Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease\u2014secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide\u2014and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future

Matching dust emission structures and magnetic field in high-latitude cloud L1642 : comparing Herschel and Planck maps

The nearby cloud L1642 is one of only two known very high latitude (b| > 30 deg) clouds actively forming stars. It is a rare example of star formation in isolated conditions, and can reveal important details of star formation in general, e.g. of the effect of magnetic fields. We compareHerschel dust emission structures and magnetic field orientation revealed byPlanck polarization maps in L1642. The high-resolution (similar to 20 arcsec)Herschel data reveal a complex structure including a dense, compressed central clump, and low-density striations. ThePlanck polarization data (at 10 arcmin resolution) reveal an ordered magnetic field pervading the cloud and aligned with the surrounding striations. There is a complex interplay between the cloud structure and large-scale magnetic field. This suggests that the magnetic field is closely linked to the formation and evolution of the cloud. CO rotational emission confirms that the striations are connected with the main clumps and likely to contain material either falling into or flowing out of the clumps. There is a clear transition from aligned to perpendicular structures approximately at a column density ofN(H) = 1.6 x 10(21) cm(-2). Comparing theHerschel maps with thePlanck polarization maps shows the close connection between the magnetic field and cloud structure even in the finest details of the cloud.Peer reviewe

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia

In 2013, EFSA published a literature review on epidemiological studies linking exposure to pesticides and human health outcome. As a follow up, the EFSA Panel on Plant Protection Products and their residues (PPR Panel) was requested to investigate the plausible involvement of pesticide exposure as a risk factor for Parkinson's disease (PD) and childhood leukaemia (CHL). A systematic literature review on PD and CHL and mode of actions for pesticides was published by EFSA in 2016 and used as background documentation. The Panel used the Adverse Outcome Pathway (AOP) conceptual framework to define the biological plausibility in relation to epidemiological studies by means of identification of specific symptoms of the diseases as AO. The AOP combines multiple information and provides knowledge of biological pathways, highlights species differences and similarities, identifies research needs and supports regulatory decisions. In this context, the AOP approach could help in organising the available experimental knowledge to assess biological plausibility by describing the link between a molecular initiating event (MIE) and the AO through a series of biologically plausible and essential key events (KEs). As the AOP is chemically agnostic, tool chemical compounds were selected to empirically support the response and temporal concordance of the key event relationships (KERs). Three qualitative and one putative AOP were developed by the Panel using the results obtained. The Panel supports the use of the AOP framework to scientifically and transparently explore the biological plausibility of the association between pesticide exposure and human health outcomes, identify data gaps, define a tailored testing strategy and suggests an AOP’s informed Integrated Approach for Testing and Assessment (IATA)

Planck 2015 results. XXVIII. The Planck Catalogue of Galactic Cold Clumps

We present the Planck Catalogue of Galactic Cold Clumps (PGCC), an all-sky catalogue of Galactic cold clump candidates detected by Planck. This catalogue is the full version of the Early Cold Core (ECC) catalogue, which was made available in 2011 with the Early Release Compact Source Catalogue (ERCSC) and which contained 915 high signal-to-noise sources. It is based on the Planck 48-month mission data that are currently being released to the astronomical community. The PGCC catalogue is an observational catalogue consisting exclusively of Galactic cold sources. The three highest Planck bands (857, 454, and 353 GHz) have been combined with IRAS data at 3 THz to perform a multi-frequency detection of sources colder than their local environment. After rejection of possible extragalactic contaminants, the PGCC catalogue contains 13188 Galactic sources spread across the whole sky, i.e., from the Galactic plane to high latitudes, following the spatial distribution of the main molecular cloud complexes. The median temperature of PGCC sources lies between 13 and 14.5 K, depending on the quality of the flux density measurements, with a temperature ranging from 5.8 to 20 K after removing the sources with the top 1% highest temperature estimates. Using seven independent methods, reliable distance estimates have been obtained for 5574 sources, which allows us to derive their physical properties such as their mass, physical size, mean density, and luminosity.The PGCC sources are located mainly in the solar neighbourhood, but also up to a distance of 10.5 kpc in the direction of the Galactic centre, and range from low-mass cores to large molecular clouds. Because of this diversity and because the PGCC catalogue contains sources in very different environments, the catalogue is useful for investigating the evolution from molecular clouds to cores. Finally, it also includes 54 additional sources located in the Small and Large Magellanic Clouds

Correlation of gas dynamics and dust in the evolved filament G82.65-02.00

Context. The combination of line and continuum observations can provide vital insight into the formation and fragmentation of filaments and the initial conditions for star formation. We have carried out line observations to map the kinematics of an evolved, actively star forming filament G82.65-2.00. The filament was first identified from the Planck data as a region of particularly cold dust emission and was mapped at 100-500 mu m as a part of the Herschel key program Galactic Cold Cores. The Herschel observations cover the central part of the filament, corresponding to a filament length of similar to 12 pc at the assumed distance of 620 pc.& para;& para;Aims. CO observations show that the filament has an intriguing velocity field with several velocity components around the filament. In this paper, we study the velocity structure in detail, to quantify possible mass accretion rate onto the filament, and study the masses of the cold cores located in the filament.& para;& para;Methods. We have carried out line observations of several molecules, including CO isotopologues, HCO+, HCN, and CS with the Osaka 1.85 m telescope and the Nobeyama 45 m telescope. The spectral line data are used to derive velocity and column density information.& para;& para;Results. The observations reveal several velocity components in the field, with strongest line emission concentrated to velocity range similar to[3,5] km s(-1). The column density of molecular hydrogen along the filament varies from 1.0 to 2.3 x 10(22) cm(2). We have examined six cold clumps from the central part of the filament. The clumps have masses in the range 10-20 M circle dot (similar to 70 M circle dot in total) and are close to or above the virial mass. Furthermore, the main filament is heavily fragmented and most of the substructures have a mass lower than or close to the virial mass, suggesting that the filament is dispersing as a whole. Position-velocity maps of (CO)-C-12 and (CO)-C-13 lines indicate that at least one of the striations is kinematically connected to two of the clumps, potentially indicating mass accretion from the striation onto the main filament. We tentatively estimate the accretion rate to be M = 2.23 x 10(-6) M circle dot/yr.& para;& para;Conclusions. Our line observations have revealed two or possibly three velocity components connected to the filament G82.65-2.00 and putative signs of mass accretion onto the filament. The line observations combined with Herschel and WISE maps suggest a possible collision between two cloud components.Peer reviewe

