Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that ncRNA expression profiling data requires careful evaluation to determine the utility of specific ncRNAs as biomarkers. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify possibly suitable ncRNAs and areas of toxicology where ncRNA expression profiling could address prevailing scientific deficiencies. (2) Develop consensus on how to conduct ncRNA expression profiling in a toxicological context. (3) Conduct experimental projects, including, e.g., rat (90-day) oral toxicity studies, to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. Thereby, physiological ncRNA expression profiles should be established, including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be dose-dependently linked with substance-induced apical effects. Applying a holistic approach, knowledge on ncRNAs, 'omics and epigenetics technologies should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context

Air quality and mental health: evidence, challenges and future directions

Background: Poor air quality is associated with poor health. Little attention is given to the complex array of environmental exposures and air pollutants that affect mental health during the life course. Aims: We gather interdisciplinary expertise and knowledge across the air pollution and mental health fields. We seek to propose future research priorities and how to address them. Method: Through a rapid narrative review, we summarise the key scientific findings, knowledge gaps and methodological challenges. Results: There is emerging evidence of associations between poor air quality, both indoors and outdoors, and poor mental health more generally, as well as specific mental disorders. Furthermore, pre-existing long-term conditions appear to deteriorate, requiring more healthcare. Evidence of critical periods for exposure among children and adolescents highlights the need for more longitudinal data as the basis of early preventive actions and policies. Particulate matter, including bioaerosols, are implicated, but form part of a complex exposome influenced by geography, deprivation, socioeconomic conditions and biological and individual vulnerabilities. Critical knowledge gaps need to be addressed to design interventions for mitigation and prevention, reflecting ever-changing sources of air pollution. The evidence base can inform and motivate multi-sector and interdisciplinary efforts of researchers, practitioners, policy makers, industry, community groups and campaigners to take informed action. Conclusions: There are knowledge gaps and a need for more research, for example, around bioaerosols exposure, indoor and outdoor pollution, urban design and impact on mental health over the life course.Natural Environment Research Council (NERC): NE/V002171/1; Engineering and Physical Sciences Research Council (EPSRC): EP/V052462/1; EP/W001411/1; EP/T003189/

Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies

Curcuminoid Binding to Embryonal Carcinoma Cells: Reductive Metabolism, Induction of Apoptosis, Senescence, and Inhibition of Cell Proliferation

Curcumin preparations typically contain a mixture of polyphenols, collectively referred to as curcuminoids. In addition to the primary component curcumin, they also contain smaller amounts of the co-extracted derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids can be differentially solubilized in serum, which allows for the systematic analysis of concentration-dependent cellular binding, biological effects, and metabolism. Technical grade curcumin was solubilized in fetal calf serum by two alternative methods yielding saturated preparations containing either predominantly curcumin (60%) or bisdemethoxycurcumin (55%). Continual exposure of NT2/D1 cells for 4–6 days to either preparation in cell culture media reduced cell division (1–5 µM), induced senescence (6–7 µM) or comprehensive cell death (8–10 µM) in a concentration-dependent manner. Some of these effects could also be elicited in cells transiently exposed to higher concentrations of curcuminoids (47 µM) for 0.5–4 h. Curcuminoids induced apoptosis by generalized activation of caspases but without nucleosomal fragmentation. The equilibrium binding of serum-solubilized curcuminoids to NT2/D1 cells incubated with increasing amounts of curcuminoid-saturated serum occurred with apparent overall dissociation constants in the 6–10 µM range. However, the presence of excess free serum decreased cellular binding in a hyperbolic manner. Cellular binding was overwhelmingly associated with membrane fractions and bound curcuminoids were metabolized in NT2/D1 cells via a previously unidentified reduction pathway. Both the binding affinities for curcuminoids and their reductive metabolic pathways varied in other cell lines. These results suggest that curcuminoids interact with cellular binding sites, thereby activating signal transduction pathways that initiate a variety of biological responses. The dose-dependent effects of these responses further imply that distinct cellular pathways are sequentially activated and that this activation is dependent on the affinity of curcuminoids for the respective binding sites. Defined serum-solubilized curcuminoids used in cell culture media are thus suitable for further investigating the differential activation of signal transduction pathways

