scholarly journals Epigenetic regulation of 5α reductase-1 underlies adaptive plasticity of reproductive function and pubertal timing

BMC Biology ◽  
2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Ben Bar-Sadeh ◽  
Or E. Amichai ◽  
Lilach Pnueli ◽  
Khurshida Begum ◽  
Gregory Leeman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ovarian Reserve ◽  
Early Life ◽  
Reproductive Function ◽  
Adaptive Plasticity ◽  
Mrna Levels ◽  
Altered Expression ◽  
Pubertal Onset ◽  
The Uk ◽  
Reproductive Phenotype

Abstract Background Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. Results Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women’s buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. Conclusions SRD5A1/5α reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs.

scholarly journals A Novel Mouse Model for Acute and Long-Lasting Consequences of Early Life Stress

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 4892-4900 ◽  
Author(s):  
Courtney J. Rice ◽  
Curt A. Sandman ◽  
Mohammed R. Lenjavi ◽  
Tallie Z. Baram
Keyword(s):  
Mouse Model ◽  
Paraventricular Nucleus ◽  
Life Stress ◽  
Early Life ◽  
Molecular Mechanisms ◽  
Early Life Stress ◽  
Plasma Corticosterone ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Basal Plasma

Chronic early-life stress (ES) exerts profound acute and long-lasting effects on the hypothalamic-pituitary-adrenal system, with relevance to cognitive function and affective disorders. Our ability to determine the molecular mechanisms underlying these effects should benefit greatly from appropriate mouse models because these would enable use of powerful transgenic methods. Therefore, we have characterized a mouse model of chronic ES, which was provoked in mouse pups by abnormal, fragmented interactions with the dam. Dam-pup interaction was disrupted by limiting the nesting and bedding material in the cages, a manipulation that affected this parameter in a dose-dependent manner. At the end of their week-long rearing in the limited-nesting cages, mouse pups were stressed, as apparent from elevated basal plasma corticosterone levels. In addition, steady-state mRNA levels of CRH in the hypothalamic paraventricular nucleus of ES-experiencing pups were reduced, without significant change in mRNA levels of arginine vasopressin. Rearing mouse pups in this stress-provoking cage environment resulted in enduring effects: basal plasma corticosterone levels were still increased, and CRH mRNA levels in paraventricular nucleus remained reduced in adult ES mice, compared with those of controls. In addition, hippocampus-dependent learning and memory functions were impaired in 4- to 8-month-old ES mice. In summary, this novel, robust model of chronic early life stress in the mouse results in acute and enduring neuroendocrine and cognitive abnormalities. This model should facilitate the examination of the specific genes and molecules involved in the generation of this stress as well as in its consequences.

scholarly journals Early-life environment programs reproductive strategies through epigenetic regulation of SRD5A1

2020 ◽  
Author(s):  
Ben Bar-Sadeh ◽  
Or Eden ◽  
Lilach Pnueli ◽  
Kurshida Begum ◽  
Gregory Leeman ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Early Life ◽  
Reproductive Strategies ◽  
Life History Theory ◽  
Molecular Mechanisms ◽  
Reproductive Function ◽  
Transcriptional Enhancer ◽  
Pubertal Onset ◽  
Early Life Environment

AbstractReproductive function and duration of the reproductive life span are phenotypically plastic and programmed in response to the early-life environment. Such adaptive responses are described and rationalized in life history theory in the context of resource availability, but the molecular mechanisms responsible have remained enigmatic. In this study, we hypothesized that epigenetic modifications underlie adaptive reproductive strategies, and found distinct methylation patterns in buccal DNA of Bangladeshi women who grew up in Bangladesh or the UK. The later pubertal onset and lower ovarian reserve associated with Bangladeshi childhood was seen to correlate with more numerous childhood infections, so we adopted a mouse model of pre-pubertal colitis to mimic these conditions. These mice have a similarly-altered reproductive phenotype, which enabled us to determine its mechanistic basis. Several genes encoding proteins with known functions in follicle recruitment were differentially expressed in the mice ovaries, and were also differentially methylated in the women’s buccal DNA. One of these, SRD5A1 which encodes the steroidogenic enzyme 5α reductase-1, was down-regulated in the mice ovaries and hyper methylated at the same putative transcriptional enhancer as in the women’s DNA; the levels of methylation correlating with gene expression levels. Srd5a1 expression was down-regulated also in the hypothalamus where 5α reductase-1 catalyzes production of neurosteroids that regulate gonadotropin releasing hormone (GnRH). Chemical inhibition of this enzyme affected both GnRH synthesis and release, and resulted in delayed pubertal onset in vivo. The activity of 5α reductase-1 in hypothalamus and ovary and the sensitivity of SRD5A1 to epigenetic regulation attest to its role in directing long-term physiological strategies in response to environmental conditions. In the reproductive axis, this includes timing of pubertal onset, adult reproductive function and duration of the reproductive lifespan.

