Policy relevant results from an expert elicitation on the health risks of phthalates

<p>Abstract</p> <p>Background</p> <p>The EU 6th Framework Program (FP)-funded Health and Environment Network (HENVINET) aimed to support informed policy making by facilitating the availability of relevant knowledge on different environmental health issues. An approach was developed by which scientific agreement, disagreement, and knowledge gaps could be efficiently identified, and expert advice prepared in a way that is usable for policy makers. There were two aims of the project: 1) to apply the tool to a relevant issue; the potential health impacts of the widely used plasticizers, phthalates, and 2) to evaluate the method and the tool by asking both scientific experts and the target audience, namely policy makers and stakeholders, for their opinions.</p> <p>Methods</p> <p>The tool consisted of an expert consultation in several steps on the issue of phthalates in environmental health. A diagram depicting the cause-effect chain, from the production and use of phthalates to potential health impacts, was prepared based on existing reviews. This was used as a basis for an online questionnaire, through which experts in the field were consulted. The results of this first round of consultation laid the foundation for a new questionnaire answered by an expert panel that, subsequently, also discussed approaches and results in a workshop. One major task of the expert panel was to pinpoint priorities from the cause-effect chain according to their impact on the extent of potential health risks and their relevance for reducing uncertainty. The results were condensed into a policy brief that was sent to policy makers and stakeholders for their evaluation.</p> <p>Results</p> <p>The experts agreed about the substantial knowledge gaps within the field of phthalates. The top three priorities for further research and policy action were: 1) intrauterine exposure, 2) reproductive toxicology, and 3) exposure from medical devices. Although not all relevant information from the cause-effect chain is known for phthalates, most experts thought that there are enough indications to justify a precautionary approach and to restrict their general use. Although some of the experts expressed some scepticism about such a tool, most felt that important issues were highlighted.</p> <p>Conclusions</p> <p>The approach used was an efficient way at summarising priority knowledge gaps as a starting point for health risk assessment of compounds, based on their relevance for the risk assessment outcome. We conclude that this approach is useful for supporting policy makers with state-of-the-art scientific knowledge weighed by experts. The method can assist future evidence-based policy making.</p

Policy relevant Results from an Expert Elicitation on the Human Health Risks of Decabromodiphenyl ether (decaBDE) and Hexabromocyclododecane (HBCD)

Aim: Apply a recently developed expert elicitation procedure to evaluate the state of the current knowledge of the two brominated flame retardants (BFRs) most commonly used today; decabromo-diphenyl ether (decaBDE) and hexabromocyclododecane (HBCD) and their potential impact on human health in order to support policy considerations. This expert elicitation was organized by the HENVINET (Health and Environment Network) Consortium. Method: The HENVINET expert elicitation procedure that was used in the evaluations of decaBDE and HBCD is a rapid assessment tool aimed at highlighting areas of agreement and areas of disagreement on knowledge-related key issues for environment and health policy decision making. Results: The outcome of the expert consultation on BFRs was concrete expert advice for policy makers with specific priorities for further action made clear for both stakeholders and policy makers. The experts were not in agreement whether or not the knowledge currently available on decaBDE or HBCD is sufficient to justify policy actions, but most experts considered that enough data already exists to support a ban or restriction on the use of these compounds. All experts agreed on the necessity of more research on the compounds. Priority issues for further research were, among others: more studies on the extent of human exposure to the compounds. more studies on the fate and concentration in the human body of the compounds

Group II intron in Bacillus cereus has an unusual 3′ extension and splices 56 nucleotides downstream of the predicted site

All group II introns known to date fold into six functional domains. However, we recently identified an intron in Bacillus cereus ATCC 10987, B.c.I4, that splices 56 nt downstream of the expected 3′ splice site in vivo (Tourasse et al. 2005, J. Bacteriol., 187, 5437–5451). In this study, we confirmed by ribonuclease protection assay that the 56-bp segment is part of the intron RNA molecule, and computational prediction suggests that it might form a stable stem-loop structure downstream of domain VI. The splicing of B.c.I4 was further investigated both in vivo and in vitro. Lariat formation proceeded primarily by branching at the ordinary bulged adenosine in domain VI without affecting the fidelity of splicing. In addition, the splicing efficiency of the wild-type intron was better than that of a mutant construct deleted of the 56-bp 3′ extension. These results indicate that the intron has apparently adapted to the extra segment, possibly through conformational adjustments. The extraordinary group II intron B.c.I4 harboring an unprecedented extra 3′ segment constitutes a dramatic example of the flexibility and adaptability of group II introns

Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: Microarray data from the BSU cohort have been submitted to the GEO database (www.ncbi.nlm.nih.gov/geo/): GSE28422, GSE28392, and GSE25941. Microarray data from the Oslo cohort is available on request.BACKGROUND: A striking effect of old age is the involuntary loss of muscle mass and strength leading to sarcopenia and reduced physiological functions. However, effects of heavy-load exercise in older adults on diseases and functions as predicted by changes in muscle gene expression have been inadequately studied. METHODS: Thigh muscle global transcriptional activity (transcriptome) was analyzed in cohorts of older and younger adults before and after 12-13 weeks heavy-load strength exercise using Affymetrix microarrays. Three age groups, similarly trained, were compared: younger adults (age 24 ± 4 years), older adults of average age 70 years (Oslo cohort) and above 80 years (old BSU cohort). To increase statistical strength, one of the older cohorts was used for validation. Ingenuity Pathway analysis (IPA) was used to identify predicted biological effects of a gene set that changed expression after exercise, and Principal Component Analysis (PCA) was used to visualize differences in muscle gene expressen between cohorts and individual participants as well as overall changes upon exercise. RESULTS: Younger adults, showed few transcriptome changes, but a marked, significant impact was observed in persons of average age 70 years and even more so in persons above 80 years. The 249 transcripts positively or negatively altered in both cohorts of older adults (q-value < 0.1) were submitted to gene set enrichment analysis using IPA. The transcripts predicted increase in several aspects of "vascularization and muscle contractions", whereas functions associated with negative health effects were reduced, e.g., "Glucose metabolism disorder" and "Disorder of blood pressure". Several genes that changed expression after intervention were confirmed at the genome level by containing single nucleotide variants associated with handgrip strength and muscle expression levels, e.g., CYP4B1 (p = 9.2E-20), NOTCH4 (p = 9.7E-8), and FZD4 (p = 5.3E-7). PCA of the 249 genes indicated a differential pattern of muscle gene expression in young and elderly. However, after exercise the expression patterns in both young and old BSU cohorts were changed in the same direction for the vast majority of participants. CONCLUSIONS: The positive impact of heavy-load strength training on the transcriptome increased markedly with age. The identified molecular changes translate to improved vascularization and muscular strength, suggesting highly beneficial health effects for older adults.South East Norway Health AuthorityOslo University Hospital, Ullevaal6th EU Framework ProgramLegat til Forskning, Lovisenberg Diaconal HospitalNational Institutes of Health (NIH)Eli Lilly and Compan

Regulation of Translation in Haloarchaea: 5′- and 3′-UTRs Are Essential and Have to Functionally Interact In Vivo

Recently a first genome-wide analysis of translational regulation using prokaryotic species had been performed which revealed that regulation of translational efficiency plays an important role in haloarchaea. In fact, the fractions of genes under differential growth phase-dependent translational control in the two species Halobacterium salinarum and Haloferax volcanii were as high as in eukaryotes. However, nothing is known about the mechanisms of translational regulation in archaea. Therefore, two genes exhibiting opposing directions of regulation were selected to unravel the importance of untranslated regions (UTRs) for differential translational control in vivo

The PlcR Virulence Regulon of Bacillus cereus

PlcR is a Bacillus cereus transcriptional regulator, which activates gene expression by binding to a nucleotidic sequence called the ‘PlcR box’. To build a list of all genes included in the PlcR regulon, a consensus sequence was identified by directed mutagenesis. The reference strain ATCC14579 sequenced genome was searched for occurrences of this consensus sequence to produce a virtual regulon. PlcR control of these genes was confirmed by comparing gene expression in the reference strain and its isogenic Δ-plcR strain using DNA microarrays, lacZ fusions and proteomics methods. The resulting list included 45 genes controlled by 28 PlcR boxes. Forty of the PlcR controlled proteins were exported, of which 22 were secreted in the extracellular medium and 18 were bound or attached to cell wall structures (membrane or peptidoglycan layer). The functions of these proteins were related to food supply (phospholipases, proteases, toxins), cell protection (bacteriocins, toxins, transporters, cell wall biogenesis) and environment-sensing (two-component sensors, chemotaxis proteins, GGDEF family regulators). Four genes coded for cytoplasmic regulators. The PlcR regulon appears to integrate a large range of environmental signals, including food deprivation and self cell-density, and regulate the transcription of genes designed to overcome obstacles that hinder B. cereus growth within the host: food supply, host barriers, host immune defenses, and competition with other bacterial species. PlcR appears to be a key component in the efficient adaptation of B. cereus to its host environment

Translational regulation of genes in salmonella typhimurium by vitamin B12

In this thesis I have studied the mechanism by which vitamin B12 regulates the expression of the cob operon and the btuB gene in Salmonella typhimurium. The cob operon encodes most of the 25 genes required for the de novo synthesis of vitamin B12, and the butB gene encodes the outer membrane protein needed for transport of exogenous vitamin B12 into the cell. Vitamin B12 is used as a cofactor in four enzymatic reactions in Salmonella typhimurium. The regulation by vitamin B12 of the cob operon and the btuB gene requires sequences in the long leader regions of the respective mRNAs. Proper folding of the reader mRNA is essential for normal repression, in particular a hairpin structure that sequesters the ribosomal binding site (RBS). The upstream leader region contains two conserved sequence elements that are required for the vitamin B12 regulation; the translational enhancer (TE) element element and the B12 box. The TE element confers its enhancer function by resolving the downstream inhibitory RBS hairpin through basepairing with nucleotides in the stem. In the presence of vitamin B12, either B12 itself, or a B12 regulatory factor binds to the upstream reader region and prevents the enhancer function. This will inhibit unfolding of the RBS hairpin and repress translation