Ambient air pollution and thrombosis

Abstract Air pollution is a growing public health concern of global significance. Acute and chronic exposure is known to impair cardiovascular function, exacerbate disease and increase cardiovascular mortality. Several plausible biological mechanisms have been proposed for these associations, however, at present, the pathways are incomplete. A seminal review by the American Heart Association (2010) concluded that the thrombotic effects of particulate air pollution likely contributed to their effects on cardiovascular mortality and morbidity. The aim of the current review is to appraise the newly accumulated scientific evidence (2009–2016) on contribution of haemostasis and thrombosis towards cardiovascular disease induced by exposure to both particulate and gaseous pollutants. Seventy four publications were reviewed in-depth. The weight of evidence suggests that acute exposure to fine particulate matter (PM2.5) induces a shift in the haemostatic balance towards a pro-thrombotic/pro-coagulative state. Insufficient data was available to ascertain if a similar relationship exists for gaseous pollutants, and very few studies have addressed long-term exposure to ambient air pollution. Platelet activation, oxidative stress, interplay between interleukin-6 and tissue factor, all appear to be potentially important mechanisms in pollution-mediated thrombosis, together with an emerging role for circulating microvesicles and epigenetic changes. Overall, the recent literature supports, and arguably strengthens, the contention that air pollution contributes to cardiovascular morbidity by promoting haemostasis. The volume and diversity of the evidence highlights the complexity of the pathophysiologic mechanisms by which air pollution promotes thrombosis; multiple pathways are plausible and it is most likely they act in concert. Future research should address the role gaseous pollutants play in the cardiovascular effects of air pollution mixture and direct comparison of potentially susceptible groups to healthy individuals

Bioaerosol exposure from composting facilities and health outcomes in workers and in the community: a systematic review update

Background Rapid population growth and urbanisation around the world has led to increasing waste generation rates. Composting of organic waste in large-scale facilities is part of a growing trend in the UK, and elsewhere, to better manage and re-use the organic waste. However, composting inevitably generates bioaerosols, which have been associated with human health effects. In 2015, we reported that there was some, albeit limited, qualitative evidence linking bioaerosol emissions from composting facilities to poor respiratory health in nearby residents. However, the limited evidence precluded any quantitative assessment. Since then, the number of operational industrial-scale composting facilities in England has increased by 9% - nearly twice the growth from 2012-2014. At the same time, rapid urbanisation has led to expansion of city borders with more people living near large composting facilities and exposed to bioaerosol pollution. It is essential that regulatory authorities have access to the most up to date and accurate information. Objective In this update of a systematic review published in 2015, we review and summarise the evidence from more recent studies that have assessed bioaerosol exposures within and near composting facilities and their associated health effects in both community and occupational health settings. Specifically, we wanted to find out if new evidence has emerged since the previous review to strengthen and confirm its conclusions. Material and methods Two electronic databases (Medline and Embase) and bibliographies were searched for studies reporting on health outcomes and/or exposure to bioaerosols from composting facilities published between 1 January 2014 and 15 June 2018. Identification of relevant articles and data extraction was undertaken and studies were assessed for risk of bias. Results 23 studies met the inclusion criteria (15 exposure studies, 4 health studies, 4 health and exposure studies (one of which used an exposure proxy)). The majority of studies were conducted in occupational settings, and over short time periods. Some progress has been been made in the characterisation of bioaerosol emissions from these composting facilities, with the application of molecular-based methods. Whilst the latest health studies do not rely solely on subjective self-reported measures of health status but include more objective health measures, these studies were almost exclusively carried out in compost workers and were characterised by profound methodological limitations. Only one community health study was identified and used a proxy measure of bioaerosol exposure. Conclusions Although this review identified an additional 23 studies since the earlier review, the conclusions remain largely unchanged. Given the absence of any consistent evidence on the toxicity of bioaerosols from composting facilities, there is insufficient evidence to provide a quantitative comment on the risk to nearby residents from exposure to compost bioaerosols. To improve risk assessment and to best advise on risk management, it is important to ensure that the research recommendations outlined in this review are addressed