Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erbalpha pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erbalpha target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erbalpha pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.

An earth-system prediction initiative for the twenty-first century

The necessity and benefits for establishing the international Earth-system Prediction Initiative (EPI) are discussed by scientists associated with the World Meteorological Organization (WMO) World Weather Research Programme (WWRP), World Climate Research Programme (WCRP), International Geosphere–Biosphere Programme (IGBP), Global Climate Observing System (GCOS), and natural-hazards and socioeconomic communities. The proposed initiative will provide research and services to accelerate advances in weather, climate, and Earth system prediction and the use of this information by global societies. It will build upon the WMO, the Group on Earth Observations (GEO), the Global Earth Observation System of Systems (GEOSS) and the International Council for Science (ICSU) to coordinate the effort across the weather, climate, Earth system, natural-hazards, and socioeconomic disciplines. It will require (i) advanced high-performance computing facilities, supporting a worldwide network of research and operational modeling centers, and early warning systems; (ii) science, technology, and education projects to enhance knowledge, awareness, and utilization of weather, climate, environmental, and socioeconomic information; (iii) investments in maintaining existing and developing new observational capabilities; and (iv) infrastructure to transition achievements into operational products and services.

Bollène-2002 experiment: radar quantitative precipitation estimation in the Cévennes–Vivarais region, France

The Bollène-2002 Experiment was aimed at developing the use of a radar volume-scanning strategy for conducting radar rainfall estimations in the mountainous regions of France. A developmental radar processing system, called Traitements Régionalisés et Adaptatifs de Données Radar pour l’Hydrologie (Regionalized and Adaptive Radar Data Processing for Hydrological Applications), has been built and several algorithms were specifically produced as part of this project. These algorithms include 1) a clutter identification technique based on the pulse-to-pulse variability of reflectivity Z for noncoherent radar, 2) a coupled procedure for determining a rain partition between convective and widespread rainfall R and the associated normalized vertical profiles of reflectivity, and 3) a method for calculating reflectivity at ground level from reflectivities measured aloft. Several radar processing strategies, including nonadaptive, time-adaptive, and space–time-adaptive variants, have been implemented to assess the performance of these new algorithms. Reference rainfall data were derived from a careful analysis of rain gauge datasets furnished by the Cévennes–Vivarais Mediterranean Hydrometeorological Observatory. The assessment criteria for five intense and long-lasting Mediterranean rain events have proven that good quantitative precipitation estimates can be obtained from radar data alone within 100-km range by using well-sited, well-maintained radar systems and sophisticated, physically based data-processing systems. The basic requirements entail performing accurate electronic calibration and stability verification, determining the radar detection domain, achieving efficient clutter elimination, and capturing the vertical structure(s) of reflectivity for the target event. Radar performance was shown to depend on type of rainfall, with better results obtained with deep convective rain systems (Nash coefficients of roughly 0.90 for point radar–rain gauge comparisons at the event time step), as opposed to shallow convective and frontal rain systems (Nash coefficients in the 0.6–0.8 range). In comparison with time-adaptive strategies, the space–time-adaptive strategy yields a very significant reduction in the radar–rain gauge bias while the level of scatter remains basically unchanged. Because the Z–R relationships have not been optimized in this study, results are attributed to an improved processing of spatial variations in the vertical profile of reflectivity. The two main recommendations for future work consist of adapting the rain separation method for radar network operations and documenting Z–R relationships conditional on rainfall type.

