Steroida! and non-steroidal estrogen-like chemicals (environmental estrogens, EE) that mimic or block hormonal estrogen actions on estrogen receptors (ER), and dioxin-like chemicals that interact with arylhydrocarbon receptors (AhR), are widespread in the environment and common contaminants at Superfund sites. ER mediated signaling is known to have a critical role in neurodevelopmental programming and in the maintenance of neuroplasticity and repair in the adult and aging brain. Although ER and AhR/ARNT signaling pathways converge at multiple points in peripheral tissues, the normal role of AhR signaling in the CNS, and brain specific mechanisms and effects of ER-AhR interactions are largely unknown. Here we investigate the hypothesis that EE and dioxins are neurotoxicants, by virtue of their ability to disrupt neural estrogen signaling and estrogen responsive genes in the CNS. A corollary of this hypothesis is that irreversible chemical effects on estrogen dependent neurodevelopmentaf programming alter responses to hormonal estrogen and subsequent EE and dioxin exposures, and dysregulate estrogendependent components of neuroplasticity and self-repair in the adult and aging brain.
Specific aims are to: (1) Determine separate and convergent actions of ER and AhR signaling pathways on gene expression during developmental programming, and in the adult and aging brain;(2) Determine corresponding changes in estrogen responsive neural genes and cellular processes of neurodevelopment, neuroplasticity and repair; (3) Characterize estrogen-dioxin actions and interactions on developmentally programmed alternative splicing decisions in the CNS;(4) Identify cis-elements and transacting cellular factors that mediate estrogen and dioxin actions and interactions on the neural cyp19B gene promoter.
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