scholarly journals Dissection of the corticotroph transcriptome in a mouse model of glucocorticoid-induced suppression of the HPA axis

2020 ◽  
Author(s):  
N Romanò ◽  
PJ Duncan ◽  
H McClafferty ◽  
O Nolan ◽  
Q Ding ◽  
...  
Keyword(s):  
Drinking Water ◽  
Mouse Model ◽  
Hpa Axis ◽  
Adult Male ◽  
Adrenal Function ◽  
Morbidity And Mortality ◽  
Mrna Levels ◽  
Rna Seq ◽  
The Uk ◽  
To Receive

ABSTRACTGlucocorticoids (GC) are prescribed for periods >3 months to 1-3% of the UK population; 10-50% of these patients develop hypothalamus-pituitary-adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of higher nodes of the axis is necessary for recovery of adrenal function. We developed a mouse model of Dexamethasone (DEX)-induced HPA axis dysfunction in order to further explore recovery in the pituitary. Adult male C57BL6/J or those crossed with Pomc-eGFP mice were randomly assigned to receive DEX (~0.4 mg/kg bodyweight/day) or vehicle via drinking water for 4 weeks following which treatment was withdrawn. Tissues were harvested at 0, 1, and 4 weeks following withdrawal of treatment. Corticotrophs were isolated from Pomc-eGFP pituitaries using FACS, and RNA extracted for RNA-seq. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, at time 0, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whilst only 2 genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and 6 genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress.

scholarly journals Adaptive response to a future life challenge: consequences of early-life environmental complexity in dual-purpose chicks

2020 ◽  
Vol 98 (11) ◽  
Author(s):  
Chao Yan ◽  
Kate Hartcher ◽  
Wen Liu ◽  
Jinlong Xiao ◽  
Hai Xiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gut Microbiota ◽  
Early Life ◽  
Plasma Corticosterone ◽  
Adaptive Plasticity ◽  
Environmental Complexity ◽  
Dual Purpose ◽  
Stress Related Genes ◽  
Life Challenge ◽  
Environmental Challenge

Abstract Conditions in early life play profound and long-lasting effects on the welfare and adaptability to stress of chickens. This study aimed to explore the hypothesis that the provision of environmental complexity in early life improves birds’ adaptive plasticity and ability to cope with a challenge later in life. It also tried to investigate the effect of the gut-brain axis by measuring behavior, stress hormone, gene expression, and gut microbiota. One-day-old chicks were split into 3 groups: (1) a barren environment (without enrichment items) group (BG, n = 40), (2) a litter materials group (LG, n = 40), and (3) a perches with litter materials group (PLG, n = 40). Then, enrichment items were removed and simulated as an environmental challenge at 31 to 53 d of age. Birds were subjected to a predator test at 42 d of age. In the environmental challenge, when compared with LG, PLG birds were characterized by decreased fearfulness, lower plasma corticosterone, improved gut microbial functions, lower relative mRNA expression of GR, and elevated mRNA expressions of stress-related genes CRH, BDNF, and NR2A in the hypothalamus (all P < 0.05). Unexpectedly, the opposite was true for the LG birds when compared with the BG (P < 0.05). Decreased plasma corticosterone and fearfulness were accompanied by altered hypothalamic gene mRNA expressions of BDNF, NR2A, GR, and CRH through the HPA axis in response to altered gut microbial compositions and functions. The findings suggest that gut microbiota may integrate fearfulness, plasma corticosterone, and gene expression in the hypothalamus to provide an insight into the gut-brain axis in chicks. In conclusion, having access to both perches and litter materials in early life allowed birds to cope better with a future challenge. Birds in perches and litter materials environment may have optimal development and adaptive plasticity through the gut-brain axis.

scholarly journals CD206+ macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yosuke Ono ◽  
Osamu Yoshino ◽  
Takehiro Hiraoka ◽  
Erina Sato ◽  
Akiko Furue ◽  
...  
Keyword(s):  
Mouse Model ◽  
Diphtheria Toxin ◽  
Immunohistochemical Study ◽  
Mrna Levels ◽  
Cytokines And Chemokines ◽  
Diphtheria Toxin Receptor ◽  
Endothelial Cell Marker ◽  
Toxin Receptor ◽  
Group A

