Smoking and vaping alter genes related to mechanisms of SARS-CoV-2 susceptibility and severity: a systematic review and meta-analysis.

BACKGROUND: Evidence for the impact of smoking on coronavirus disease 2019 (COVID-19) is contradictory, and there is little research on vaping. Here we provide greater clarity on mechanisms perturbed by tobacco cigarette, electronic cigarette and nicotine exposures that may impact the risks of infection and/or disease severity. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the Ovid and Web of Science databases were searched. Study design and exposure-induced gene expression changes were extracted. Each study was quality assessed and higher confidence scores were assigned to genes consistently changed across multiple studies following the same exposure. These genes were used to explore pathways significantly altered following exposure. RESULTS: 125 studies provided data on 480 genes altered by exposure to tobacco cigarettes, e-cigarettes, nicotine or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Genes involved in both SARS-CoV-2 viral-entry and inflammation were changed following exposure. Pathway analysis revealed that many of those genes with high confidence scores are involved in common cellular processes relating to hyperinflammatory immune responses. CONCLUSION: Exposure to tobacco cigarettes, e-cigarettes or nicotine may therefore impact initial host-pathogen interactions and disease severity. Smokers and vapers of e-cigarettes with nicotine could potentially be at increased risk of SARS-CoV-2 infection, associated cytokine storm, and acute respiratory distress syndrome. However, further research is required, particularly on e-cigarettes, to determine the biological mechanisms involved in perturbation of viral-entry genes and host-pathogen interactions and subsequent responses within the respiratory tract. This will improve our physiological understanding of the impact of smoking and vaping on COVID-19, informing public health advice and providing improved guidance for management of SARS-CoV-2 and other respiratory viruses.

Occupational exposure to particulate matter and staff sickness absence on the London underground.

The London Underground (LU) employs over 19,000 staff, some of whom are exposed to elevated concentrations of particulate matter (PM) within the network. This study quantified the occupational exposure of LU staff to subway PM and investigated the possible association with sickness absence (SA). A job exposure matrix to quantify subway PM2.5 staff exposure was developed by undertaking measurement campaigns across the LU network. The association between exposure and SA was evaluated using zero-inflated mixed-effects negative binomial models. Staff PM2.5 exposure varied by job grade and tasks undertaken. Drivers had the highest exposure over a work shift (mean: 261 µg/m3), but concentrations varied significantly by LU line and time the train spent subway. Office staff work in office buildings separate to the LU network and are unexposed to occupational subway PM2.5. They were found to have lower rates of all-cause and respiratory infection SA compared to non-office staff, those who work across the LU network and are occupational exposed to subway PM2.5. Train drivers on five out of eight lines showed higher rates of all-cause SA, but no dose-response relationship was seen. Only drivers from one line showed higher rates of SAs from respiratory infections (incidence rate ratio: 1.24, 95% confidence interval 1.10-1.39). Lower-grade customer service (CS) staff showed higher rates of all-cause and respiratory infection SA compared to higher grade CS staff. Doctor-certified chronic respiratory and cardiovascular SAs were associated with occupational PM2.5 exposure in CS staff and drivers. While some groups with higher occupational exposure to subway PM reported higher rates of SA, no evidence suggests that subway PM is the main contributing factor to SA. This is the largest subway study on health effects of occupational PM2.5 exposure and may have wider implications for subway workers, contributing to safer working environments.

The potential impacts of micro-and-nano plastics on various organ systems in humans.

Humans are exposed to micro-and-nano plastics (MNPs) through various routes, but the adverse health effects of MNPs on different organ systems are not yet fully understood. This review aims to provide an overview of the potential impacts of MNPs on various organ systems and identify knowledge gaps in current research. The summarized results suggest that exposure to MNPs can lead to health effects through oxidative stress, inflammation, immune dysfunction, altered biochemical and energy metabolism, impaired cell proliferation, disrupted microbial metabolic pathways, abnormal organ development, and carcinogenicity. There is limited human data on the health effects of MNPs, despite evidence from animal and cellular studies. Most of the published research has focused on specific types of MNPs to assess their toxicity, while other types of plastic particles commonly found in the environment remain unstudied. Future studies should investigate MNPs exposure by considering realistic concentrations, dose-dependent effects, individual susceptibility, and confounding factors.

A scoping review: What are the cellular mechanisms that drive the allergic inflammatory response to fungal allergens in the lung epithelium?

Allergic airway disease (AAD) is a collective term for respiratory disorders that can be exacerbated upon exposure to airborne allergens. The contribution of fungal allergens to AAD has become well established over recent years. We conducted a comprehensive review of the literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to better understand the mechanisms involved in the allergic response to fungi in airway epithelia, identify knowledge gaps and make recommendations for future research. The search resulted in 61 studies for final analysis. Despite heterogeneity in the models and methods used, we identified major pathways involved in fungal allergy. These included the activation of protease-activated receptor 2, the EGFR pathway, adenosine triphosphate and purinergic receptor-dependent release of IL33, and oxidative stress, which drove mucin expression and goblet cell metaplasia, Th2 cytokine production, reduced barrier integrity, eosinophil recruitment, and airway hyperresponsiveness. However, there were several knowledge gaps and therefore we recommend future research should focus on the use of more physiologically relevant methods to directly compare key allergenic fungal species, clarify specific mechanisms of fungal allergy, and assess the fungal allergy in disease models. This will inform disease management and future interventions, ultimately reducing the burden of disease.

