ABSTRACT
BACKGROUND: Despite epidemiological findings showing increased air pollution related cardiovascular diseases (CVD), the knowledge of the involved molecular mechanisms remains moderate or weak. Particulate matter (PM) produces a local strong inflammatory reaction in the pulmonary environment but there is no final evidence that PM physically enters and deposits in blood vessels. Extracellular vesicles (EVs) and their miRNA cargo might be the ideal candidate to mediate the effects of PM, since they could be potentially produced by the respiratory system, reach the systemic circulation and lead to the development of cardiovascular effects.The SPHERE ("Susceptibility to Particle Health Effects, miRNAs and Exosomes") project was granted by ERC-2011-StG 282413, to examine possible molecular mechanisms underlying the effects of PM exposure in relation to health outcomes. METHODS/DESIGN: The study population will include 2000 overweight (25 < BMI < 30 kg/cm2) or obese (BMI ≥ 30 kg/cm2) subjects presenting at the Center for Obesity and Work (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy).Each subject donates blood, urine and hair samples. Extensive epidemiological and clinical data are collected. Exposure to PM is assigned to each subject using both daily PM10 concentration series from air quality monitors and pollutant levels estimated by the FARM (Flexible air Quality Regional Model) modelling system and elaborated by the Regional Environmental Protection Agency.The recruitment period started in September 2010 and will continue until 2015. At December 31, 2013 we recruited 1250 subjects, of whom 87% lived in the province of Milan.Primary study outcomes include cardiometabolic and respiratory health effects. The main molecular mechanism we are investigating focuses on EV-associated microRNAs. DISCUSSION: SPHERE is the first large study aimed to explore EVs as a novel potential mechanism of how air pollution exposure acts in a highly susceptible population. The rigorous study design, the availability of banked biological samples and the potential to integrate epidemiological, clinical and molecular data will also furnish a powerful base for investigating different complementary molecular mechanisms. Our findings, if confirmed, could lead to the identification of potentially reversible alterations that might be considered as possible targets for new diagnostic and therapeutic interventions.
Subject(s)
Air Pollution/adverse effects , Cardiovascular Diseases/etiology , Disease Susceptibility , Obesity , Respiratory Tract Diseases/etiology , Air Pollutants/analysis , Cardiovascular Diseases/blood , Cardiovascular Diseases/urine , Environmental Monitoring , Exosomes/chemistry , Female , Humans , Italy , Male , MicroRNAs/analysis , Middle Aged , Models, Theoretical , Respiratory Tract Diseases/blood , Respiratory Tract Diseases/urineABSTRACT
The consequences of exposure to particulate matter (PM) have been thoroughly investigated in humans and other model species, but there is a dearth of studies of the effects of PM on physiology and life-history traits of non-human organisms living in natural or semi-natural environments. Besides toxicological relevance, PM has been recently suggested to exert epigenetic effects by altering DNA methylation patterns. Here, we investigated for the first time the association between the exposure to free-air PM10 and DNA methylation at two loci ('poly-Q exon' and '5'-UTR') of the Clock gene in blood cells of the nestlings of a synanthropic passerine bird, the barn swallow (Hirundo rustica). The Clock gene is a phylogenetically highly conserved gene playing a major role in governing circadian rhythms and circannual life cycles of animals, implying that change in its level of methylation can impact on important fitness traits. We found that methylation at both loci significantly increased with PM10 levels recorded few days before blood sampling, and also with PM10 exposure experienced by the mother during or shortly before egg laying. This study is the first where methylation at a functionally important gene has been shown to vary according to the concentration of anthropogenic pollutants in any animal species in the wild. Since early-life environmental conditions produce epigenetic effects that can transgenerationally be transmitted, DNA methylation of genes controlling photoperiodic response can have far reaching consequences for the ecology and the evolution of wild animal populations.
Subject(s)
Air Pollutants/toxicity , Circadian Clocks/genetics , DNA Methylation , Particulate Matter/toxicity , Swallows/physiology , Air Pollutants/analysis , Animals , Circadian Rhythm/drug effects , Female , Humans , Male , Maternal Exposure , Particulate Matter/analysis , Time FactorsABSTRACT
Individuals often considerably differ in the timing of their life-cycle events, with major consequences for individual fitness, and, ultimately, for population dynamics. Phenological variation can arise from genetic effects but also from epigenetic modifications in DNA expression and translation. Here, we tested if CpG methylation at the poly-Q and 5'-UTR loci of the photoperiodic Clock gene predicted migration and breeding phenology of long-distance migratory barn swallows (Hirundo rustica) that were tracked year-round using light-level geolocators. Increasing methylation at Clock poly-Q was associated with earlier spring departure from the African wintering area, arrival date at the European breeding site, and breeding date. Higher methylation levels also predicted increased breeding success. Thus, we showed for the first time in any species that CpG methylation at a candidate gene may affect phenology and breeding performance. Methylation at Clock may be a candidate mechanism mediating phenological responses of migratory birds to ongoing climate change.
Subject(s)
Animal Migration , CLOCK Proteins/genetics , Epigenesis, Genetic , Phenotype , Sexual Behavior, Animal , Swallows/genetics , Swallows/physiology , Animals , DNA MethylationABSTRACT
BACKGROUND: The vascular type of Ehlers-Danlos syndrome is an autosomal dominant connective tissue disorder caused by a mutation in the COL3A1 gene encoding pro-alpha1 chain of type III collagen. The vascular type of Ehlers-Danlos syndrome causes severe fragility of connective tissues with arterial and intestinal ruptures and complications in surgical and radiological treatments. CASE PRESENTATION: We present a case of a 38-year-old Italian woman who was diagnosed as having the vascular type of Ehlers-Danlos syndrome. Genetic testing, conducted by Target Enrichment approach (Agilent Technologies), identified a new mutation c.1493G>A, p.G498D in exon 21 of COL3A1 gene (heterozygous state). This mutation disrupts the normal glycine-X-Y repetitions of type III procollagen by converting glycine to aspartic acid. CONCLUSIONS: We report a new genetic mutation associated with the vascular type of Ehlers-Danlos syndrome. We also describe clinical and genetic findings that are important to understand the genotype/phenotype correlation in patients with the vascular type of Ehlers-Danlos syndrome.