Although autism spectrum disorder (ASD) primarily affects brain function, our data have also identified widespread changes in the immune system of children with autism (AU), both at the systemic and cellular levels. Characterization of the relationship between the immune and neuronal systems and their synergy with respect to environmental exposure is key to understanding the mechanisms through which toxicants can alter neurodevelopment. Ca^* dependent signaling, for example through the mTOR pathway, provides a denominator that is common to both the neural and immune systems. Our data converges on specific neuro and immune-modulatory effects, implicating mTOR pathways, following ex vivo exposure of cells to congeners of PBDE (polybrominated diphenyl ethers). Project 3 hypothesizes that the maternal gestational body burden of non-coplanar environmental toxicants such as PBDE will correlate to immune dysregulation. Furthermore, we hypothesize that children with AU will exhibit increased sensitivity to PBDE exposure. We propose that increased PBDE body burden will lead to changes in the profiles of cytokines/chemokines production and that ex vivo toxicant exposure of peripheral blood mononuclear cells collected during gestation from mothers who give birth to an ASD child will be exaggerated. We further propose that children with ASD will have increased sensitivity to ex vivo exposure to PBDE leading to differentially altered immune cell function that will correlate with the altered expression of specific mTOR pathway related genes. In particular, we hypothesize that alterations in mTOR signaling will affect regulation of immune responses including changes in DNA methlyation of F0XP3 expressed in regulatory T cells (Project 2). In conjunction with Project 4, we propose that there is a direct relationship between cytokine/chemokine profiles and changes in neuronal development. We have formulated these hypotheses on the basis of our published work and preliminary data demonstrating that PMBC from children with ASD respond differentially to ex vivo PBDE exposure. We will: 1) Examine the maternal gestational environment by leveraging samples taken during each trimester from mothers enrolled in the MARBLES (Markers of Autism Risk in Babies - Learning Early Signs) Study;2) Examine the maternal gestational environment by using samples taken during each trimester from mothers enrolled in the MARBLES Study;and 3) Determine F0XP3 and global methylation on DNA from existing samples of PBDE-exposed peripheral blood mononuclear cells (CHARGE) to determine if methylation differences are reflective of differential cell function including cytokine/chemokine production.
The proposed studies investigate for the first time the mechanistic relationship between toxicant exposure and immune dysfunction in the context of a genetic susceptibility (e.g. mTOR pathway gene effects on toxicant cytokine/chemokine profiles following toxicant exposure, in the gestational environment of mothers at high risk for giving birth to an autistic child). Our approach permits detailed analysis of the molecular and cellular mechanisms by which gene X environment interactions relevant to neurodevelopment may occur.
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