Abstract
We tested the hypothesis that in utero exposure to heavy metals increases autism-like behavioral phenotypes in adult animals and induces epigenetic changes in genes that have roles in the etiology of autism. Mouse dams were treated with cadmium, lead, arsenate, manganese, and mercury via drinking water from gestational days (E) 1-10. Valproic acid (VPA) injected intraperitoneally once on (E) 8.5 served as a positive control. Young male offspring were tested for behavioral deficits using four standardized behavioral assays. In this study, in utero exposure to heavy metals resulted in multiple behavioral abnormalities that persisted into adulthood. VPA and manganese induced changes in perseverative/impulsive behavior and social dominance behavior, arsenic caused changes only in perseverative/impulsive behavior, and lead induced abnormalities in social interaction in comparison to the control animals. Brain samples from Mn, Pb, and VPA treated and control animals were evaluated for changes in CpG island methylation in promoter regions and associated changes in gene expression. The Chd7 gene, essential for neural crest cell migration and patterning, was found to be hypomethylated in each experimental animal tested compared to water-treated controls. Furthermore, distinct patterns of CpG island methylation yielded novel candidate genes for further investigation.