The human early-life exposome (HELIX): project rationale and design

Background: Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure–health effect relationships. The “exposome” concept encompasses the totality of exposures from conception onward, complementing the genome. Objectives: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the “early-life exposome.” Here we describe the general design of the project. Methods: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother–child pairs, and biomarkers will be measured in a subset of 1,200 mother–child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure–response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. Conclusions: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome

PM2.5 metal exposures and nocturnal heart rate variability: a panel study of boilermaker construction workers

<p>Abstract</p> <p>Background</p> <p>To better understand the mechanism(s) of particulate matter (PM) associated cardiovascular effects, research priorities include identifying the responsible PM characteristics. Evidence suggests that metals play a role in the cardiotoxicity of fine PM (PM_2.5) and in exposure-related decreases in heart rate variability (HRV). We examined the association between daytime exposure to the metal content of PM_2.5and night HRV in a panel study of boilermaker construction workers exposed to metal-rich welding fumes.</p> <p>Methods</p> <p>Twenty-six male workers were monitored by ambulatory electrocardiogram (ECG) on a workday while exposed to welding fume and a non-workday (baseline). From the ECG, rMSSD (square root of the mean squared differences of successive intervals) was summarized over the night (0:00–7:00). Workday, gravimetric PM_2.5samples were analyzed by x-ray fluorescence to determine metal content. We used linear mixed effects models to assess the associations between night rMSSD and PM_2.5metal exposures both with and without adjustment for total PM_2.5. Matched ECG measurements from the non-workday were used to control for individual cardiac risk factors and models were also adjusted for smoking status. To address collinearity between PM_2.5and metal content, we used a two-step approach that treated the residuals from linear regression models of each metal on PM_2.5as surrogates for the differential effects of metal exposures in models for night rMSSD.</p> <p>Results</p> <p>The median PM_2.5exposure was 650 μg/m³; median metal exposures for iron, manganese, aluminum, copper, zinc, chromium, lead, and nickel ranged from 226 μg/m³to non-detectable. We found inverse linear associations in exposure-response models with increased metal exposures associated with decreased night rMSSD. A statistically significant association for manganese was observed, with a decline of 0.130 msec (95% CI: -0.162, -0.098) in night rMSSD for every 1 μg/m³increase in manganese. However, even after adjusting for individual metals, increases in total PM_2.5exposures were associated with declines in night rMSSD.</p> <p>Conclusion</p> <p>These results support the cardiotoxicity of PM_2.5metal exposures, specifically manganese. However the metal component alone did not account for the observed declines in night HRV. Therefore, results suggest the importance of other PM elemental components.</p

Vegetation fire smoke, indigenous status and cardio-respiratory hospital admissions in Darwin, Australia, 1996–2005: a time-series study

<p>Abstract</p> <p>Background</p> <p>Air pollution in Darwin, Northern Australia, is dominated by smoke from seasonal fires in the surrounding savanna that burn during the dry season from April to November. Our aim was to study the association between particulate matter less than or equal to 10 microns diameter (PM₁₀) and daily emergency hospital admissions for cardio-respiratory diseases for each fire season from 1996 to 2005. We also investigated whether the relationship differed in indigenous Australians; a disadvantaged population sub-group.</p> <p>Methods</p> <p>Daily PM₁₀exposure levels were estimated for the population of the city from visibility data using a previously validated model. We used over-dispersed Poisson generalized linear models with parametric smoothing functions for time and meteorology to examine the association between admissions and PM₁₀up to three days prior. An interaction between indigenous status and PM₁₀was included to examine differences in the impact on indigenous people.</p> <p>Results</p> <p>We found both positive and negative associations and our estimates had wide confidence intervals. There were generally positive associations between respiratory disease and PM₁₀but not with cardiovascular disease. An increase of 10 μg/m³in same-day estimated ambient PM₁₀was associated with a 4.81% (95%CI: -1.04%, 11.01%) increase in total respiratory admissions. When the interaction between indigenous status and PM₁₀was assessed a statistically different association was found between PM₁₀and admissions three days later for respiratory infections of indigenous people (15.02%; 95%CI: 3.73%, 27.54%) than for non-indigenous people (0.67%; 95%CI: -7.55%, 9.61%). There were generally negative estimates for cardiovascular conditions. For non-indigenous admissions the estimated association with total cardiovascular admissions for same day ambient PM₁₀and admissions was -3.43% (95%CI: -9.00%, 2.49%) and the estimate for indigenous admissions was -3.78% (95%CI: -13.4%, 6.91%), although ambient PM₁₀did have positive (non-significant) associations with cardiovascular admissions of indigenous people two and three days later.</p> <p>Conclusion</p> <p>We observed positive associations between vegetation fire smoke and daily hospital admissions for respiratory diseases that were stronger in indigenous people. While this study was limited by the use of estimated rather than measured exposure data, the results are consistent with the currently small evidence base concerning this source of air pollution.</p

