Differential Immune Response to the Environmental Toxicant, BDE-49 in Chidlren with Autism Spectrum Disorders

Background: Divergent findings from genetic studies support gene-by- environment interactions as a key contributing factor in autism spectrum disorders (ASD). Several environmental agents have been shown to influence the immune system, including the persistent organic environmental pollutants, polybrominated diphenyl ethers (PBDEs). These toxicants may furthermore interfere with normal endocrine, immune and/or neural development. A recent study demonstrated the impact of ex vivo exposure to a PBDE congener, BDE-47, on innate immune function in children with ASD. In another study, in comparison with BDE-47 and congener with a lower body burden, BDE-49, was shown to be extremely neurotoxic to cortical neurons in vitro (Kim, et al., 2011). In addition, various animal model studies indicate there is a sex-specific difference in the response to PBDE exposure. 

Objectives:  This study sought to evaluate the differential effects of ex vivo exposure to a more potent PBDE congener, BDE-49, on immune function in peripheral blood mononuclear cells (PBMCs) isolated from children ages 2-5 yrs with ASD (ASD= 31, M=33, F=8) and compared with age-matched typically developing controls (TD= 53, M=44, F=10). 

Methods:  Isolated PBMCs were exposed ex vivo for 4 hours to 250 nM, 50 nM BDE-49, or DMSO as a vehicle control, prior to challenge with bacterial lipopolysaccharide (LPS), an innate immune cell activator, or the T cell mitogen, phytohemagglutin A (PHA). After exposure for 48 hrs, cytokine and chemokine levels from cell supernatants were analyzed via a 21-multiplex bead-based assay. 

Results:   Preliminary results indicate that when adjusted for child’s sex for both subject groups, BDE-49 exposure at 250nM had an increase effect on the adaptive and innate immune response for production of inflammatory cytokines such as IFN-gamma, IL-1a, and the chemokines MIP-1a, MIP-1b and MCP-1. When diagnosis was taken into account, ex vivo exposure of PBMCs to BDE-49 at 250nM resulted in a differential immune response in children with ASD compared to TD. Activation of T cells from children with ASD exposed to 250nM BDE-49 resulted in a significant decrease for the production of MIP-1b and IL-1a compared to TD. In activated monocytes/macrophages there was a significant decrease for the production of MIP-1b.   

Conclusions:  Ex vivo exposure of PBMCs from a pediatric population to BDE-49 had global effects on the production of certain cytokines and chemokines, regardless of diagnosis.  Of particular interest, there was a differential effect of BDE-49 exposure on PBMC from children with ASD compared to the TD controls for some cytokines and, in particular, the chemokine, MIP-1b which has been shown to be elevated in Alzheimer brain tissue. These findings may aid in a better understanding of the interplay between immunological and environmental factors and their combined role in the etiology of autism.