The catastrophic flash-flood event of 8–9 September 2002 in the Gard region, France: a first case study for the Cévennes–Vivarais Mediterranean Hydrometeorological Observatory

The Cévennes–Vivarais Mediterranean Hydrometeorological Observatory (OHM-CV) is a research initiative aimed at improving the understanding and modeling of the Mediterranean intense rain events that frequently result in devastating flash floods in southern France. A primary objective is to bring together the skills of meteorologists and hydrologists, modelers and instrumentalists, researchers and practitioners, to cope with these rather unpredictable events. In line with previously published flash-flood monographs, the present paper aims at documenting the 8–9 September 2002 catastrophic event, which resulted in 24 casualties and an economic damage evaluated at 1.2 billion euros (i.e., about 1 billion U.S. dollars) in the Gard region, France. A description of the synoptic meteorological situation is first given and shows that no particular precursor indicated the imminence of such an extreme event. Then, radar and rain gauge analyses are used to assess the magnitude of the rain event, which was particularly remarkable for its spatial extent with rain amounts greater than 200 mm in 24 h over 5500 km2. The maximum values of 600–700 mm observed locally are among the highest daily records in the region. The preliminary results of the postevent hydrological investigation show that the hydrologic response of the upstream watersheds of the Gard and Vidourle Rivers is consistent with the marked space–time structure of the rain event. It is noteworthy that peak specific discharges were very high over most of the affected areas (5–10 m3 s−1 km−2) and reached locally extraordinary values of more than 20 m3 s−1 km−2. A preliminary analysis indicates contrasting hydrological behaviors that seem to be related to geomorphological factors, notably the influence of karst in part of the region. An overview of the ongoing meteorological and hydrological research projects devoted to this case study within the OHM-CV is finally presented.

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

Filamin A (FlnA) cross-links actin filaments and connects the Von Willebrand factor receptor GPIb-IX-V to the underlying cytoskeleton in platelets. Because FlnA deficiency is embryonic lethal, mice lacking FlnA in platelets were generated by breeding FlnA(loxP/loxP) females with GATA1-Cre males. FlnA(loxP/y) GATA1-Cre males have a macrothrombocytopenia and increased tail bleeding times. FlnA-null platelets have decreased expression and altered surface distribution of GPIbalpha because they lack the normal cytoskeletal linkage of GPIbalpha to underlying actin filaments. This results in approximately 70% less platelet coverage on collagen-coated surfaces at shear rates of 1,500/s, compared with wild-type platelets. Unexpectedly, however, immunoreceptor tyrosine-based activation motif (ITAM)- and ITAM-like-mediated signals are severely compromised in FlnA-null platelets. FlnA-null platelets fail to spread and have decreased alpha-granule secretion, integrin alphaIIbbeta3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C-gamma2, in response to stimulation through the collagen receptor GPVI and the C-type lectin-like receptor 2. This signaling defect was traced to the loss of a novel FlnA-Syk interaction, as Syk binds to FlnA at immunoglobulin-like repeat 5. Our findings reveal that the interaction between FlnA and Syk regulates ITAM- and ITAM-like-containing receptor signaling and platelet function.

The gut microbiota: a major player in the toxicity of environmental pollutants?

Exposure to environmental chemicals has been linked to various health disorders, including obesity, type 2 diabetes, cancer and dysregulation of the immune and reproductive systems, whereas the gastrointestinal microbiota critically contributes to a variety of host metabolic and immune functions. We aimed to evaluate the bidirectional relationship between gut bacteria and environmental pollutants and to assess the toxicological relevance of the bacteria–xenobiotic interplay for the host. We examined studies using isolated bacteria, faecal or caecal suspensions—germ-free or antibiotic-treated animals—as well as animals reassociated with a microbiota exposed to environmental chemicals. The literature indicates that gut microbes have an extensive capacity to metabolise environmental chemicals that can be classified in five core enzymatic families (azoreductases, nitroreductases, β-glucuronidases, sulfatases and β-lyases) unequivocally involved in the metabolism of >30 environmental contaminants. There is clear evidence that bacteria-dependent metabolism of pollutants modulates the toxicity for the host. Conversely, environmental contaminants from various chemical families have been shown to alter the composition and/or the metabolic activity of the gastrointestinal bacteria, which may be an important factor contributing to shape an individual’s microbiotype. The physiological consequences of these alterations have not been studied in details but pollutant-induced alterations of the gut bacteria are likely to contribute to their toxicity. In conclusion, there is a body of evidence suggesting that gut microbiota are a major, yet underestimated element that must be considered to fully evaluate the toxicity of environmental contaminants.