In this re-submitted application, we seek to evaluate maternal biomarkers of oxidative stress in relation to schizophrenia (SZ) and autism spectrum disorders (ASD) in offspring, their relationships with one another, and with other environmental exposures during development. The proposal is based on the Finnish Prenatal Studies of Schizophrenia (FiPS-S), and Autism (FiPS-A), the largest seroepidemiologic studies of prenatal exposures in these disorders to date, and the first to utilize a national birth cohort. This nested case-control study draws on the Finnish Maternity Cohort (FMC), which consists of virtually all pregnancies in Finland from 1987-2017; the total sample size is approximately 1 million. Maternal prenatal serum samples were obtained and archived from each gravida, and the Finnish psychiatric registries contain validated diagnoses of SZ and ASD on virtually all hospitalized and non-hospitalized cases in Finland. We have identified large samples of SZ and ASD case and control offspring and demonstrated relationships between several prenatal biomarkers and these disorders in this cohort. Although maternal oxidative stress causes abnormal fetal development, is associated with developmental insults, and leads to brain and behavioral abnormalities concordant with SZ and ASD, no previous study has ever examined relationships between this prenatal factor and psychiatric diagnostic outcomes in offspring.
We aim to address the role of maternal exposure to oxidative stress and these disorders by assays of maternal serum specimens in pregnancies from large samples of case and matched control offspring. We will test the hypothesis that maternal biomarkers of the antioxidant defense system are negatively associated with SZ and ASD in offspring and a pro-oxidant biomarker is positively associated with these outcomes. We will also evaluate whether correlations observed between these maternal biomarkers in control offspring are disrupted in SZ and ASD offspring. Moreover, we shall assess whether sex and perinatal complications modify relationships between maternal oxidative stress biomarkers and SZ/ASD. For this purpose, maternal serum samples from SZ and ASD cases and matched controls will be analyzed for biomarkers of oxidative stress. This research has the potential to result in a better understanding of prenatal risk factors for SZ and ASD. Since oxidative stress is a common pathogenic mechanism that is caused by several types of environmental insults which have been implicated in these disorders, the study offers the potential for their prevention by reducing these exposures and may suggest new pathogenic mechanisms in future translational studies. In summary, the proposed work builds on an existing national birth cohort, and is anticipated to impact an emerging and potentially transformative area of research epidemiology and clinical/basic neuroscience, leading to improvements in public health policy.
This study has significant relevance for public health, as it is aimed at identifying prenatal risk factors, including markers of maternal oxidative stress, in schizophrenia and autism spectrum disorders in a large national birth cohort. These factors have never before been investigated in maternal sera in relation to these outcomes. The proposed research may offer the potential for prevention of these disorders by public health measures including reduction of exposure to factors that increase maternal oxidative stress, and could also result in an improved understanding of how prenatal insults alter brain development in these disorders.