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Reporting period: 2019-10-01 to 2022-03-31

What is the problem/issue being addressed?
The impact of prolonged exposure to apparently non-toxic doses of neurotoxicants during early development may have on children’s health, represents a major risk factor for neurodevelopmental disorders (NDs). The etiology 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. 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.
The analytical framework for environmental sampling has been applied in the assessment of wild fish and seafood contribution to dietary exposure to persistent pollutants. In addition, air toxicants have been identified in various ambient and indoor environments. In terms of modelling environmental exposure, assessment of BPA, PM and PAHs has been carried out, as well as a comprehensive assessment of Hg exposure through the food chain.
With regard to human biomonitoring, analysis of organochlorine compounds and metals in biological samples (blood, brain, milk) in venous serum of pregnant mothers from Arctic areas, farmworkers exposure to pesticides in Spain, phthalates and DINCH metabolites, bisphenols, parabens, and triclosan in Slovenian populations, and metals in from population samples from the PHIME study has been carried out. Information from environmental exposure and personal sensors, as well as from Agent Based models data has been used to estimate personal exposure and validate it against HBM data.
Biological samples collected within the PHIME (overall 1002 individuals from Italy, Slovenia and Croatia) have been subjected to genome profile analysis, for assessing the polygenic risk scores. With regard to other omics analysis, metabolomics analysis has been concluded in the subjects of the PHIME cohort study, in both plasma and urine samples from mothers and children respectively, as well as from the Spain-EXHES cohort.
To mimic exposure to environmentally relevant exposure to neurotoxicants during neurodevelopment, SH-SY5Y cells (neuroblastoma cell line) were exposed to an environmentally representative mixture of 8 pollutants. Several cellular and molecular outcomes have been assessed, including cell metabolic activity, death and apoptosis, followed by transcriptome and immunocytochemical analysis.
The concentrations used to expose SH-SY5Y cells were based on the expected concentrations of each pollutant in the human brain calculated by PBPK modelling developed. More detailed toxicokinetic interactions regarding the blood-brain-barrier have been investigated in vitro. The generic PBBK model has been parameterized using literature as well as QSAR delivered parameterization data for phthalates, bisphenols, PFOS-PFOA and metals, while toxicokinetic interactions of the BPA, BPF and BPS tertiary mixture, as well as the DEHP, BBzP, DINP and DNBP quaternary mixture have been quantified.
Bioinformatics analysis from in vitro samples revealed the dysfunctions by identifying the disturbances in metabolic pathways than can lead to the development of reactive oxygen species inside cells, as well as the energy metabolism dysfunction. The omics analysis of the human samples into metabolic pathways, using bioinformatics. The key finding is that maternal exposure to phthalates and metals may affect child neuro development mainly through perturbations in the metabolism of citric acid (TCA cycle), urea cycle, and amino acid metabolism with possible disruption of mitochondrial oxidative phosphorylation.
EWAS analysis from the cohort studies revealed that different factors have positive and negative contributions, while the importance of dietary factors on child neurodevelopment, as well as the impact of social factors. It was also found that the imbalance between the cellular reactive oxygen species, which may be an effect of exposure to metals, and the inability of the cell to detoxify them, leads to oxidative stress.
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 (Figure 1).
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.
Figure 1. NEUROSOME methodological framework