adulthood. Notably, only males respond positively to therapeutics with a proposed anxiolytic. Objectives Since the influence of prenatal DEX on neurodevelopmental behaviour remains to be elucidated and could help explain this difference in drug efficacy, we aim to clarify the effects of this GC on neurodevelopment during infancy, comparing male and female offspring neurodevelopment at this early age. Methodology To obtain an animal model of chronic anxiety, Wistar pregnant dams were injected subcutaneously with DEX (1mg/kg) on gestational days 18 and 19. The vestibular system development, locomotion, upper limbs strength, discriminatory ability, auditory response and eye opening day were assessed in male and female offspring between P5 and P17. Animal procedures were approved by the Animal Welfare Committee and done in agreement with the law. Results Male and female offspring prenatally exposed to DEX had a better performance in the tests assessing the vestibular system development and discriminatory ability, especially at P5 and P6. Additionally, DEX anticipated the day of eye opening and had a positive impact in the upper limb strength of the offspring of both sexes. However, the locomotor ability and auditory response were impaired comparing with controls. Conclusion Exposure to DEX improves limb strength, balance, spatial orientation and anticipates eye opening. These results may suggest that prenatal DEX exposure promotes offspring development and maturation in both males and females. Prenatal DEX did not differently affect male and female neurodevelopment at early age. It remains to clarify the underlying motives that induce a dimorphic gender response to anxiolytic therapy in adulthood.

Programming of a developmental imbalance in hypothalamic glutamatergic/GABAergic afferents mediates low basal activity of the hypothalamic-pituitary-adrenal axis induced by prenatal dexamethasone exposure in male offspring rats

This study was intended to demonstrate that prenatal dexamethasone exposure (PDE) can induce low basal activity of the hypothalamic-pituitary-adrenal axis (HPAA) in male offspring rats and explore the underlying mechanism. Pregnant rats were subcutaneously administered 0.2 mg/kg/d dexamethasone from gestational day (GD) 9 to GD20. Male GD20 fetuses and postnatal day 85 adult male offspring rats were sacrificed under anesthesia. Hypothalamic cells were from GD20∼postnatal day (PD) 7 fetal male rats, treated with different concentrations of dexamethasone and the glucocorticoid receptor (GR) antagonist mifepristone for 5 days. The results suggested that dexamethasone enhanced the expression of hypothalamic L-glutamic acid decarboxylase (GAD) 67 by activating GR, further stimulating the conversion of glutamate to gamma-aminobutyric acid (GABA) and inducing an imbalance in glutamatergic/GABAergic afferents in the hypothalamic paraventricular nucleus (PVN). This imbalance change was maintained postnatally, leading to the inhibition of parvocellular neurons, and mediating the low basal activity of the HPAA in PDE offspring rats, which was manifested by decreased levels of blood adrenocorticotropic hormone and corticosterone as well as reduced expression levels of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus. Programming of a developmental imbalance in glutamatergic/GABAergic afferents in the PVN is a potential mechanism responsible for low basal activity of the HPAA in male PDE rats.