Epigenetic Memory Is Involved in the Persistent Alterations of Drug-Processing Genes in Adult Mice Due to PCN-Activated PXR During Early Life

Abstract Pregnane X receptor (PXR), which can be activated by xenobiotic chemicals (including pediatric drugs), plays a key role in the regulation of drug-processing genes (DPGs). The induction of DPGs due to PXR activation may reduce therapeutic efficacy or cause toxicity. This work aims to demonstrate the impact of pregnenolone 16α-carbonitrile (PCN)-mediated PXR activation during early life on DPGs expression and drug sensitivity in adulthood, as well as the underlying mechanism. In this study, mice were sacrificed at postnatal day 60 to detect the hepatic expression of selected DPGs and histone modifications in the Cyp3a11 promoter. We found that all doses of PCN treatment (50–200 mg/kg/day) at postnatal days 5–8 resulted in persistently increased CYP2B10 expression, whereas only high doses of PCN treatment (150 and 200 mg/kg/day) persistently induced the expression of CYP3A11, 1A2, and UGT1A1. We also demonstrated that PCN treatment before postnatal day 15 had a long-term impact on the expression of CYP3A11, 2B10, ABCC4, and PAPSS2. Additionally, elevated expression of CYP3A11, SULT2A1, UGT1A1, and PAPSS2 was observed in PCN-treated groups at days 25–28. Attenuated inducibility of CYP3A11 by PCN was seen in the primary hepatocytes derived from PCN-pretreated mice. Moreover, enhanced H3K4me3 level and reduced H3K27me3 level in the PXR response elements (PXREs) of the Cyp3a11 promoter may contribute to the persistent upregulation of CYP3A11 by neonatal PCN treatment. Overall, our study suggests that PXR activation during early life could persistently alter the hepatic expression of DPGs and epigenetic memory may be an underlying mechanism in mice.

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Citrus reticulatae pericarpium Extract Decreases the Susceptibility to HFD-Induced Glycolipid Metabolism Disorder in Mice Exposed to Azithromycin in Early Life

Frontiers in Immunology ◽

10.3389/fimmu.2021.774433 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hanqi Lu ◽

Yanting You ◽

Xinghong Zhou ◽

Qiuxing He ◽

Ming Wang ◽

...

Keyword(s):

Gut Microbiome ◽

High Fat Diet ◽

Early Life ◽

Underlying Mechanism ◽

Inflammatory Factors ◽

Glycolipid Metabolism ◽

Metabolism Disorder ◽

Adult Mice ◽

Gut Microbe ◽

Old Mice

BackgroundStudies have shown that gut microbe disorder in mice due to early-life antibiotic exposure promotes glycolipid metabolism disorder in adulthood. However, the underlying mechanism remains unclear and there is not yet an effective intervention or treatment for this process.PurposeThe study investigated whether early-life azithromycin (AZT) exposure in mice could promote high-fat diet (HFD)-induced glycolipid metabolism disorder in adulthood. Moreover, the effect of citrus reticulata pericarpium (CRP) extract on glycolipid metabolism disorder via regulation of gut microbiome in mice exposed to antibodies early in life were investigated.Methods and ResultsThree-week-old mice were treated with AZT (50 mg/kg/day) via drinking water for two weeks and then were fed a CRP diet (1% CRP extract) for four weeks and an HFD for five weeks. The results showed that early-life AZT exposure promoted HFD-induced glycolipid metabolism disorder, increased the levels of inflammatory factors, promoted the flora metabolism product trimethylamine N-oxide (TMAO), and induced microbial disorder in adult mice. Importantly, CRP extract mitigated these effects.ConclusionTaken together, these findings suggest that early-life AZT exposure increases the susceptibility to HFD-induced glycolipid metabolism disorder in adult mice, and CRP extract can decrease this susceptibility by regulating gut microbiome.

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Maternal exercise conveys protection against NAFLD in the offspring via hepatic metabolic programming

Scientific Reports ◽

10.1038/s41598-020-72022-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Inga Bae-Gartz ◽

Philipp Kasper ◽

Nora Großmann ◽

Saida Breuer ◽

Ruth Janoschek ◽

...

