Epigenetics in the early life exposure to air pollution and neurodevelopment and behaviour disorders within families in the INMA Sabadell birth cohort (SIBLINGS). PROYECTO INMA

Duration

01/01/2013 ? 31/12/2015

Coordinator

Jordi Sunyer Deu

Funded by

MINISTERIO DE ECONOMÍA Y COMPETITIVIDAD

Exposure to indoor and outdoor air pollution during susceptibility windows of the developmental period may result in white matter lesions and vascular pathology in brain areas that could be the basis for cognitive deficits and behavioural impairment later in life. Animal studies have demonstrated that these lesions are related to either deposition of ultrafine particles (UFP) containing metals in the olfactory bulb or in frontal cortical and subcortical areas, or alternatively to the neuroinflammation process that follows the inflammatory systemic responses secondary to oxidative stress triggered by air pollutants. Epidemiological research on neurodevelopment is recent and limited and there is need for large studies assessing the development of the global mental function and its specific areas, as well as on the clinical impact in social impairment and attention-deficit hyperactivity disorder (ADHD) by performing prospective assessment of environmental exposures during early life phases. According to recent studies, adverse effects of air pollution and inflammation are probably mediated by epigenetic changes that alter gene expression. However, studies on epigenetic changes are small, scarce and none related to adverse neurological effects. Besides, the INMA birth cohort provides an opportunity given the prospective design in collecting information on exposures at birth and early life, and the study of siblings with discordant information on exposures within families providing a perfect control of cofactors. The INMA project is a set of birth cohorts that aims to asses the role of early-life environment on children development and health in different areas of Spain. We have reported both indoor (i.e., use of gas cooking and maternal smoking) and outdoor air pollution to be determinants of cognitive impairment and ADHD symptoms. These adverse effects are probably due to the neurotoxic effect of ultrafine particles that may be mediated through changes in epigenetic marks. However, the potential for residual confounding for variables related with social class or genetics could not be discarded. A way of controlling for these effects is the conduction of sibling studies. The tremendous amounts of information that can be obtained from examining health outcomes within the context of the family have great potential. The present project aims to recruit all the siblings (around 600 sibling from a total of 1000) of the participants in the INMA-Sabadell cohort. The objectives are: 1. To asses the association of prenatal and early life exposure to air pollution with neurodevelopment and behaviour disorders within sibling pairs 2. To asses the effects of prenatal exposure to air pollution on epigenetic marks, in terms of DNA methylation changes, by using/comparing sibling pairs 3. To asses the intermediate role of DNA methylation changes on the association between air pollution and neurodevelopment and behaviour disorders. The plan is to exam within each family the sibling(s) of the INMA children, in order to avoid the role of factors that are constant within the family, using the same tools and devices used for the ‘probands’. Individual exposure estimates of outdoor in air pollution (particles, nitrogen dioxide, and volatile organic compounds) during pregnancy and at birth will be obtained, as well as other exposures such as indoor combustion sources and maternal smoking for both siblings. 2 The outcomes that will be examined in each sibling are the cognitive function (through validated psychometric tools performed by psychologists, either the Bayley, McCarthy or WISC upon the age), standardised computer assisted tests on executive function and attention, as well as a short questionnaire to the parents on the clinical history and environmental exposures during each pregnancy and early life of each sibling as well as record linkage with clinical records during pregnancy. Changes in DNA methylation will be assessed using the HumanMethylation450 (Illumina) chip assayed in DNA samples of the discordant siblings (around 400 children from 200 pairs). Results could contribute to the understanding of the causal links between environmental exposures and neurological impairment in children which is expected to be translated in the following aspects: 1. could have a direct application on implementation of environmental policies both at home and urban air level for improving children health 2. will expand the epidemiological knowledge of ADHD and other neurodevelopment variables 3. will provide evidences for the extension of this type of design in the rest of cohorts in the INMA study in Spain and also to other birth cohorts in Europe. 4. The identification of epigenetic marks associated with ADHD and other neurodevelopment variables in childhood could provide more insight into the complex pathophysiology of mental disorders and help develop early interventions to prevent these diseases. Communication to the participants and the general population of the results, beyond the research community is a mandate for the INMA researchers. Dissemination actions are carried out through: 1) direct communication with the main participants and professionals involved in the Sabadell cohort, including parents, doctors and nurses, schools, and the city council 2) communication with the main professional bodies responsible for developing prevention programs 3) dissemination to the scientific community 4) dissemination to general population through www.proyectoinma.org