Incidence des leucémies de l'enfant en fonction de la proximité et des caractéristiques générales de diverses sources d'expositions environnementales

Le rôle de l'environnement dans l'étiologie des leucémies aigües de l enfant (LA) fait aujourd'hui l'objet de recherches intenses. Dans ce contexte, le présent travail a pour objectif d étudier la relation entre l incidence de LA et la proximité des centrales nucléaires de production d électricité (CNPE) et des lignes à haute tension (LHT). Avant cette analyse fine, un premier travail a consisté à étudier les variations départementales de l'incidence de LA.Les cas inclus dans ces études sont toutes les LA du Registre National des Hémopathies malignes de l Enfant sur la période étudiée : 1990-2004 pour l étude de l incidence départementale et 2002-2007 pour les études de l association avec les facteurs d exposition environnementale. Dans l approche cas-témoins principalement utilisée pour ces dernières, les 30 000 sujets témoins constitue un échantillon représentatif de la population pédiatrique française sur la période d intérêt. D autre part, la géolocalisation des adresses des sujets et des sources d'exposition permet de définir des critères de proximité en relation avec la probabilité et/ou l'intensité d'exposition aux facteurs d'intérêt. L étude des LA par département n a pas mis en évidence de tendance ni de structure spatiale dans l incidence à ce niveau géographique : que ce soit globalement, par classe d âge, par sexe ou par sous-type de leucémie. Sur la période 2002-2007 contrairement aux périodes précédentes, un quasi-doublement de l incidence des LA à moins de 5 km des CNPE a été mis en évidence, avec une approche cas-témoin comme avec l étude d incidence. Ce résultat n était pas spécifique d une CNPE ou d un type de CNPE et non lié à la cartographie des émissions aériennes de radioactivité par les CNPE. L association trouvée entre l incidence de LA et la proximité aux LHT de plus de 225 kV (<50 m) semble restreinte aux enfants de moins de 5 ans ou n habitant en milieu urbain ; aucune association n a été trouvée avec la proximité aux LHT de moins de 150 kV.The role of the environment in the etiology of childhood acute leukemia (AL) is currently investigated. In this context, the aim of the present work is to study the association between the incidence of AL and the proximity no nuclear power plants (NPP) and to high voltage overhead power lines (HV OLs). At first, the geographical variations of AL have been studied at the Département level.The cases included in the studies are all cases of AL of the French National Registry of Childhood Haemopatopoietic Malignancies on the studied periods: 1990-2004 for the study of incidence on Départements and 2002-2007 for the studies of association between incidence of AL and environmental exposure factors. Concerning those latter studies, a case-control approach has been used. The control sample, representative of the French pediatric population, contains 30,000 subjects and has been drawn by the INSEE. The precise localization of addresses of subjects and of exposure sources in relation with the type of sources is essential to build indicators of exposure reflecting the probability and intensity of exposure. The study of AL by Département has highlighted neither trend nor spatial structure in the incidence at this geographical level globally as well as by age, gender and subtype of leukemia. On 2002-2007, on the contrary of on previous periods, the incidence of AL at less than 5 km from a NPP was nearly twice higher than expected, with the case-control study as well as with the incidence approach. This result was not specific to any age group, NPP, a type of NPP and was not associated with the geographic zoning of gaseous discharges of NPPs. The study of the proximity to HV OLs highlighted an association between the incidence of AL and the close proximity (< 50 m) of lines of more than 225 kV, association which was restricted to children of less than 5 y.o. or living in non-urban areas; but not with the proximity to lines of less than 150 kV.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Genome analyses of the microalga Picochlorum provide insights into the evolution of thermotolerance in the green lineage

While the molecular events involved in cell responses to heat stress have been extensively studied, our understanding of the genetic basis of basal thermotolerance, and particularly its evolution within the green lineage, remains limited. Here, we present the 13.3-Mb haploid genome and transcriptomes of a halotolerant and thermotolerant unicellular green alga, Picochlorum costavermella (Trebouxiophyceae) to investigate the evolution of the genomic basis of thermotolerance. Differential gene expression at high and standard temperatures revealed that more of the gene families containing up-regulated genes at high temperature were recently evolved, and less originated at the ancestor of green plants. Inversely, there was an excess of ancient gene families containing transcriptionally repressed genes. Interestingly, there is a striking overlap between the thermotolerance and halotolerance transcriptional rewiring, as more than one-third of the gene families up-regulated at 35 degrees C were also up-regulated under variable salt concentrations in Picochlorum SE3. Moreover, phylogenetic analysis of the 9,304 protein coding genes revealed 26 genes of horizontally transferred origin in P. costavermella, of which five were differentially expressed at higher temperature. Altogether, these results provide new insights about how the genomic basis of adaptation to halo- and thermotolerance evolved in the green lineage