Keyword(s):

Early Life ◽

Body Weight Gain ◽

Hepatic Metabolism ◽

Underlying Mechanism ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Hepatic Expression ◽

Maternal Exercise

Abstract Maternal exercise (ME) during pregnancy has been shown to improve metabolic health in offspring and confers protection against the development of non-alcoholic fatty liver disease (NAFLD). However, its underlying mechanism are still poorly understood, and it remains unclear whether protective effects on hepatic metabolism are already seen in the offspring early life. This study aimed at determining the effects of ME during pregnancy on offspring body composition and development of NAFLD while focusing on proteomic-based analysis of the hepatic energy metabolism during developmental organ programming in early life. Under an obesogenic high-fat diet (HFD), male offspring of exercised C57BL/6J-mouse dams were protected from body weight gain and NAFLD in adulthood (postnatal day (P) 112). This was associated with a significant activation of hepatic AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor alpha (PPARα) and PPAR coactivator-1 alpha (PGC1α) signaling with reduced hepatic lipogenesis and increased hepatic β-oxidation at organ programming peak in early life (P21). Concomitant proteomic analysis revealed a characteristic hepatic expression pattern in offspring as a result of ME with the most prominent impact on Cholesterol 7 alpha-hydroxylase (CYP7A1). Thus, ME may offer protection against offspring HFD-induced NAFLD by shaping hepatic proteomics signature and metabolism in early life. The results highlight the potential of exercise during pregnancy for preventing the early origins of NAFLD.

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CC16 deficiency in the context of early life Mycoplasma pneumoniae infection results in augmented airway responses in adult mice.

Infection and Immunity ◽

10.1128/iai.00548-21 ◽

2021 ◽

Author(s):

Natalie Iannuzo ◽

Michael Insel ◽

Craig Marshall ◽

William P. Pederson ◽

Kenneth J. Addison ◽

...

Keyword(s):

Lung Function ◽

Mycoplasma Pneumoniae ◽

Early Life ◽

Defense Mechanisms ◽

Airway Remodeling ◽

Secretory Protein ◽

Protective Role ◽

Tracheal Epithelial Cells ◽

Adult Mice ◽

The Impact

Studies have shown that club cell secretory protein (CC16) plays important protective roles in the lungs, yet its complete biological functions are unclear. We devised a translational mouse model in order to investigate the impact of early life infections, in the context of CC16 deficiency, on lung function in adult mice. CC16 sufficient (WT) and deficient (CC16 -/- ) mice were infected with Mycoplasma pneumoniae (Mp) as weanlings and assessed as adults ( e arly l ife i nfection m odel; ELIM) and compared to adult mice infected for only three days ( a dult i nfection m odel; AIM). CC16 -/- Mp-infected mice had significantly increased airway hyperresponsiveness (AHR) in both models compared to WT mice. However, CC16 -/- mice infected in early life (ELIM) displayed significantly increased AHR compared to CC16 -/- mice infected in adulthood (AIM). In stark contrast, lung function in ELIM WT mice returned to levels similar to saline-treated controls. While WT mice cleared Mp infection in the ELIM, CC16 -/- mice remained colonized with Mp throughout the model, which likely contributed to increased airway remodeling and persistence of Muc5ac expression. When CC16 -/- mouse tracheal epithelial cells (MTECs) were infected with Mp, increased Mp colonization and collagen gene expression were also detected compared to WT cells, suggesting that CC16 plays a protective role during Mp infection, in part through epithelial-driven host defense mechanisms.

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The impact of early-life stress on the expression of HPA-associated genes in the adult murine brain

Behaviour ◽

10.1163/1568539x-00003482 ◽

2018 ◽

Vol 155 (2-3) ◽

pp. 181-203 ◽

Cited By ~ 7

Author(s):

V.V. Reshetnikov ◽

A.A. Studenikina ◽

J.A. Ryabushkina ◽

T.I. Merkulova ◽

N.P. Bondar

Keyword(s):

