Scientific Strategy

The main objective of the NEUROSOME project is to develop an integrative exposure biology-based framework starting from Human Biomonitoring (HBM) data for identifying the causal associations among the human genome, environmental exposure and neurodevelopmental diseases. This would rely on the evaluation and reanalysis of existing cohort biosamples (e.g. PHIME, INMA, PROBE, Taranto, CROME, HEALS, PELAGIE, MECANA) and selected re-sampling and external exposome assessment of the populations involved in the above studies. From the assessment of these studies, it was found that the effect of toxic compounds was variable among individuals, even if the exposure levels were similar. The extent to which the differences observed might be explained by genetics (e.g. differences in toxicokinetics associated to polymorphisms of metabolising enzymes), sociodemographic factors (e.g. parental educational status) or by co-exposures to multiple environmental chemicals remains unclear. In the NEUROSOME study, we shall investigate:

a) the effect of genetics and the signalling pathways which could modulate the detrimental effects of heavy metals (Hg and MeHg among them) and selected organic compounds (phthalates, phenols, PAHs POPs) at low exposure in Mediterranean cohorts.

b) the effect of cumulative exposure4 of compounds relevant to neurological disorders such as metals and specific persistent organic chemicals (e.g. organophosphate pesticides, PAHs), since there is a significant body of evidence showing a greater than additive effect of co-exposures to metals5 and organic6 compounds.

c) the interplay between genetic variability and co-exposure to environmental chemicals for extended periods of time and how this contributes to the development or exacerbation of central nervous system disorders during child development (neurodevelopmental disorders).

d) The modifying effect of sociodemographic factors such as educational level of the parents, age of mother at birth and family SES; and dietary patterns, since consumption of specific food items has been proven to be beneficial (e.g. food items rich in selenium or omega-3 saturated fatty acids) and/or harmful for neurodevelopmental progress.

Special focus will be given to in-utero exposure. The research program will include collection of urine and hair samples for analyses of organic compounds and metals and collection of saliva samples for genotyping. Children will be tested for neuropsychological performance using Wechsler Intelligence Scale for Children (WISC IV). This is an individually administered measure of intelligence intended for children aged six years to 16 years and 11 3 Guxens M, Ballester F, Espada M, Fernandez MF, Grimalt JO, Ibarluzea J, Olea N, Rebagliato M, Tardon A, Torrent M, Vioque J, Vrijheid M, Sunyer J. Cohort Profile: the INMA–INfancia y Medio Ambiente–(Environment and Childhood) Project. Int J Epidemiol 2012; 41: 930-40. 4 Sarigiannis DA, Hansen U. Considering the cumulative risk of mixtures of chemicals – A challenge for policy makers. Environmental Health: A Global Access Science Source 2012; 11. 5 von Stackelberg K, Guzy E, Chu T, Henn BC. Mixtures, Metals, Genes and Pathways: A Systematic Review. Working Paper prepared for: Methods for Research Synthesis: A Cross-Disciplinary Workshop. Harvard Center for Risk Analysis, October 3, 2013. 6 Zeliger HI. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases. Interdisciplinary Toxicology 2013; 6: 103-110. NEUROSOME – ETN  Part B – Page 6 of 59 months. WISC-III yields measure of general intelligence as reflected in both verbal and nonverbal (performance) abilities and specific indices including verbal comprehension, perceptual reasoning, working memory and processing speed. Overview. Overall, the proposal 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 neurodevelopmental disorders using the latest advances in environmental health science, namely the exposome paradigm. NEUROSOME involves the use of high dimensional biological data generated from multi-omics technological platforms. The goal is the development of functional links among the different components of environmental, exposure, HBM, toxicological and epidemiological studies to understand the causal associations between exposure to organic compounds and metals to neurodevelopmental disorders. Specific Research Objectives. The main objectives of NEUROSOME could be summarized as follows:

• To mechanistically connect multiple types of environmental, exposure, human biomonitoring multi-omics in vitro and clinical (phenotypic) data, to better support the development of environment-wide exposure and health associations with neurodevelopmental disorders data through an exposome approach for cumulative health risk and impact assessment.
• To improve scientific knowledge in the identification of cause and effect relations between multiple environmental stressors, biomonitoring data and observed adverse health outcome taking into account exposure and health effect modification due to intrinsic (such as genetic susceptibility) and extrinsic (such as diet and socio-economic status) factors.
• To develop new standards for HBM data interpretation in conjunction with environmental and exposure information in selected areas of South Europe (Greece, Croatia, Slovenia, Italy, France and Spain).
• To raise the level of understanding among policy makers and increase awareness of the public and competent authorities in the participating countries about the possibility of using advanced biomonitoring and environment and health data analysis for efficient exposure assessment and health risk management.
• To support the Environment and Health Action Plan (EHAP), the Chemicals Safety Regulation (REACH) and the 7th Environmental Action Plan of the European Commission by extending health impact assessment (HIA) methods and tools to draw environment-wide association studies between environmental stressors and human health to improve chemical risk assessment including the health risk of mixtures and emerging compounds.

Gender equality and protection of vulnerable groups are key cornerstones of the objectives and activities of the EU. Gender issues are a cornerstone of PROGRESS, the EU programme in favour of employment and social solidarity (2007-2014) in collaboration with the European Social Fund. In this context it is essential to address the role of gender with regard to susceptibility to chemical substances in diet, food contact materials and the environment; this may be a consequence of differences in physiological state (e.g. pregnancy), in behaviour and lifestyle leading to different exposure levels, in physiology (e.g. fat composition, intake of food), differences in basic metabolic profiles as well as different biological mechanisms involved in human physiology between the two genders (e.g. different regulatory networks activated by exposure to the same xenobiotic) which may have important consequences regarding gender-specific risk under identical exposures. Aspects like female underrepresentation will be explicitly addressed in the project and a strategy for recognising and highlighting gender issues in combined exposure and health risk assessment will be drawn up. Consideration will be given to the influence of different life stages and types of behaviour as they pertain to gender differences (e.g. breastfeeding women and those who have recently given birth) and age. NEUROSOME intends to improve health outcomes for all; still, women can benefit from results on issues they are disproportionately at risk. The scientific concept of NEUROSOME requires the contribution from all consortium members, combining universities, research institutions, and highly interested partners from the private sector (particularly SMEs) forming a transdisciplinary network. The underlying research work for this has been done in the frame of several European projects funded by the EC and by the chemical industry (CEFIC-LRI) comprising NO MIRACLE, INTARESE, HEIMTSA, 2-FUN, PHIME, HEALS, CROME, EUROMIX, INTERA, TAGS and INTEGRA; all of them contributed to building up the method and analysis tools for integrated health risk and impact assessment of environmental stressors, towards optimal and cost-effective environmental management strategies. These key innovations will build the methodology proposed that 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 usable for designing targeted interventions that would optimally manage the environmental and public health problems in the study area.