Variations géographiques de l'incidence des leucémies de l'enfant et association avec l'exposition aux radiations ionisantes d'origine naturelle

Les rayonnements ionisants sont un facteur de risque reconnu pour les leucémies chez l'homme pour des fortes doses d'exposition médicale ou accidentelle. En revanche, l'hypothèse de l'existence d'un risque associé aux rayonnements ionisants à des niveaux d exposition inférieurs, habituellement rencontrés dans l'environnement et de manière continue reste à démontrer. Notre travail propose d évaluer l hypothèse de l existence d une association entre les expositions environnementales aux radiations ionisantes d origine naturelle et le risque de leucémie de l enfant (LA) en utilisant des observations réalisées en France métropolitaine.Les cas de leucémie inclus dans ce travail sont toutes les LA du Registre National des Hémopathies malignes de l Enfant, qui enregistre l'ensemble des cas de moins de 15 ans diagnostiqués en France métropolitaine, sur la période étudiée.Un premier travail a consisté à étudier la répartition spatiale de l incidence des leucémies de l enfant au niveau des 1 916 bassins de vie (BV) définis par l INSEE. Des méthodes de détection de cluster ont été appliquées sur les 7 675 cas de leucémies de l'enfant diagnostiqués entre 1990 et 2006 afin d identifier les zones potentiellement associées à un plus fort risque de leucémies aiguës de l enfant. Cette étude n'a pas mis en évidence d hétérogénéité spatiale des taux d'incidence des LA de l'enfant au cours de la période 1990-2006 au niveau des BV. Cependant, quelques clusters spatiaux ont été identifiés dans des lieux et périodes spécifiques. Bien que les niveaux de significativité de ces clusters ne soutiennent pas fortement l'existence de facteurs de risque localisés, les clusters peuvent montrer un léger impact de facteurs de risque partagés à l'échelle des BV.Pour tester l hypothèse de l existence d une association entre l exposition aux radiations ionisantes d origine naturelle et l incidence des leucémies de l enfant, une étude d incidence basée sur les 9 056 cas de LA de la période 1990-2009 a été réalisée. Cette étude a été complétée par une étude cas-témoins en population fondée sur les 2 763 cas de LA enregistrés sur la période 2002-2007 et un ensemble témoin de 30 000 sujets constituant un échantillon contemporain représentatif de la population pédiatrique française. Dans cette approche, la géolocalisation des adresses des cas et des témoins ainsi que celle des sources d'exposition et leur caractérisation permet de définir les critères de l'intensité d'exposition aux facteurs d'intérêt et de les mettre en relation avec le statut cas vs témoins des sujets.Les données concernant l'exposition à la radioactivité d origine naturelle ont été produites par l'IRSN (Institut de Radioprotection et de Sûreté Nucléaire). Une cartographie du potentiel d exhalation du radon émis par le sol et un échantillon national de 10 843 points de mesures localisés dans des habitations ont permis d estimer l exposition résidentielle au radon au niveau de la commune et du domicile. L exposition aux rayonnements gamma telluriques et cosmiques a été estimée par zone d emploi à partir d un ensemble de 28 000 mesures issues de la campagne nationale IRSN et de mesures réalisées dans approximativement 1 000 sites couvrant la France entière, dans un but de surveillance de la radioactivité ambiante.Notre étude n a pas montré d association entre les leucémies de l enfant et l exposition aux radiations ionisantes d origine naturelle estimée au diagnostic et de façon cumulée pendant l enfance. Elle avait une bonne puissance pour mettre en évidence les risques attendus d après les modèles de risque actuels (UNSCEAR) issus des études sur les risques observés à forte dose. Cette question reste néanmoins suffisamment importante et peu explorée pour mériter des études complémentaires dans d autres pays.Ionizing radiation due to medical or accidental exposure to high doses is an established risk factor for leukemia in humans. However, the evidence of a risk associated with exposure to ionizing radiation at lower levels usually encountered in the environment remains to be demonstrated. Our work aims to evaluate the hypothesis of the existence of an association between natural background ionizing radiation and the risk of childhood leukemia (CL) using observations made in France.Leukemia cases included in this study are all the CL recorded in the National Registry of Childhood Hematological Malignancies, an exhaustive repository of all cases of patients younger than 15 years old in France over the studied period.First step was the study of the spatial distribution of the incidence of CL at the level of the 1,916 Living Zone (LZ) defined by INSEE. Cluster detection methods have been used on 7,675 cases of CL diagnosed during the period 1990-2006 to identify areas potentially associated with a higher risk of acute childhood leukemia. The study did not show any spatial heterogeneity of incidence of CL during the period at LZ level. However, some spatial clusters were highlighted in specific places and times. Although the levels of significance of these clusters do not strongly support the existence of risk factors, localized clusters can show a slight impact of risk factors shared across LZ, including contextual environmental exposures.To test the hypothesis of the existence of an association between environmental exposure to ionizing radiation of natural origin and incidence of childhood leukemia, an incidence study based on 9,056 cases of CL for the period 1990-2009 was conducted. This study was complemented by a record-based cases-controls study based on the 2,763 cases of CL recorded over the 2002-2007 period and a control set of 30,000 subjects constituting a representative sample of the contemporary French pediatric population. In this approach, localizations of cases and controls and exposure identifications were geocoded and compared to the status cases vs control population.Data of exposure to natural background radiation were produced by the IRSN (Institute for Radiological Protection and Nuclear Safety). Mapping of the potential radon exhalation emitted by the ground and a national sampling of 10,843 measurement points located in dwellings were used to estimate residential exposure to radon at a level of granularity of cities and houses. Exposure to terrestrial gamma and cosmic rays was estimated by zone d emploi based on a set of more than 28,000 environmental measurements in approximately 1,000 sites covering whole France, and by the IRSN national campaign data. Our study did not show any association of childhood leukemia with exposures to natural background radiation estimated nor at diagnosis nor cumulatively during childhood. However it had a good power to highlight the risks expected from current models of risk (UNSCEAR) built from studies on the observed high doses risks. If this work does not support the hypothesis that there is an association between exposure to ionizing radiation from natural sources observed and the incidence of childhood leukemia which may be directly observable at the epidemiologic level, this question remains important enough and not investigated enough to merit further complementary studies in countries where it has not been investigated.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