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Long Term Memory ◽

Adult Mice ◽

Specific Manner ◽

Behavioural Phenotypes ◽

The Impact

Abstract Early life is an important period for the development of the nervous system and for the programming of behavioural phenotypes in adulthood. In our study, two types of early-life stress were used: prolonged separation of pups from their mothers (for 3 h/day, maternal separation (MS)) and brief separation (for 15 min/day, handling (HD)). We analysed the effects of early-life stress on behaviour and the expression of HPA-associated genes in the hypothalamus, hippocampus, and frontal cortex of male mice. Adult mice in the MS group demonstrated reduced locomotor activity and deficiencies in spatial long-term memory, while the HD showed no significant changes. Additionally, early-life MS resulted in reduced hippocampal Crhr1 mRNA, increased MR/GR mRNA in the hippocampus and hypothalamus. Both groups, HD and MS, showed increased Avp mRNA in the hypothalamus. Thus, prolonged maternal separation but not brief leads to adverse behavioural changes and influences the expression of HPA-associated genes in a brain region-specific manner.

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Nuclear Receptors in Acute and Chronic Cholestasis

Digestive Diseases ◽

10.1159/000371688 ◽

2015 ◽

Vol 33 (3) ◽

pp. 357-366 ◽

Cited By ~ 19

Author(s):

Ester Gonzalez-Sanchez ◽

Delphine Firrincieli ◽

Chantal Housset ◽

Nicolas Chignard

Keyword(s):

Lipid Metabolism ◽

Nuclear Receptors ◽

Energy Homeostasis ◽

Therapeutic Targets ◽

Pregnane X Receptor ◽

Estrogen Receptor Α ◽

Farnesoid X Receptor ◽

Peroxisome Proliferator ◽

Hepatic Expression ◽

The Impact

Background: Nuclear receptors (NRs) form a family of 48 members. NRs control hepatic processes such as bile acid homeostasis, lipid metabolism and mechanisms involved in fibrosis and inflammation. Due to their central role in the regulation of hepatoprotective mechanisms, NRs are promising therapeutic targets in cholestatic disorders. Key Messages: NRs can be classified into five different physiological clusters. NRs from the ‘bile acids and xenobiotic metabolism' and from the ‘lipid metabolism and energy homeostasis' clusters are strongly expressed in the liver. Furthermore, NRs from these clusters, such as farnesoid X receptor α (FXRα), pregnane X receptor (PXR) and peroxisome proliferator-activated receptors (PPARs), have been associated with the pathogenesis and the progression of cholestasis. The latter observation is also true for vitamin D receptor (VDR), which is barely detectable in the whole liver, but has been linked to cholestatic diseases. Involvement of VDR in cholestasis is ascribed to a strong expression in nonparenchymal liver cells, such as biliary epithelial cells, Kupffer cells and hepatic stellate cells. Likewise, NRs from other physiological clusters with low hepatic expression, such as estrogen receptor α (ERα) or reverse-Erb α/β (REV-ERB α/β), may also control pathophysiological processes in cholestasis. Conclusions: In this review, we will describe the impact of individual NRs on cholestasis. We will then discuss the potential role of these transcription factors as therapeutic targets.

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A Perspective On The Impact of COVID-19 Pandemic in Basic Science Research and its Future implications

Coronaviruses ◽

10.2174/2666796701999201223161636 ◽

2020 ◽

Vol 01 ◽

Author(s):

Yam Nath Paudel ◽

Efthalia Angelopoulou ◽

Bhupendra Raj Giri ◽

Christina Piperi ◽

Iekhsan Othman ◽

...

Keyword(s):

Basic Science ◽

Large Scale ◽

Preventive Measure ◽

Science Research ◽

Research Institutes ◽

Basic Science Research ◽

Long Term Consequences ◽

Long Term Impact ◽

The Impact

: COVID-19 has emerged as a devastating pandemic of the century that the current generations have ever experienced. The COVID-19 pandemic has infected more than 12 million people around the globe and 0.5 million people have succumbed to death. Due to the lack of effective vaccines against the COVID-19, several nations throughout the globe has imposed a lock-down as a preventive measure to lower the spread of COVID-19 infection. As a result of lock-down most of the universities and research institutes has witnessed a long pause in basic science research ever. Much has been talked about the long-term impact of COVID-19 in economy, tourism, public health, small and large-scale business of several kind. However, the long-term implication of these research lab shutdown and its impact in the basic science research has not been much focused. Herein, we provide a perspective that portrays a common problem of all the basic science researchers throughout the globe and its long-term consequences.

