Prenatal exposure to toxicants and childhood neurodevelopmental disorders and cognitive functions (NeuroTox)

Environmental toxins can affect fetal development, but there is little knowledge about harmful effects on brain development and cognitive functions, or the risk of neurodevelopmental disorders in children. Harmful chemicals are risk factors that can be prevented, and research on these should be given high priority. In the NeuroTox project, we measured environmental toxins in maternal blood during pregnancy and investigated whether they are related to child neurodevelopment. We investigated perfluoroalkyl substances (PFASs, eg PFOS and PFOA), various metals (eg mercury, lead and arsenic) and essential elements (eg manganese, copper). These substances are transmitted via the placenta and may interfere with fetal brain development. We also investigated whether mixtures of these substances can be more harmful than individual substances alone. We used data from 3600 mother-child pairs from the Norwegian mother, father and child survey (MoBa); including questionnaire data, biological samples, and clinical examinations (cognitive skills, psychiatric symptoms). Information about the diagnoses ADHD, autism spectrum disorders (ASD), cerebral palsy (CP) and epilepsy in children came from the Norwegian Patient Register. We measured environmental toxins in blood taken from pregnant MoBa women in week 17 of pregnancy. In addition, data on thyroid-stimulating hormone (TSH) in newborns obtained from the Newborn Screening were used. TSH is related to thyroid function which is routinely measured in blood spots from heel sticks of newborns 48-72 hours after birth. Thyroid (metabolic) hormones are very important for normal brain development early in life. We wanted to find out if changes in newborn TSH can increase the risk of ADHD, ASD, CP or epilepsy in children, and whether environmental toxins disrupt levels of TSH in newborns and thus affect brain development. We also wanted to explore whether environmental toxins could cause epigenetic changes (measured as total DNA methylation) in the mother and newborn and whether this may inform how environmental toxins may affect brain development. NeuroTox' large sample and unique data made it possible to test whether whether toxins and their mixtures were associated with changes in normal brain development during fetal life even at low levels in the population. The results from the project contribute to increased knowledge which, together with other information, can be used both in risk assessment and regulation of chemicals, as well as other measures aimed at reducing levels of environmental toxins to which pregnant women are exposed and in that way prevent unfortunate outcomes in children. NeuroTox has become a very useful platform for further research and is a partner in an international center on social inequality in health at NTNU (CHAIN). In NeuroTox-CHAIN, we investigate whether social inequality (socioeconomic status) contributes to different exposures to environmental toxins, which in turn can have harmful effects on the child's brain development. In a systematic literature review on the connection between maternal thyroid hormones during pregnancy and ADHD in the child, we found that some studies showed this, but there was less evidence for a connection between thyroid levels in newborns and ADHD (2019, Epidemiol). In the PhD project we found: 1) some PFASs (including PFOS and PFOA) were associated with reduced working memory, otherwise there were few correlations between levels of PFASs in the mother and ADHD symptoms and cognitive functions in the child at 3,5 years (Int J Hyg Env Health 2020); 2) correlation between maternal levels of PFOS and PFOA and increased risk of ADHD and/or ASD in children (Env Res, 2021); and 3) maternal levels of the heavy metals cadmium, lead, and arsenic, and the essential elements magnesium, copper, and manganese were associated with increased risk of ADHD and/or ASF (Env Int, 2021). One study showed an increased risk of ADHD in newborns with low TSH levels (hyperthyroid status), where the association was most prominent among girls (Paed Per Epi, 2020). Furthermore, we found that global DNA methylation in pregnant women and newborns was associated with levels of certain metals and essential elements, and that there were interaction effects between these (2021, Sci Tot Envir). Articles on environmental toxins during pregnancy and relation to CP and Epilepsy are expected published in 2022. So will a publication on prenatal environmental toxins and ADHD symptoms and cognitive functions, one on mixture effects of PFASs and metals on newborn TSH levels, and an article which explores whether newborn TSH and DNA methylation mediate the association between prenatal environmental toxins and ADHD symptoms and cognitive functions in children. Within the framework of NeuroTox, we have contributed to national and international collaborations (eg Nanjing Medical University and Chinese birth cohorts) resulting in several publications and a book chapte

Prosjektet har hatt mange positive virkninger: prosjektmedarbeiderne har fått utvidet kontaktnett nasjonalt og internasjonalt, på forskning om konsekvenser av miljøgifter for barn og unge. Det er skapt mange kontakter og vi er invitert med på nye søknader, prosjekter og publikasjoner verden over. Prosjektet er innlemmet i samarbeid med internasjonalt forskningsnettverk om sosial ulikhet i helse ved NTNU (CHAIN) og har ledet til utvidet samarbeidet med Nanjing Medical University i Kina. Prosjektgruppen har etablert samarbeid med Nyfødtscreeningen ved Rikshospitalet og tatt i bruk data fra bloddråpekort. Dette er data innhente for alle nyfødte barn i Norge som sjelden benyttes i forskning. Ved å bygge videre på NeuroTox håper vi å øke bevisstheten om hvilken risiko miljøgifter i små doser kan ha på barn i utvikling, at behovet for å overvåke eksponering i befolkningen er nødvendig, og derigjennom at tiltak som informasjonskampanjer og restriksjoner mot potensielt farlige stoffer vil øke.

Environmental chemicals may affect child development already in the womb. However, empirical knowledge regarding adverse effects of toxicants on brain development and cognitive functions, or as risk for neurological or neurodevelopmental disorders in children is limited, yet of great public health importance. These disorders have significant adverse impact on the child and its family, as well as society. Thus, the identification of preventable risk factors like hazardous substances in the environment should be prioritized. We aim to investigate the maternal blood levels (as a proxy for in utero exposure) of known or suspected developmental neurotoxicants present in our environment; PFAS and metals (e.g. mercury, lead), and their potential negative effects on neurodevelopment in children using a mixture approach. We will use data from The Norwegian Mother and Child Cohort Study (MoBa), including questionnaire data, biospecimen from mother and child, clinical examinations of the child, and diagnoses of attention-deficit hyperactivity disorder, autism spectrum disorders, cerebral palsy, and epilepsy identified through linkage to the Norwegian Patient Registry. Additionally, we will incorporate data on neonatal thyroid hormone levels from the National newborn screening program to investigate thyroid disruption, as well as measure neonatal DNA methylation as possible toxic mechanisms. This project is bold and innovative with its multidisciplinary and extensive design, incorporating questionnaire data, clinical test results, registry data and biological samples for measurements of exposures and mechanistic biomarkers. The unique combination of data and large sample size will increase the project's ability to test the hypotheses that variations in exposure levels to neurotoxicants and their mixtures can alter normal fetal brain development, even at low levels of exposure, and become risk factors for these disorders or affect cognitive functions and behavior in children.