Exploring environmental factors and gene-environment interactions in Autism Spectrum Disorder: a pilot study

Autism Spectrum Disorder (ASD) is a pervasive and clinically heterogeneous neurodevelopmental disorder by deficits in social communication and interactions skills, and repetitive and stereotyped behaviours. It has becomes apparent that ASD has a strong genetics component. However, the level of heritability is still debated: compared to older and smaller studies, results from recent studies estimate a lower heritability percentage (83%), thus leaving a meaningful percentage of the risk that could be explained by environmental factors. Exposure to potentially harmful environmental factors can result in neurodevelopmental issues, due to neurotoxicity. Such environmental factors include endocrine disruptive chemicals like BPA, PBDEs, phthalates, PAHs, pesticides, and heavy metals, which disrupts optimal hormonal function, as well as pharmaceutical drugs which are able to cross physiological barriers and come into contact with the fetus. Moreover, the incorrect metabolization of these xenobiotics due to defective enzymatic activity may be linked to an increased risk of ASD. It has been suggested that individuals carrying polymorphisms that hinder the activity of cytochrome p450 enzymes, responsible for phase I metabolism, as well as UDP-glucuronosyltransferases and glutathione S-transferase enzymes responsible for phase II metabolism, will be more susceptible to potentially toxic chemicals. Therefore, considering the role played by environmental factors, this pilot study aims to investigate and contribute to the understanding of gene-environment interactions in ASD. In order to do this, we explored the usage of the Early Life Exposure Assessment Tool (ELEAT): a questionnaire which indirectly examines child’s exposure to exogenous factors that could be related to ASD from 3 months before conception, during pregnancy, to the first year of the child’s life, by analyzing maternal exposure. We aimed to investigate the type of data that could be obtained from this questionnaire, how it could be treated, and ultimately how it could be related to genetic information obtained from probands. The questionnaire was filled by 20 Portuguese mothers who had been part of a previous study. Additionally, we were able to obtain 14 biological samples from the children whose mothers filled out the questionnaire, who were then screened for various functional polymorphisms in genes known to interact with the environmental factors investigated in ELEAT. Finally, we related probands’ genotype to exposure reported in the ELEAT. Our results suggest that mothers were indeed exposed to some of the environmental factors being studied by the ELEAT in these critical periods of neurodevelopment. Additionally, genotyping results showed that this group of probands did carry a number of the polymorphisms being investigated in this pilot study, which could make them more susceptible to certain xenobiotics. When we merged probands’ genotype to reported exposure, we concluded that probands may have been exposed to the chemicals they were sensitive to during neurodevelopment. Most of the variants investigated in this study have not been yet related to ASD, but have the potential to indirectly contribute to the disorder’s onset. Our results demonstrate that meaningful results can be obtained from combining the ELEAT with genetic information. Seeing as the general population is somewhat regularly exposed to some levels of these chemicals, genetic factors play a crucial role in increasing susceptibility and thus leading to negative consequences such as increased ASD risk. This pilot study is an important step for future studies that intend to use the ELEAT to identify environmental risk factors for ASD. These should include a large population sample, and an equal number of controls, in order to obtain statistical power when calculating the multiplicative effect of given environmental exposures with genetic liability. In conclusion, the ELEAT could play a vital role in the understanding of gene-environment interactions, and the development of preventive strategies for autism.N/