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Effects of dietary n-3 PUFA levels in early life on susceptibility to high-fat-diet-induced metabolic syndrome in adult mice

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2020.108578 ◽

2020 ◽

pp. 108578

Author(s):

Dan-Dan Wang ◽

Fang Wu ◽

Ling-Yu Zhang ◽

Ying-Cai Zhao ◽

Cheng-Cheng Wang ◽

...

Keyword(s):

Metabolic Syndrome ◽

High Fat Diet ◽

Early Life ◽

High Fat ◽

Adult Mice

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Adolescent depression, early psychiatric comorbidities, and adulthood welfare burden: a 25-year longitudinal cohort study

Social Psychiatry and Psychiatric Epidemiology ◽

10.1007/s00127-021-02056-2 ◽

2021 ◽

Author(s):

Iman Alaie ◽

Richard Ssegonja ◽

Anna Philipson ◽

Anne-Liis von Knorring ◽

Margareta Möller ◽

...

Keyword(s):

Cohort Study ◽

Early Life ◽

Adolescent Depression ◽

Longitudinal Cohort Study ◽

Health Concern ◽

Psychiatric Comorbidities ◽

Longitudinal Cohort ◽

Transfer Payments ◽

Social Transfer ◽

The Impact

Abstract Purpose Depression at all ages is recognized as a global public health concern, but less is known about the welfare burden following early-life depression. This study aimed to (1) estimate the magnitude of associations between depression in adolescence and social transfer payments in adulthood; and (2) address the impact of major comorbid psychopathology on these associations. Methods This is a longitudinal cohort study of 539 participants assessed at age 16–17 using structured diagnostic interviews. An ongoing 25-year follow-up linked the cohort (n = 321 depressed; n = 218 nondepressed) to nationwide population-based registries. Outcomes included consecutive annual data on social transfer payments due to unemployment, work disability, and public assistance, spanning from age 18 to 40. Parameter estimations used the generalized estimating equations approach. Results Adolescent depression was associated with all forms of social transfer payments. The estimated overall payment per person and year was 938 USD (95% CI 551–1326) over and above the amount received by nondepressed controls. Persistent depressive disorder was associated with higher recipiency across all outcomes, whereas the pattern of findings was less clear for subthreshold and episodic major depression. Moreover, depressed adolescents presenting with comorbid anxiety and disruptive behavior disorders evidenced particularly high recipiency, exceeding the nondepressed controls with an estimated 1753 USD (95% CI 887–2620). Conclusion Adolescent depression is associated with considerable public expenditures across early-to-middle adulthood, especially for those exposed to chronic/persistent depression and psychiatric comorbidities. This finding suggests that the clinical heterogeneity of early-life depression needs to be considered from a longer-term societal perspective.

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The Long-Term Impact of Different Offline Population Inclusion Strategies in Probability-Based Online Panels: Evidence From the German Internet Panel and the GESIS Panel

Social Science Computer Review ◽

10.1177/0894439320984131 ◽

2021 ◽

pp. 089443932098413

Author(s):

Carina Cornesse ◽

Ines Schaurer

Keyword(s):

Survey Data ◽

Positive Impact ◽

Alternative Mode ◽

Mail Surveys ◽

Internet Users ◽

Online Panels ◽

Long Term Impact ◽

The Impact ◽

Postal Mail

While online panels offer numerous advantages, they are often criticized for excluding the offline population. Therefore, some probability-based online panels have developed offline population inclusion strategies. Two dominant approaches prevail: providing internet equipment and offering an alternative survey participation mode. We investigate the impact of these approaches on two probability-based online panels in Germany: the German Internet Panel, which provides members of the offline population with internet equipment, and the GESIS Panel, which offers members of the offline population to participate via postal mail surveys. In addition, we explore the impact of offering an alternative mode only to non-internet users versus also offering the alternative mode to internet users who are unwilling to provide survey data online. Albeit lower recruitment and/or panel wave participation probabilities among offliners than onliners, we find that including the offline population has a positive long-term impact on sample accuracy in both panels. In the GESIS Panel, the positive impact is particularly strong when offering the alternative participation mode to non-internet users and internet users who are unwilling to provide survey data online.

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