Project Description:
Our lab demonstrated sex differences in G protein expression and activity in both mice and humans. Sex differences in susceptibility to autism are well documented. Although gonadal steroid levels are not sexually dimorphic in four and five year olds, males and females are exposed to divergent levels of androgens and estrogens in utero and for the first six months of life. We speculated that the observed sex differences relate to sexually dimorphic past exposure to gonadal steroids. Exposure to aberrant levels of estrogens in utero or during the perinatal period is now known to lead to later permanent alterations in gene expression. Although this phenomenon has been termed ?hormonal imprinting,? the actual mechanisms remain poorly understood. Prenatal exposure to Bisphenol A (BPA), a common environmental toxin with estrogenic properties, has been shown to lead to permanent changes in gene expression: Exposure to BPA and other estrogens in utero or during the perinatal period leads to hypomethylation of DNA later in life, which leads to increased expression of normally silenced genes in mice and rats (14-17). Studies in rodents demonstrate that neonatal exposure to BPA and other estrogenic compounds may increase aggression and anxiety in adulthood (18). Our overall hypothesis is that early exposure to BPA and/or to aberrant levels of estrogens causes hypomethylation of DNA in brain, leading to transcriptional over expression of normally silenced genes or alleles, including Gαs. We speculate that this leads to abnormal neuronal signaling and austim.
Specific aims.
1) We will expose mouse neuronal cell lines and primary brain cultures from male and female mice to BPA, other estrogens, androgens, and demethylating agents. A) We will quantitate mRNA expression of 6 imprinted genes linked to autism, in addition to 2 paternally expressed differentially methylated genes. B) We will measure the degree of DNA methylation of promoters of a subset of the above imprinted genes, as well as C) global DNA methylation.
2) We will perform gene-specific and global DNA methylation studies on peripheral blood DNA from 8 autistic male subjects, and in 8 typically developing male and female subjects. Genome-wide methylation specific micro-arrays will be performed in a subset of 5 subjects.
Primary Target Audience Geographic Descriptor:
Single-County, Mulit-County
