Increasing popularity of electronic cigarettes (e-cigs), including among women of reproductive age, is attributed to its perceived safety compared to conventional tobacco. However, there is a major ...knowledge gap surrounding the effects of e-cig aerosols on pregnancy and fetal development. We aimed to evaluate the effects of vaping e-cigs during gestation on offspring growth and to asses if growth deficits are accompanied by altered maternal and fetal vascular hemodynamics. Sprague–Dawley dams were assigned to Pair-Fed Control, Pair-Fed Juice, or Juice+Nicotine groups, and then underwent either a prenatal or prenatal+postnatal exposure paradigm in a custom-engineered vaping system. Mass spectrometry identified major aerosolized constituents from e-cig vaping. The Juice+Nicotine group exhibited significantly decreased fetal weight and crown-rump length (↓46.56%, and ↓23.83%, respectively). Pre- and postnatal exposure to Juice+Nicotine resulted in decreased pup weight at postnatal day (PND) 4–10. Crown-rump length was decreased by 24.71% on PND 10. Blood flow in the Juice+Nicotine group was decreased in the maternal uterine and fetal umbilical circuits by 49.50% and 65.33%, respectively. We conclude that chronic exposure to e-cig aerosols containing nicotine during early development can have deleterious health effects on the exposed offspring. Vaping e-cigs containing nicotine during pregnancy lead to a reduction in offspring weight and crown-rump length, associated with a marked decrease in blood flow in both the maternal uterine and fetal umbilical circulation (a strong indicator of growth restriction). Thus, chronic exposure to e-cig aerosols containing nicotine can lead to potentially harmful developmental effects in early life.
Abstract
Blood lead (Pb) level (BLL) is a commonly used biomarker to evaluate associations with health effects. However, interventions to reduce the adverse effects of Pb require relating BLL to ...external exposure. Moreover, risk mitigation actions need to ensure protection of more susceptible individuals with a greater tendency to accumulate Pb. Because little data is available to quantify inter-individual variability in biokinetics of Pb, we investigated the influence of genetics and diet on BLL in the genetically diverse Collaborative Cross (CC) mouse population. Adult female mice from 49 CC strains received either a standard mouse chow or a chow mimicking the American diet while being provided water ad libitum with 1000 ppm Pb for 4 weeks. In both arms of the study, inter-strain variability was observed; however, in American diet-fed animals, the BLL was greater and more variable. Importantly, the degree of variation in BLL among strains on the American diet was greater (2.3) than the default variability estimate (1.6) used in setting the regulatory standards. Genetic analysis identified suggestive diet-associated haplotypes that were associated with variation in BLL, largely contributed by the PWK/PhJ strain. This study quantified the variation in BLL that is due to genetic background, diet, and their interactions, and observed that it may be greater than that assumed for current regulatory standards for Pb in drinking water. Moreover, this work highlights the need of characterizing inter-individual variation in BLL to ensure adequate public health interventions aimed at reducing human health risks from Pb.
Systemic infections can yield distinct outcomes in different tissues. In mice, intravenous inoculation of
leads to bacterial replication within liver abscesses, while other organs such as the spleen ...clear the pathogen. Abscesses are macroscopic necrotic regions that comprise the vast majority of the bacterial burden in the animal, yet little is known about the processes underlying their formation. Here, we characterize
liver abscesses and identify host determinants of abscess susceptibility. Spatial transcriptomics revealed that liver abscesses are associated with heterogenous immune cell clusters comprised of macrophages, neutrophils, dendritic cells, innate lymphoid cells, and T-cells that surround necrotic regions of the liver. Abscess susceptibility is heightened in the C57BL lineage, particularly in C57BL/6N females. Backcross analyses demonstrated that abscess susceptibility is a polygenic trait inherited in a sex-dependent manner without direct linkage to sex chromosomes. As early as 1 d post infection, the magnitude of
replication in the liver distinguishes abscess-susceptible and abscess-resistant strains of mice, suggesting that the immune pathways that regulate abscess formation are induced within hours. We characterized the early hepatic response with single-cell RNA sequencing and found that mice with reduced activation of early inflammatory responses, such as those lacking the LPS receptor TLR4 (Toll-like receptor 4), are resistant to abscess formation. Experiments with barcoded
revealed that TLR4 mediates a tradeoff between abscess formation and bacterial clearance. Together, our findings define hallmarks of
liver abscess formation and suggest that hyperactivation of the hepatic innate immune response drives liver abscess susceptibility.
The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGFβ signaling and activates the EGF receptor (EGFR), but the relative ...contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFR-deficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGFβ expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFR-dependent signaling for TGFβ expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGFβ-mediated fibrogenesis. We conclude that TGFβ-mediated tissue fibrosis relies on a persistent feed-forward mechanism of EGFR/ERK activation through an unexpected signaling pathway, highlighting EGFR as a potential therapeutic target for modulating tissue fibrogenesis.
