Impact of Simulated Rotating Shift Work on Mammary Tumor Development in the Mouse Model for Breast Cancer.

Epidemiological studies associate night shift work with increased breast cancer risk. However, the underlying mechanisms are not clearly understood. To better understand these mechanisms, animal models that mimic the human situation of different aspects of shift work are needed.

Prolonged Differentiation of Neuron-Astrocyte Co-Cultures Results in Emergence of Dopaminergic Neurons.

Dopamine is present in a subgroup of neurons that are vital for normal brain functioning. Disruption of the dopaminergic system, e.g.

Corrigendum: The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside.

[This corrects the article DOI: 10.3389/fragi.2022.

Exploration of genome-wide DNA methylation profiles in night shift workers.

The past decades, studies indicated that night shift work is associated with adverse health effects, however, molecular mechanisms underlying these effects are poorly understood. A few previous studies have hypothesized a role for DNA-methylation (DNAm) in this relationship. We performed a cross-sectional epigenome-wide association study, to investigate if night shift work is associated with genome-wide DNAm changes and DNAm-based biological age acceleration, based on previously developed so-called 'epigenetic clocks.

The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside.

Despite efficient repair, DNA damage inevitably accumulates with time affecting proper cell function and viability, thereby driving systemic aging. Interventions that either prevent DNA damage or enhance DNA repair are thus likely to extend health- and lifespan across species. However, effective genome-protecting compounds are largely lacking.

A randomized crossover trial assessing time of day snack consumption and resulting postprandial glycemic response in a real-life setting among healthy adults.

The postprandial glycemic response is an important metabolic health factor, which, from laboratory studies, is known to change from low to high over the course of the day, and from which negative health outcomes have been linked to nightly eating. We applied interstitial continuous glucose monitoring to examine the glycemic response to a standardized carbohydrate-rich snack (198 kcal) across the day in a real-life setting. Twenty-four healthy participants (12 men, 12 women, 27-61 y old) consumed the snack nine times during 6 d in a crossover design, altering the time of consumption between morning, afternoon and evening.

Neuronal differentiation pathways and compound-induced developmental neurotoxicity in the human neural progenitor cell test (hNPT) revealed by RNA-seq.

There is an increased awareness that the use of animals for compound-induced developmental neurotoxicity (DNT) testing has limitations. Animal-free innovations, especially the ones based on human stem cell-based models are pivotal in studying DNT since they can mimic processes relevant to human brain development. Here we present the human neural progenitor test (hNPT), a 10-day protocol in which neural progenitor cells differentiate into a neuron-astrocyte co-culture.

Integrating in vitro chemical transplacental passage into a generic PBK model: A QIVIVE approach.

With the increasing application of cell culture models as primary tools for predicting chemical safety, the quantitative extrapolation of the effective dose from in vitro to in vivo (QIVIVE) is of increasing importance. For developmental toxicity this requires scaling the in vitro observed dose-response characteristics to in vivo fetal exposure, while integrating maternal in vivo kinetics during pregnancy, in particular transplacental transfer. Here the transfer of substances across the placental barrier, has been studied using the in vitro BeWo cell assay and six embryotoxic compounds of different kinetic complexity.

Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice.

Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair-deficient Ercc1 mice, contrary to DR tested in parallel.

Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness.

Decline of immune function during aging has in part been ascribed to the accumulation of regulatory T cells (Tregs) and decreased T-cell responses with age. Aside from changes to T cells that occur over a lifetime, the impact of intracellular aging processes such as compromised DNA repair on T cells remains incompletely defined. Here we aimed to define the impact of compromised DNA repair on T-cell phenotype and responsiveness by studying T cells from mice with a deficiency in their DNA excision-repair gene .

Going Back and Forth: Episomal Vector Reprogramming of Peripheral Blood Mononuclear Cells to Induced Pluripotent Stem Cells and Subsequent Differentiation into Cardiomyocytes and Neuron-Astrocyte Co-cultures.

Human induced pluripotent stem cells (iPSCs) can capture the diversity in the general human population as well as provide deeper insight in cellular mechanisms. This makes them suitable to study both fundamental and applied research subjects, such as disease modeling, gene-environment interactions, personalized medicine, and chemical toxicity. In an independent laboratory, we were able to generate iPSCs originating from human peripheral blood mononuclear cells according to a modified version of a temporal episomal vector (EV)-based induction method.

An efficient neuron-astrocyte differentiation protocol from human embryonic stem cell-derived neural progenitors to assess chemical-induced developmental neurotoxicity.

