The prevalence of neurodevelopmental disorders of behavior and cognition such as autism spectrum disorders (ASDs) is increased by prenatal exposure to pathogenic environmental stressors such as the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) and organophosphate insecticides such as chlorpyrifos. The under- lying cellular and molecular mechanisms are not known. Many mental disorders are sexually dimorphic. Some (e.g., ASD and ADHD) are more common in males whereas others (e.g., major depression and anxiety) are more common in females. A goal of this research program is to investigate the biological basis for these sex differences in fetal mouse brain exposed to environmental stressors during early gestation, prior to the appear- ance of sex hormones. Published work by the PI has identified VPA-induced sex differences in the activating epigenetic mark, H3K4me3, leading to sexually-dimorphic expression of Bdnf, the gene encoding brain-derived neurotrophic factor. These studies with Bdnf establish an experimental paradigm for identifying other sexually- dimorphic proteins that regulate brain development and that may mediate the pathogenic effects of environ- mental stressors on brain development. An important clue to the underlying mechanism is that the enzymes that regulate H3K4me3, the H3K4-demethylases, JARID1C and JARID1D, are encoded by genes on the X and Y-chromosomes, respectively, and are therefore postulated to be differentially expressed in the two sexes.
The specific aims of this research program are to 1) identify genes involved in early brain development (in addition to Bdnf) that are expressed differently in males and females in response to VPA due to sexually dimorphic H3K4 trimethylation and 2) test the hypothesis that JARID1 gene expression and enzyme activity are greater in males than in females, thereby providing a plausible mechanism for sexually dimorphic gene expression in the fetal brain. Identification of such genes, particularly if found to be associated with one or more developmentally relevant signaling pathways, will lead to a clearer understanding of the etiology of neurodevelopmental disor- ders such as ASDs and provide the basis for future, hypothesis driven initiatives to determine the pathogenic mechanisms of action of other environmental stressors acting during early gestation.
? RELEVANCE Exposure of the fetus to toxic substances in the environment such as pesticides, air pollution and certain drugs can lead to such disorders of behavior and cognition as autism spectrum disorders (ASDs); ASDs are more common in males. The biological basis for neither the pathogenic mechanisms of environmental factors nor the sex differences is known. Using fetal mice, this research program will test the hypothesis that environmental stressors alter the expression of genes encoding critical regulators of brain development and that enzymes en- coded on the sex chromosomes regulate gene expression differently in males and females, ultimately causing sexually-dimorphic developmental disorders such as ASDs. Elucidating these biological mechanisms can lead to potential preventative and therapeutic strategies.