The medium-size noncoding RNA transcriptome of Ostreococcus tauri, the smallest living eukaryote, reveals a large family of small nucleolar RNAs displaying multiple genomic expression strategies

International audienceAbstract The small nucleolar RNAs (snoRNAs), essential for ribosome biogenesis, constitute a major family of medium-size noncoding RNAs (mncRNAs) in all eukaryotes. We present here, for the first time in a marine unicellular alga, the characterization of the snoRNAs family in Ostreococcus tauri, the smallest photosynthetic eukaryote. Using a transcriptomic approach, we identified 131 O. tauri snoRNAs (Ot–snoRNA) distributed in three classes: the C/D snoRNAs, the H/ACA snoRNAs and the MRP RNA. Their genomic organization revealed a unique combination of both the intronic organization of animals and the polycistronic organization of plants. Remarkably, clustered genes produced Ot–snoRNAs with unusual structures never previously described in plants. Their abundances, based on quantification of reads and northern blots, showed extreme differences in Ot–snoRNA accumulation, mainly determined by their differential stability. Most of these Ot–snoRNAs were predicted to target rRNAs or snRNAs. Seventeen others were orphan Ot–snoRNAs that would not target rRNA. These were specific to O. tauri or Mamiellophyceae and could have functions unrelated to ribosome biogenesis. Overall, these data reveal an ‘evolutionary response’ adapted to the extreme compactness of the O. tauri genome that accommodates the essential Ot–snoRNAs, developing multiple strategies to optimize their coordinated expression with a minimal cost on regulatory circuits

A Viral Immunity Chromosome in the Marine Picoeukaryote, <i>Ostreococcus tauri</i>