Human embryonic stem cell neuronal differentiation models provide promising in vitro tools for the prediction of developmental neurotoxicity of chemicals. Such models mimic essential elements of human relevant neuronal development, including the differentiation of a variety of brain cell types and their neuronal network formation as evidenced by specific gene and protein biomarkers. However, the reproducibility and lengthy culture duration of cell models present drawbacks and delay regulatory implementation.

Defining embryonic developmental effects of chemical mixtures using the embryonic stem cell test.

The embryonic stem cell test (EST) was applied to evaluate dose addition in combined exposures of teratogenic compounds in the EFSA-defined cumulative assessment group "craniofacial malformations", which was one of the selected cases in the EU-H2020 project "EuroMix". Test compounds were selected through reported effects in rodents, and represented a wide variety of chemical families and modes of action (MOA), including triazoles to inhibit CYP26; (synthetic) retinoids, to activate RAR/RXR; valproic acid, to inhibit histone deacetylase; dithiocarbamates, to disrupt extracellular matrix formation; dioxin (-like) compounds, to activate the aryl hydrocarbon receptor; 17alpha-ethynylestradiol, to activate the estrogen receptor; 5-fluorouracil, to disrupt DNA-synthesis; MEHP and PFOS, to activate peroxisome proliferation activated receptors; and methyl mercury, to induce oxidative stress and inhibit protein function. The EST appeared particularly useful to evaluate differentiation-inhibiting effects of compounds targeting early processes in craniofacial development, possibly related to the early fate of neural crest cells.

Differential effects of fluoxetine and venlafaxine in the neural embryonic stem cell test (ESTn) revealed by a cell lineage map.

There is a need for in vitro tests for the evaluation of chemicals and pharmaceuticals that may cause developmental neurotoxicity (DNT) in humans. The neural embryonic stem cell test (ESTn) is such an in vitro test that mimics early neural differentiation. The aim of this study was to define the biological domain of ESTn based on the expression of selective markers for certain cell types, and to investigate the effects of two antidepressants, fluoxetine (FLX) and venlafaxine (VNX), on neural differentiation.

A signature of renal stress resistance induced by short-term dietary restriction, fasting, and protein restriction.

During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels.

Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.

Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction).

Confounding Factors in the Transcriptome Analysis of an In-Vivo Exposure Experiment.

Confounding Factors: In transcriptomics experimentation, confounding factors frequently exist alongside the intended experimental factors and can severely influence the outcome of a transcriptome analysis. Confounding factors are regularly discussed in methodological literature, but their actual, practical impact on the outcome and interpretation of transcriptomics experiments is, to our knowledge, not documented. For instance, in-vivo experimental factors; like Individual, Sample-Composition and Time-of-Day are potentially formidable confounding factors.

Diurnal Variation of Hormonal and Lipid Biomarkers in a Molecular Epidemiology-Like Setting.

Introduction: Many molecular epidemiology studies focusing on high prevalent diseases, such as metabolic disorders and cancer, investigate metabolic and hormonal markers. In general, sampling for these markers can occur at any time-point during the day or after an overnight fast. However, environmental factors, such as light exposure and food intake might affect the levels of these markers, since they provide input for the internal time-keeping system.

Biomarkers for circadian rhythm disruption independent of time of day.

Frequent shift work causes disruption of the circadian rhythm and might on the long-term result in increased health risk. Current biomarkers evaluating the presence of circadian rhythm disturbance (CRD), including melatonin, cortisol and body temperature, require 24-hr ("around the clock") measurements, which is tedious. Therefore, these markers are not eligible to be used in large-scale (human) studies.

Preoperative fasting protects against renal ischemia-reperfusion injury in aged and overweight mice.

Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice.

A range finding protocol to support design for transcriptomics experimentation: examples of in-vitro and in-vivo murine UV exposure.

In transcriptomics research, design for experimentation by carefully considering biological, technological, practical and statistical aspects is very important, because the experimental design space is essentially limitless. Usually, the ranges of variable biological parameters of the design space are based on common practices and in turn on phenotypic endpoints. However, specific sub-cellular processes might only be partially reflected by phenotypic endpoints or outside the associated parameter range.

A day and night difference in the response of the hepatic transcriptome to cyclophosphamide treatment.

Application of omics-based technologies is a widely used approach in research aiming to improve testing strategies for human health risk assessment. In most of these studies, however, temporal variations in gene expression caused by the circadian clock are a commonly neglected pitfall. In the present study, we investigated the impact of the circadian clock on the response of the hepatic transcriptome after exposure of mice to the chemotherapeutic agent cyclophosphamide (CP).