AbstractIn endometriosis, M2 MΦs are dominant in endometriotic lesions, but the actual role of M2 MΦ is unclear. CD206 positive (+) MΦ is classified in one of M2 type MΦs and are known to produce cytokines and chemokines. In the present study, we used CD206 diphtheria toxin receptor mice, which enable to deplete CD206+ cells with diphtheria toxin (DT) in an endometriosis mouse model. The depletion of CD206+ MΦ decreased the total weight of endometriotic-like lesions significantly (p < 0.05). In the endometriotic-like lesions in the DT group, a lower proliferation of endometriotic cells and the decrease of angiogenesis were observed. In the lesions, the mRNA levels of VEGFA and TGFβ1, angiogenic factors, in the DT group significantly decreased to approximately 50% and 30% of control, respectively. Immunohistochemical study revealed the expressions of VEGFA and an endothelial cell marker CD31 in lesions of the DT group, were dim compared to those in control. Also, the number of TGFβ1 expressing MΦ was significantly reduced compared to control. These data suggest that CD206+ MΦ promotes the formation of endometriotic-like lesions by inducing angiogenesis around the lesions.

scholarly journals Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yan Gong ◽  
Jesse Li-Ling ◽  
Dongsheng Xiong ◽  
Jiajing Wei ◽  
Taiqing Zhong ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Clinical Trial Registry ◽  
Altered Expression ◽  
Vitro Fertilization ◽  
Age Related ◽  
Tertiary Teaching ◽  
Poor Ovarian Responders

Abstract Background Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes play important roles in folliculogenesis. Altered expression of the two have been found among patients with poor ovarian response (POR). In this prospective cohort study, we have determined the expression of the GDF9 and BMP15 genes in follicle fluid (FF) and granulosa cells (GCs) derived from poor ovarian responders grouped by age, and explored its correlation with the outcome of in vitro fertilization and embryo transfer (IVF-ET) treatment. Methods A total of 196 patients with POR were enrolled from a tertiary teaching hospital. The patients were diagnosed by the Bologna criteria and sub-divided into group A (< 35 year old), group B (35–40 year old), and group C (> 40 year old). A GnRH antagonist protocol was conducted for all patients, and FF and GCs were collected after oocyte retrieval. Expression of the GDF9 and BMP15 genes in the FF and GCs was determined with enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Results Compared with group C, groups A and B had significantly more two pronuclei (2PN) oocytes and transplantable embryos, in addition with higher rates of implantation and clinical pregnancy (P <  0.05). The expression level of GDF9 and BMP15 genes in the FF and GCs differed significantly among the three groups (P <  0.05), showing a trend of decline along with age. The ratio of GDF9/BMP15 mRNA levels were similar among the three groups (P > 0.05). The relative levels of GDF9 and BMP15 proteins in GCs have correlated with the relative mRNA levels in GCs and protein concentrations in FF (P <  0.05). Conclusions For poor ovarian responders, in particular those over 40, the expression of GDF9 and BMP15 is declined along with increased age and in accompany with poorer oocyte quality and IVF outcome, whilst the ratio of GDF9/BMP15 mRNA levels remained relatively constant. Trial registration Chinese Clinical Trial Registry Center (ChiCTR1800016107). Registered on 11 May 2018.

scholarly journals Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 357
Author(s):  
Mojca Trstenjak Prebanda ◽  
Petra Matjan-Štefin ◽  
Boris Turk ◽  
Nataša Kopitar-Jerala
Keyword(s):  
Mouse Model ◽  
Redox Homeostasis ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Altered Expression ◽  
Lps Challenge ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
The Brain ◽  
Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

Abstract 107: Mir-431 as a Potential Master Regulator in Angiotensin Ii-induced Vascular Injury

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kugeng Huo ◽  
Tlili Barhoumi ◽  
Julio C Fraulob-Aquino ◽  
Chantal Richer ◽  
Mathieu Lajoie ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Molecular Networks ◽  
Type I ◽  
Mirna Cluster ◽  
Mrna Levels ◽  
Ang Ii ◽  
Master Regulator ◽  
Developmental Processes ◽  
Altered Expression ◽  
Total Rna

