It has been hypothesized that ASD pathology is associated with exposure to environmental neurotoxicants including heavy metals. We have previously shown that perinatal exposure to Et-Hg in SHR rats results in increased cerebellar oxidative stress marker 3-nitrotyrosine (3-NT), decreased deiodinase Type 2 (D2) suggesting local decrease in thyroid hormone (TH) levels, and aberrant expression of specific TH-regulated genes. We have also shown increased oxidative stress in postmortem human brain samples derived from ASD donors.
Objectives:
The objective of this study was to evaluate the hypothesis that inhibition of local brain D2 expression brought about by exposure to heavy metals may be also altered in ASD, resulting in local brain TH deficiency and aberrant gene expression. Specifically, the objectives were: (1) to compare TH-regulated gene expression between brain samples derived from control and Et-Hg exposed rats; (2) to examine changes in D2 expression in brain samples derived from control and ASD donors; (3) to determine whether TH-regulated gene expression differs between brain samples derived from control and ASD donors.
Methods:
To assess oxidative stress, 3-NT was measured in brain homogenates by an ELISA method. D2 activity was measured in the brain homogenates by quantifying 125I release from a 125I labeled T4 tracer. Gene expression was measured using a Quantitative Real-Time PCR (qRT PCR) real-time PCR.
Results:
We observed a significant decrease in D2 expression (61.9%) in brains derived from Et-Hg-exposed male but not in female rat pups; these decrease was associated with upregulation of SWAP( ~80%) and Odf4 (~50%) genes in brains of exposed male but not female pups. Analysis of human postmortem samples confirmed an increase in 3-NT and showed a trend towards decreased D2 expression (19%) in brains derived from ASD donors.
Conclusions:
The neurotoxic effects of perinatal exposure to heavy metals in rats are associated with decreased deiodinase Type 2 (D2) expression suggestive of decreased local brain T3 levels. Altered local brain TH levels affect expression of specific genes regulated by TH; these effects are brain region and sex specific. Preliminary data suggest similar changes in postmortem brain samples derived from ASD donors. Altered expression of brain TH-dependent genes during the perinatal period may impact neurodevelopment and contribute to ASD pathology.