Superfund Research Program
Estrogen Receptor-Arylhydrocarbon Receptor Interactions in the CNS
Project Leader: Gloria V. Callard
Grant Number: P42ES007381
Funding Period: 2000-2012
Epidemiological, wildlife, and laboratory studies indicate that disorders of development and physiology can be ascribed to exposure to environmental chemicals that disrupt essential hormone actions. Termed “endocrine disrupting chemicals” (EDC), these agents are chemically diverse and often found as complex mixtures at Superfund sites (e.g., PCBs, dioxins). Even at low doses and transient exposures, EDC have the potential to induce lifelong anatomical and functional defects by permanently altering processes of normal development. More difficult to predict and study are the effects of chronic and multigenerational exposures to EDC. The objective of Dr. Gloria Callard’s research is to understand how estrogen-like and dioxin-like environmental contaminants directly or indirectly disrupt processes of neurodevelopment, neuroplasticity, and neural repair.
In laboratory and field studies using fish models (zebrafish, killifish), Dr. Callard’s research focuses on genetic markers that can be used to screen known and unknown environmental chemicals for their actions in the developing nervous system. Results of these studies reveal interactions between estrogen receptor (ER) and arylhydrocarbon receptor (AhR) signaling pathways in the nervous system and, most significantly, indicate a novel mechanism of action of estrogen-like chemicals: namely, disruption of alternative splicing decisions on estrogen-regulated promoters. Most recently, the researchers have used a global gene discovery approach (microarray analysis) to identify >4000 genes that are activated or repressed during neurodegeneration or retinal ganglion cells after optic nerve damage in adult zebrafish. These findings not only provide them with a wide array of potential markers of neurotoxicant exposure effect for application to laboratory and environmental models but, in addition, suggest an endogenous role for AhR in neural repair processes and a specific mechanism to explain how dioxin-like chemicals exert their toxic actions.