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EXPLORING THE NEUROLOGICAL EXPOSOME

Periodic Reporting for period 1 - NEUROSOME (EXPLORING THE NEUROLOGICAL EXPOSOME)

Reporting period: 2017-10-01 to 2019-09-30

• What is the problem/issue being addressed?
Concern is increasing on the impact that prolonged exposure to apparently non-toxic doses of neurotoxicants during early development may have on children’s health, possibly representing a major risk factor for neurodevelopmental disorders (NDs). The aetiology of most NDs is unknown, but there is general agreement that they result from complex interaction between multiple genes conferring vulnerability and adverse environmental factors. Exposures, whether chemical, physical, or microbiological, may act directly upon neural cells or may affect the expression of genes that regulate relevant fetal/infant processes. They operate during sensitive periods of gestation by disrupting endocrine systems and altering the hormonal milieu necessary for fetal brain development. Moreover, environmental exposures could contribute to a dysregulated immune system that interacts at the molecular level with glial cells and astrocytes, creating a neuroinflammatory condition.
• Why is it important for society?
NEUROSOME aims at protecting public health against neurodevelopmental disorders using the latest advances in environmental health science, namely the exposome paradigm. The project and its methodological advances are expected to have a positive impact on local society and the economy contributing to more cost-effective environmental management, enhanced human health and reduced costs associated to the health burden from exposure to neurotoxicants.
• What are the overall objectives?
NEUROSOME aims to explore the environmental causes of neurodevelopmental disorders and their complex interplay with genetic predisposition and susceptibility. This will be done by developing a functional link between human biological monitoring and data on exposure to specific environmental compounds and NDs using the latest advances in environmental health science, namely the exposome paradigm (Fig. 1). The goal is the development of functional links among the different components of environmental, exposure, Human Biomonitoring (HBM), toxicological and epidemiological studies to understand the causal associations between exposure to organic compounds and metals to NDs.
The project’s training goal is to produce a new generation of exposome researchers, trained in academia, applied research and industry, with transdisciplinary skills (environmental end exposure modelling, HBM, -omics technologies, high dimensional bioinformatics and environmental epidemiology,) and understanding of fundamental science and its direct application to environmental health challenges.
Progress has been made towards the development of the analytical framework for environmental sampling from different environmental media towards exposome assessment. A demonstration of this methodology was performed organizing sampling campaigns in Marseille, Alicante, Genoa, Alguer, Civitavecchia and Palma (Balearic islands) focusing in particular on Hg exposure through the environment and the food chain.
Metal analysis in biological samples (blood, brain, milk) has advanced both for human and animal tissues, thus paving the way towards integrated environmental and biomonitoring assessment of exposure to multiple metal compounds. The next step was to assess the toxicity (in particular neurotoxicity) associated with these exposure levels. Results regarding Se and Pb showed altered maternal care in female mice treated with Pb during pregnancy and early changes in behavior in the mouse offspring exposed to low doses of Pb. The levels of Pb in the mice blood was commensurate with the levels found in human population, subjects of the PHIME study.
Besides metals, NEUROSOME is also set to assess human exposure to non-persistent contaminants. Thus, samples from the DEMOCOPHES cohort have been analysed and their data and meta-data statistically processed. Additional samples from the national HBM program in Slovenia were further analysed for bisphenol A, S and F, parabens and triclosan.
The work on in vitro analysis associated to neurodevelopmental disorders has started using the SHSY5Y human cell line. The experimental and cell culture protocols were defined including multiple pollutants to assess properly the effect of combined exposure.
Exposure modeling has advanced towards the development of a lifetime physiology-based biokinetic (PBBK) modeling set to describe the internal exposure during developmental stages (or age windows) of particular susceptibility. The model takes into account interactions between multiple chemicals at the metabolism level and it has been applied to the BTEX quaternary mixture, which has neurotoxic properties, to assess how co-exposure to these VOCs can modify the biologically effective dose of each chemical in the mixture through metabolic interactions. A specific model for neurotoxicity assessment is also being developed including brain sub-compartments for assessing the neuronal risk based on mixture interactions. The model considers the detailed physiology of the brain, enzyme transport kinetics of xenobiotic mixtures and blood-brain barrier properties. Furthermore, fundamental steps have been done in understanding the concepts of exposure modeling using PBBK models that have been properly parameterized with the help of QSARs approaches.
Information from environmental exposure and personal sensors data is being used in order to calculate personal exposure and validate it against HBM data.
Untargeted metabolomics has been performed in samples from the EXHES cohort (urine and plasma samples from pregnant mothers and neonates). Pathway analysis was performed using Agilent Genespring to derive the biological basis for AOP development.
Big data analytics has been used to couple the early results from metabolomics, exposure and health outcome data in humans to develop the appropriate EWAS framework for neurodevelopmental toxicity studies.
Genome-wide profiling and identification of SNPs relevant to susceptibility to neurodevelopmental disorders has started using samples from the PHIME cohort to assess the feasibility of data linkage of the samples with data from the baseline questionnaires filled in by mothers during pregnancy and the neurodevelopmental assessment outcomes carried out at 18 months of age of the infants.
NEUROSOME uses an innovative integrated exposome-driven paradigm to explore the ways in which different types of environmental compounds (metals and organics) contribute to common health outcomes and the identification of the common pathways of disease between early-life toxic insult and late-life neurodegeneration and the mechanisms resulting in neurodevelopmental and neurodegenerative disorders.
Enabling a comprehensive and innovative approach to environmental health and risk management necessitates transdisciplinary research training. To this end the ESR projects have been designed to address the current gaps and set the basis for a transdisciplinary scientific curriculum at the doctoral level in environmental chemical risk.
The innovations of NEUROSOME will enable competent authorities to derive scientifically robust interpretations of human biomonitoring data for better assessment of the adverse health impact associated with environmental contamination. In addition, this information will be readily usable for designing targeted interventions that would optimally manage the environmental and public health problems in the area.
Connectivity-based workflow for exposome studies in NEUROSOME