Objective: Vascular injury is an early manifestation and a cause of end-organ damage in hypertension. microRNAs (miRNAs) play an important role in cardiovascular disease, but their implication in vascular injury is remains unclear. We aim to use RNA sequencing (seq) and a systems biology approach to identify master regulators that mediate global gene expression changes in the course of vascular injury. Methods and Results: Ten week-old male C57BL/6 mice were infused or not with angiotensin (Ang) II (1 μg/kg/min, SC) for 14 days. Blood pressure (BP) was measured by telemetry. Total RNA was extracted from the mesenteric vasculature for total RNA and small RNA-seq. Differentially expressed (DE) miRNAs (23 up and 12 down) and mRNAs (550 up and 256 down) were identified (1.5-fold, q <0.05). Molecular networks were constructed to integrate predicted interactions between DE miRNAs and inversely expressed DE mRNAs and between DE transcription factors (TF) and DE genes. Gene enrichment analysis revealed DE mRNAs involved in extracellular matrix (ECM) and developmental processes regulated by DE miRNAs ( q <1.5E-11). Seventeen upregulated miRNAs are located in the miRNA cluster of the Dlk1-Dio3 region that is highly conserved in humans, 9 of which had expression levels correlated with BP ( P <0.05). Among those 9, miR-431 that ranked first as DE miRNA ( q <0.0005) and is 100% conserved in humans, and a conserved putative DE target, a BP-correlated ( P <0.05) TF ETS homologous factor ( Ehf ), which regulates numerous ECM genes including collagen type I α1 ( Col1a1 ), were selected for functional studies. Transfection of a miR-431 mimic in human aortic smooth muscle cells (HASMCs) decreased Ehf (0.1±0.1-fold, P <0.001) and increased Ehf -suppressing target Col1a1 (1.7±0.5-fold, P <0.001) mRNA levels. Transfection of a miR-431 inhibitor caused reciprocal effects ( P <0.05). Ehf siRNA knockdown increased Col1a1 (1.2±0.1-fold, P <0.001) mRNA levels. Conclusions: Ang II infusion altered expression of miRNAs in the Dlk1-Dio3 cluster and genes involved in ECM and developmental processes. miR-431 targets TF Ehf , which leads to increased Col1a1 in HASMCs. miR-431 may act as a master regulator for vascular injury and could be a potential therapeutic target.

scholarly journals Exploring the impact of early life factors on inequalities in risk of overweight in UK children: findings from the UK Millennium Cohort Study

2016 ◽  
Vol 101 (8) ◽  
pp. 724-730 ◽  
Author(s):  
Samuel Massion ◽  
Sophie Wickham ◽  
Anna Pearce ◽  
Ben Barr ◽  
Catherine Law ◽  
...  
Keyword(s):  
Early Life ◽  
Social Inequalities ◽  
Childhood Overweight ◽  
Smoking During Pregnancy ◽  
The Social ◽  
Maternal Smoking During Pregnancy ◽  
Early Life Factors ◽  
Uk Millennium Cohort Study ◽  
The Uk ◽  
Academic Qualifications

BackgroundOverweight and obesity in childhood are socially patterned, with higher prevalence in more disadvantaged populations, but it is unclear to what extent early life factors attenuate the social inequalities found in childhood overweight/obesity.MethodsWe estimated relative risks (RRs) for being overweight (combining with obesity) at age 11 in 11 764 children from the UK Millennium Cohort Study (MCS) according to socio-economic circumstances (SEC). Early life risk factors were explored to assess if they attenuated associations between SECs and overweight.Results28.84% of children were overweight at 11 years. Children of mothers with no academic qualifications were more likely to be overweight (RR 1.72, 95% CI 1.48 to 2.01) compared to children of mothers with degrees and higher degrees. Controlling for prenatal, perinatal, and early life characteristics (particularly maternal pre-pregnancy overweight and maternal smoking during pregnancy) reduced the RR for overweight to 1.44, 95% CI 1.23 to 1.69 in the group with the lowest academic qualifications compared to the highest.ConclusionsWe observed a clear social gradient in overweight 11-year-old children using a representative UK sample. Moreover, we identified specific early life risk factors, including maternal smoking during pregnancy and maternal pre-pregnancy overweight, that partially account for the social inequalities found in childhood overweight. Policies to support mothers to maintain a healthy weight, breastfeed and abstain from smoking during pregnancy are important to improve maternal and child health outcomes, and our study provides some evidence that they may also help to address the continuing rise in inequalities in childhood overweight.

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