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. Callard’s project is to understand how estrogen-like chemicals that interact with estrogen receptors (ER) and dioxin-like chemicals that interact with arylhydrocarbon receptors (AhR) directly or indirectly disrupt estrogen-regulated processes of neurodevelopment, neuroplasticity, and neural repair.
In laboratory and field studies using fish models (zebrafish, killifish), the researchers focus on genetic markers that can be used to screen chemicals for their actions in the nervous system and have used gene-discovery methods (microarrays) to understand better how these chemicals impact neural genes, processes, cell types, and regulatory pathways.
Most recently, the researchers have focused on neural-repair mechanisms, which are essential for maintaining normal functioning of the nervous system in response to the stresses and damage that can occur throughout life (e.g., neurodegeneration is not an inevitable consequence of aging). Although these processes are subtle and difficult to study in common laboratory mammals, the adult-fish nervous system displays a remarkable potential for damage-induced repair. After optic-nerve crush, the retinal ganglion cells of the eye re-grow their axons to connect with neurons in the brain so that vision is restored within three weeks. By profiling genes that are turned on or off sequentially in a successful model of neuroregeneration, the researchers discovered a role for AhR signaling in suppressing repair-associated neural genes. Interestingly, part of the pathway regulated by AhR in nervous system is used in other regenerating tissues. These results are significant because they reveal a mechanism to explain the neurotoxicity of dioxin and dioxin-like chemicals. Importantly, they provide the researchers with an array of mechanism-based neural markers to assess processes of neural repair in laboratory fish and in killifish populations living long term in polluted environments.