<div><p>Micro-algae of the genus <i>Ostreococcus</i> and related species of the order Mamiellales are globally distributed in the photic zone of world's oceans where they contribute to fixation of atmospheric carbon and production of oxygen, besides providing a primary source of nutrition in the food web. Their tiny size, simple cells, ease of culture, compact genomes and susceptibility to the most abundant large DNA viruses in the sea render them attractive as models for integrative marine biology. In culture, spontaneous resistance to viruses occurs frequently. Here, we show that virus-producing resistant cell lines arise in many independent cell lines during lytic infections, but over two years, more and more of these lines stop producing viruses. We observed sweeping over-expression of all genes in more than half of chromosome 19 in resistant lines, and karyotypic analyses showed physical rearrangements of this chromosome. Chromosome 19 has an unusual genetic structure whose equivalent is found in all of the sequenced genomes in this ecologically important group of green algae.</p></div

Pulsed-field gel electrophoresis (PFGE) analysis of susceptible and resistant lines ethidium bromide stained (top) and corresponding hybridization (bottom) using a probe for a gene on chromosome 19.

<p>Chromosome number and size are indicated on the left. Symbols on the upper gel images show, at positions observed by the ethidium-bromide fluorescence: <b>−</b> : absence of a band that was present in controls, <b>+</b>: presence of a band that was not present in controls, <b>v</b>: presence of a band at the expected size of the OtV5 genome. To aid the comparison, symbols from the upper images of ethidium-stained gels are shown at the same positions on the bottom Southern blot autoradiograph images. Note that since the probe hybridizes to a specific part of chromosome 19, occasionally the band of differing mobility does not correspond to the band identified by radioactive labelling, witnessing fragmentation of chromosome 19 after deletions, insertions, or translocations that may have occurred.</p

Experimental strategy for production of <i>Ostreococcus tauri</i> clonal lines susceptible or resistant to OtV5.

<p>A single colony of <i>O</i>. <i>tauri</i> was used to produce two 1-litre cultures of <i>O</i>. <i>tauri</i> cells, one used to prepare DNA for genome re-sequencing and to produce 46 independent clonal lines and another that was lysed by clonal OtV5. The viral lysate was subsequently used to inoculate 38 small flasks. Fresh medium (small blue flasks) was added to each lysate or control flask, and after ~1 week OtV5-resistant cells grew. A single colony from all lines was randomly chosen after plating and maintained in liquid culture for transcriptome sequencing and further analyses.</p

Proportion of resistant producer (RP) and resistant non-producer (RNP) lines over the course of the study.

<p>Percentage of RP and RNP in resistant lines on the ordinate and date when virus production test was performed on the abscissa.</p

Differential gene expression in OtV5-resistant compared to susceptible control <i>O</i>. <i>tauri</i>.

<p>Up (orange) and Down (purple) regulated genes in virus resistant lines. <b>(A)</b> Counts of differentially transcribed genes per chromosome. <b>(B)</b> Plot of the log₂ fold change values of differentially transcribed genes per chromosome. <b>(C)</b> Predicted glycosyltransferase gene counts per chromosome based on matches to InterPro domains and families associated with glycosyltransferases. Genes with no difference in regulation are shown in grey. <b>(D)</b> Counts of differentially transcribed genes grouped according to functional categories shown on the ordinate. Labels describe the genes in each category (full gene descriptions in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005965#ppat.1005965.s008" target="_blank">S2</a> and <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005965#ppat.1005965.s010" target="_blank">S4</a> Tables). Genes located on the large inverted duplicated region on chromosome 19 were only counted once.</p

Virus production in two <i>O</i>. <i>tauri</i> resistant strains.

<p>Very few cells (less than 0.5%) show visible viral particles in their cytoplasm. Morphology of lysing R^P cells is similar to that of susceptible cells. <b>(A)</b> Most of the cells of <i>O</i>. <i>tauri</i> R^P2 strain without visible viral particles. (<b>B)</b> Dividing <i>O</i>. <i>tauri</i> R^P2 strain cell. <b>(C)</b> Dividing <i>O</i>. <i>tauri</i> R^P3 strain cell with visible intracellular viral particles (vi). <b>(D)</b> <i>O</i>. <i>tauri</i> R^P3 strain cell with visible intracellular viral particles (vi). <b>E</b>. Lysis of an <i>O</i>. <i>tauri</i> R^P3 strain cell. <b>(F)</b> Lysis of an <i>O</i>. <i>tauri</i> R^P2 strain with visible viral particles (vi). The scale bar is 500 nm long.</p