Planck 2015 results. I. Overview of products and scientific results

The European Space Agency’s Planck satellite, which is dedicated to studying the early Universe and its subsequent evolution, was launched on 14 May 2009. It scanned the microwave and submillimetre sky continuously between 12 August 2009 and 23 October 2013. In February 2015, ESA and the Planck Collaboration released the second set of cosmology products based ondata from the entire Planck mission, including both temperature and polarization, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper gives an overview of the main characteristics of the data and the data products in the release, as well as the associated cosmological and astrophysical science results and papers. The data products include maps of the cosmic microwave background (CMB), the thermal Sunyaev-Zeldovich effect, diffuse foregrounds in temperature and polarization, catalogues of compact Galactic and extragalactic sources (including separate catalogues of Sunyaev-Zeldovich clusters and Galactic cold clumps), and extensive simulations of signals and noise used in assessing uncertainties and the performance of the analysis methods. The likelihood code used to assess cosmological models against the Planck data is described, along with a CMB lensing likelihood. Scientific results include cosmological parameters derived from CMB power spectra, gravitational lensing, and cluster counts, as well as constraints on inflation, non-Gaussianity, primordial magnetic fields, dark energy, and modified gravity, and new results on low-frequency Galactic foregrounds

In vitro evaluation of baseline and induced DNA damage in human sperm exposed to benzo[a]pyrene or its metabolite benzo[a]pyrene-7,8-diol-9,10-epoxide, using the comet assay

Exposure to genotoxins may compromise DNA integrity in male reproductive cells, putting future progeny at risk for developmental defects and diseases. To study the usefulness of sperm DNA damage as a biomarker for genotoxic exposure, we have investigated cellular and molecular changes induced by benzo[a]pyrene (B[a]P) in human sperm in vitro, and results have been compared for smokers and non-smokers. Sperm DNA obtained from five smokers was indeed more fragmented than sperm of six non-smokers (mean % Tail DNA 26.5 and 48.8, respectively), as assessed by the alkaline comet assay (P < 0.05). B[a]P-related DNA adducts were detected at increased levels in smokers as determined by immunostaining. Direct exposure of mature sperm cells to B[a]P (10 or 25 μM) caused moderate increases in DNA fragmentation which was independent of addition of human liver S9 mix for enzymatic activation of B[a]P, suggesting some unknown metabolism of B[a]P in ejaculates. In vitro exposure of samples to various doses of B[a]P (with or without S9) did not reveal any significant differences in sensitivity to DNA fragmentation between smokers and non-smokers. Incubations with the proximate metabolite benzo[a]pyrene-r-7,t-8-dihydrodiol-t9,10-epoxide (BPDE) produced DNA fragmentation in a dose-dependent manner (20 or 50 μM), but only when formamidopyrimidine DNA glycosylase treatment was included in the comet assay. These levels of DNA fragmentation were, however, low in relation to very high amounts of BPDE–DNA adducts as measured with 32P postlabelling. We conclude that sperm DNA damage may be useful as a biomarker of direct exposure of sperm using the comet assay adapted to sperm, and as such the method may be applicable to cohort studies. Although the sensitivity is relatively low, DNA damage induced in earlier stages of spermatogenesis may be detected with higher efficiencies

Changes in hemostasis parameters in nonfatal methicillin-sensitive Staphylococcus aureus bacteremia complicated by endocarditis or thromboembolic events : a prospective gender-age adjusted cohort study

The aim of this study was to examine the changes in hemostasis parameters in endocarditis and thromboembolic events in nonfatal methicillin-sensitive Staphylococcus aureus bacteremia (MS-SAB) - a topic not evaluated previously. In total, 155 patients were recruited and were categorized according to the presence of endocarditis or thromboembolic events with gender-age adjusted controls. Patients who deceased within 90 days or patients not chosen as controls were excluded. SAB management was supervised by an infectious disease specialist. Patients with endocarditis (N = 21), compared to controls (N = 21), presented lower antithrombin III at day 4 (p <0.05), elevated antithrombin III at day 90 (p <0.01), prolonged activated partial thromboplastin time at days 4 and 10 (p <0.05), and enhanced thrombin-antithrombin complex at day 4 (p <0.01). Thromboembolic events (N = 8), compared to controls (N = 34), significantly increased thrombin-antithrombin complex at day 4 (p <0.05). In receiver operating characteristic analysis, the changes in these hemostasis parameters at day 4 predicted endocarditis and thromboembolic events (p <0.05). No differences in hemoglobin, thrombocyte, prothrombin fragment, thrombin time, factor VIII, D-dimer or fibrinogen levels were observed between cases and controls. The results suggest that nonfatal MS-SAB patients present marginal hemostasis parameter changes that, however, may have predictability for endocarditis or thromboembolic events. Larger studies are needed to further assess the connection of hemostasis to complications in SAB.Peer reviewe