Polybrominated Diphenyl Ethers, Autism, Developmental Delay, and Immune Markers: A Pilot Study

Background: Polybrominated diphenyl ethers (PBDEs) are flame retardants used widely, with a rapid increase in body burdens in the U.S. over the last few decades. PBDEs and their metabolites cross the placenta and studies in rodents show neurodevelopmental toxicity from prenatal exposures. Objectives: To review PBDEs and the development of 100 children from CHARGE (Childhood Autism Risk from Genetics and the Environment), a case-control epidemiologic study of autism/autism spectrum (AU/ASD), developmental delays (DD) and typically developing (TD) population-based controls. Methods: Developmental diagnoses were confirmed by the ADOS, ADI-R, Mullen's Scales of Early Learning, and Vineland Adaptive Behavior Scales. Eleven PBDE congeners were measured by GC/MS from serum specimens collected after children were assessed. Immunoglobulins and cytokines were measured by LuminexTM multiplex platform. Multiple logistic and linear regression models were used to control confounding factors in the evaluation associations between plasma PBDEs and (a) case status; (b) plasma IgG, IgA, IgE, and IgM, and (c) 13 cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-13, IFN-gamma, GM-CSF, TNF-alpha, and TGF-beta). Results: Levels of PBDEs are higher than reported for any other population worldwide. AU/ASD and DD children were similar to TD controls for all congeners, but levels were high for all three groups. Highly brominated congeners were associated with reduced IgM, IL-1beta, IFN-gamma and TGF-beta, and with increased IL-2. Lower brominated congeners were associated with increased IL-4, Il-6, IL-10, and IL-12p40, GM-CSF, and TNF-alpha. Conclusions: The similar PBDE body burdens in children diagnosed with AU/ASD as compared with TD controls may be explained by our inability to obtain plasma prior to the diagnosis or during critical windows of development. Current concentrations in plasma may not represent early life exposures due to changes in diet and introduction of new household products containing PBDEs. The strong links of lower brominated congeners with increased levels of several pro-inflammatory cytokines is consistent with autism as a neuro-inflammatory condition. At the same time, reduced IgM and TGF-beta have been reported in autism, but the associations of these markers with concurrently measured PBDEs were independent of case status, supporting PBDEs as a potential contributor to autism risk. Because timing of blood samples was not optimal, the lack of association of PBDEs with autism does not preclude a causal role of these compounds. Based on the strong, multiple associations with numerous immune markers in this pilot study, we hypothesize that early life exposures to PBDEs have the potential to disrupt immune development. Whether immunotoxicity at a critical time period could contribute to abnormalities in brain development requires further investigation.