Host response to infection is a major determinant of disease severity in Ebola virus disease (EVD), but gene expression programs associated with outcome are poorly characterized. Collaborative Cross ...(CC) mice develop strain-dependent EVD phenotypes of differential severity, ranging from tolerance to lethality. We screen 10 CC lines and identify clinical, virologic, and transcriptomic features that distinguish tolerant from lethal outcomes. Tolerance is associated with tightly regulated induction of immune and inflammatory responses shortly following infection, as well as reduced inflammatory macrophages and increased antigen-presenting cells, B-1 cells, and γδ T cells. Lethal disease is characterized by suppressed early gene expression and reduced lymphocytes, followed by uncontrolled inflammatory signaling, leading to death. We apply machine learning to predict outcomes with 99% accuracy in mice using transcriptomic profiles. This signature predicts outcomes in a cohort of EVD patients from western Africa with 75% accuracy, demonstrating potential clinical utility.
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•Host responses produce distinct Ebola virus outcomes in genetically diverse mice•Tolerant outcomes result from early inflammatory responses and sustained regulation•Lethality is linked to early gene suppression and uncontrolled inflammation•Murine transcriptional profiles can be used to predict clinical outcome in humans
Using a panel of genetically diverse mice, Price et al. define host responses linked to Ebola virus tolerance and identify distinct gene expression programs underlying pathogenesis. The application of these profiles predicts disease outcomes in mice and human patients.
Staphylococcus aureus (S. aureus) is an opportunistic pathogen causing diseases ranging from mild skin infections to life threatening conditions, including endocarditis, pneumonia, and sepsis. To ...identify host genes modulating this host-pathogen interaction, we infected 25 Collaborative Cross (CC) mouse strains with methicillin-resistant S. aureus (MRSA) and monitored disease progression for seven days using a surgically implanted telemetry system. CC strains varied widely in their response to intravenous MRSA infection. We identified eight 'susceptible' CC strains with high bacterial load, tissue damage, and reduced survival. Among the surviving strains, six with minimal colonization were classified as 'resistant', while the remaining six tolerated higher organ colonization ('tolerant'). The kidney was the most heavily colonized organ, but liver, spleen and lung colonization were better correlated with reduced survival. Resistant strains had higher pre-infection circulating neutrophils and lower post-infection tissue damage compared to susceptible and tolerant strains. We identified four CC strains with sexual dimorphism: all females survived the study period while all males met our euthanasia criteria earlier. In these CC strains, males had more baseline circulating monocytes and red blood cells. We identified several CC strains that may be useful as new models for endocarditis, myocarditis, pneumonia, and resistance to MRSA infection. Quantitative Trait Locus (QTL) analysis identified two significant loci, on Chromosomes 18 and 3, involved in early susceptibility and late survival after infection. We prioritized Npc1 and Ifi44l genes as the strongest candidates influencing survival using variant analysis and mRNA expression data from kidneys within these intervals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in ...development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
► KRAS-mediated tumorigenesis is inhibited in pancreatic Egfr and Adam17 knockouts ► Pancreatitis-induced tumors are blocked by pancreatic Egfr or Adam17 ablation ► Pancreatic Egfr and Adam17 knockouts resist metaplasia in vitro and in vivo ► KRAS requires EGFR to robustly activate ERK, which is necessary for tumorigenesis
•Ten innovations, six transformative and four incremental were identified.•New methods that are highly species-specific are under development.•Increases are expected in rodent eradication ...feasibility, efficiency and humaneness.•Increases in the frequency and scale of rodent eradications are expected.•Reductions are expected in cost, non-target impacts and stakeholder resistance.
Rodents remain one of the most widespread and damaging invasive alien species on islands globally. The current toolbox for insular rodent eradications is reliant on the application of sufficient anticoagulant toxicant into every potential rodent territory across an island. Despite significant advances in the use of these toxicants over recent decades, numerous situations remain where eradication is challenging or not yet feasible. These include islands with significant human populations, unreceptive stakeholder communities, co-occurrence of livestock and domestic animals, or vulnerability of native species. Developments in diverse branches of science, particularly the medical, pharmaceutical, invertebrate pest control, social science, technology and defense fields offer potential insights into the next generation of tools to eradicate rodents from islands. Horizon scanning is a structured process whereby current problems are assessed against potential future solutions. We undertook such an exercise to identify the most promising technologies, techniques and approaches that might be applied to rodent eradications from islands. We highlight a Rattus-specific toxicant, RNA interference as species-specific toxicants, rodenticide research, crab deterrent in baits, prophylactic treatment for protection of non-target species, transgenic rodents, virus vectored immunocontraception, drones, self-resetting traps and toxicant applicators, detection probability models and improved stakeholder community engagement methods. We present a brief description of each method, and discuss its application to rodent eradication on islands, knowledge gaps, challenges, whether it is incremental or transformative in nature and provide a potential timeline for availability. We outline how a combination of new tools may render previously intractable rodent eradication problems feasible.
Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic ...integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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