The Smell of Age: Perception and Discrimination of Body Odors of Different Ages

Our natural body odor goes through several stages of age-dependent changes in chemical composition as we grow older. Similar changes have been reported for several animal species and are thought to facilitate age discrimination of an individual based on body odors, alone. We sought to determine whether humans are able to discriminate between body odor of humans of different ages. Body odors were sampled from three distinct age groups: Young (20–30 years old), Middle-age (45–55), and Old-age (75–95) individuals. Perceptual ratings and age discrimination performance were assessed in 41 young participants. There were significant differences in ratings of both intensity and pleasantness, where body odors from the Old-age group were rated as less intense and less unpleasant than body odors originating from Young and Middle-age donors. Participants were able to discriminate between age categories, with body odor from Old-age donors mediating the effect also after removing variance explained by intensity differences. Similarly, participants were able to correctly assign age labels to body odors originating from Old-age donors but not to body odors originating from other age groups. This experiment suggests that, akin to other animals, humans are able to discriminate age based on body odor alone and that this effect is mediated mainly by body odors emitted by individuals of old age

Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum

The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2AR) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2AR and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2AR-CB1R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically-modified animal models, together with biochemical and pharmacological approaches, we provide a high resolution expression map and a detailed functional characterization of A2AR-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A2AR-CB1R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington’s disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases

Controlled human exposures to ambient pollutant particles in susceptible populations

Epidemiologic studies have established an association between exposures to air pollution particles and human mortality and morbidity at concentrations of particles currently found in major metropolitan areas. The adverse effects of pollution particles are most prominent in susceptible subjects, including the elderly and patients with cardiopulmonary diseases. Controlled human exposure studies have been used to confirm the causal relationship between pollution particle exposure and adverse health effects. Earlier studies enrolled mostly young healthy subjects and have largely confirmed the capability of particles to cause adverse health effects shown in epidemiological studies. In the last few years, more studies involving susceptible populations have been published. These recent studies in susceptible populations, however, have shown that the adverse responses to particles appear diminished in these susceptible subjects compared to those in healthy subjects. The present paper reviewed and compared control human exposure studies to particles and sought to explain the "unexpected" response to particle exposure in these susceptible populations and make recommendations for future studies. We found that the causes for the discrepant results are likely multifactorial. Factors such as medications, the disease itself, genetic susceptibility, subject selection bias that is intrinsic to many controlled exposure studies and nonspecificity of study endpoints may explain part of the results. Future controlled exposure studies should select endpoints that are more closely related to the pathogenesis of the disease and reflect the severity of particle-induced health effects in the specific populations under investigation. Future studies should also attempt to control for medications and genetic susceptibility. Using a different study design, such as exposing subjects to filtered air and ambient levels of particles, and assessing the improvement in biological endpoints during filtered air exposure, may allow the inclusion of higher risk patients who are likely the main contributors to the increased particle-induced health effects in epidemiological studies

Long-term exposure to low ambient air pollution concentrations and mortality among 28 million people: results from seven large European cohorts within the ELAPSE project.

BACKGROUND: Long-term exposure to ambient air pollution has been associated with premature mortality, but associations at concentrations lower than current annual limit values are uncertain. We analysed associations between low-level air pollution and mortality within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE). METHODS: In this multicentre longitudinal study, we analysed seven population-based cohorts of adults (age ≥30 years) within ELAPSE, from Belgium, Denmark, England, the Netherlands, Norway, Rome (Italy), and Switzerland (enrolled in 2000-11; follow-up until 2011-17). Mortality registries were used to extract the underlying cause of death for deceased individuals. Annual average concentrations of fine particulate matter (PM2·5), nitrogen dioxide (NO2), black carbon, and tropospheric warm-season ozone (O3) from Europe-wide land use regression models at 100 m spatial resolution were assigned to baseline residential addresses. We applied cohort-specific Cox proportional hazard models with adjustment for area-level and individual-level covariates to evaluate associations with non-accidental mortality, as the main outcome, and with cardiovascular, non-malignant respiratory, and lung cancer mortality. Subset analyses of participants living at low pollutant concentrations (as per predefined values) and natural splines were used to investigate the concentration-response function. Cohort-specific effect estimates were pooled in a random-effects meta-analysis. FINDINGS: We analysed 28 153 138 participants contributing 257 859 621 person-years of observation, during which 3 593 741 deaths from non-accidental causes occurred. We found significant positive associations between non-accidental mortality and PM2·5, NO2, and black carbon, with a hazard ratio (HR) of 1·053 (95% CI 1·021-1·085) per 5 μg/m3 increment in PM2·5, 1·044 (1·019-1·069) per 10 μg/m3 NO2, and 1·039 (1·018-1·059) per 0·5 × 10-5/m black carbon. Associations with PM2·5, NO2, and black carbon were slightly weaker for cardiovascular mortality, similar for non-malignant respiratory mortality, and stronger for lung cancer mortality. Warm-season O3 was negatively associated with both non-accidental and cause-specific mortality. Associations were stronger at low concentrations: HRs for non-accidental mortality at concentrations lower than the WHO 2005 air quality guideline values for PM2·5 (10 μg/m3) and NO2 (40 μg/m3) were 1·078 (1·046-1·111) per 5 μg/m3 PM2·5 and 1·049 (1·024-1·075) per 10 μg/m3 NO2. Similarly, the association between black carbon and non-accidental mortality was highest at low concentrations, with a HR of 1·061 (1·032-1·092) for exposure lower than 1·5× 10-5/m, and 1·081 (0·966-1·210) for exposure lower than 1·0× 10-5/m. INTERPRETATION: Long-term exposure to concentrations of PM2·5 and NO2 lower than current annual limit values was associated with non-accidental, cardiovascular, non-malignant respiratory, and lung cancer mortality in seven large European cohorts. Continuing research on the effects of low concentrations of air pollutants is expected to further inform the process of setting air quality standards in Europe and other global regions. FUNDING: Health Effects Institute

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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