Children's Environmental Health in Thailand: Past, Present, and Future.

BACKGROUND: There is increasing evidence of a link between environmental pollution and preventable diseases in developing countries, including Thailand. Economic development has generated several types of pollution that can affect population health. While these environmental health effects can be observed throughout life, pregnant women and children represent particularly vulnerable and sensitive groups. METHODS: The published epidemiological literature investigating environmental chemical exposure in Thai children was reviewed, highlighting those that investigated associations between exposure and subsequent health outcomes. RESULTS: The majority of the Thai epidemiological studies on environmental health in children were cross-sectional in design, with some demonstrating associations between exposure and outcome. The three main types of chemical exposure in Thai children were pesticides, heavy metals, and air pollution, which resulted from agricultural activities in countryside areas, industrial zones (both registered and unregistered establishments), mining, and traffic in inner cities. Major health outcomes included detrimental effects on cognitive function and cancer risk. Pesticide exposure was focused on, but not limited to, agricultural areas. The success of the Thai environmental policy to introduce lead-free petrol can be demonstrated by the decline of mean blood lead levels in children, particularly in urban areas. However, unregistered lead-related factories and smelters act as hidden sources. In addition, there is increasing concern, but little acknowledgement, about the effects of chronic arsenic exposure related to mining. Lastly, air pollution remains a problem in both dense city populations due to traffic and in rural areas due to contamination of indoor air and house dust with heavy metals, endotoxins and other allergens. CONCLUSIONS: The increasing number of published articles demonstrates an improved awareness of children's environmental health in Thailand. Chemical hazards, including the improper use of pesticides, environmental contamination with heavy metals (lead and arsenic), and air pollution in inner cities and indoor air, continue to be growing issues.

Perturbation of epigenetic processes by doxorubicin in the mouse testis.

Epigenetic processes play a major role in normal mammalian development, particularly during gametogenesis and early embryogenesis. Thus, perturbation of epigenetic processes in the testis by xenobiotics could have a major impact on testicular function and fertility, and potentially affect the development and health of subsequent generations. There has been substantial research into the epigenetic toxicity of environmental exposures over the last decade. However, few studies have focussed on pharmaceutical drugs, which due to the nature of their use are typically found at much higher concentrations within exposed individuals than environmental chemicals. Here, we investigated genome-wide changes in testicular mRNA transcription, microRNA expression and DNA methylation to assess the contribution of epigenetic mechanisms to the testicular toxicity induced by doxorubicin (DOX) as a representative, widely used and well-characterised anti-cancer drug. We demonstrated that DOX is able to induce transcriptional, microRNA and DNA methylation changes, which perturb pathways involved in stress/cell death and survival and testicular function and lead to germ cell loss and reproductive organ damage. This identified potential novel mechanisms of DOX-induced testicular toxicity for further focussed investigations. Such work is required to fully assess the role of epigenetics in toxicity, determine whether single and/or multigenerational epigenetic toxicity is a real public health concern, and begin to develop and incorporate relevant epigenetic endpoints into regulatory toxicology.

Variation in stability of endogenous reference genes in fallopian tubes and endometrium from healthy and ectopic pregnant women.

RT-qPCR is commonly employed in gene expression studies in ectopic pregnancy. Most use RN18S1, ß-actin or GAPDH as internal controls without validation of their suitability as reference genes. A systematic study of the suitability of endogenous reference genes for gene expression studies in ectopic pregnancy is lacking. The aims of this study were therefore to evaluate the stability of 12 reference genes and suggest those that are stable for use as internal control genes in fallopian tubes and endometrium from ectopic pregnancy and healthy non-pregnant controls. Analysis of the results showed that the genes consistently ranked in the top six by geNorm and NormFinder algorithms, were UBC, GAPDH, CYC1 and EIF4A2 (fallopian tubes) and UBC and ATP5B (endometrium). mRNA expression of NAPE-PLD as a test gene of interest varied between the groups depending on which of the 12 reference genes was used as internal controls. This study demonstrates that arbitrary selection of reference genes for normalisation in RT-qPCR studies in ectopic pregnancy without validation, risk producing inaccurate data and should therefore be discouraged.

Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern?

Recent work has suggested that environmental chemicals, including those contained in cigarette smoke, can have adverse effects on the exposed individuals as well as their future progeny. The mechanisms underlying transmission of environmentally induced phenotypes through the germ line are not well understood. However, a predominant process appears to be the establishment of permanent heritable epigenetic alterations, and a number of studies have implicated microRNAs in such processes. Here, we show that cigarette smoke induces specific differences in the spermatozoal microRNA content of human smokers compared with non-smokers, and that these altered microRNAs appear to predominantly mediate pathways vital for healthy sperm and normal embryo development, particularly cell death and apoptosis. microRNA-mediated perturbation of such pathways may explain how harmful phenotypes can be induced in the progeny of smokers.

Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation.

BACKGROUND: Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: Mice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted. CONCLUSIONS/SIGNIFICANCE: These data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage.