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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R21ES035818&format=word)
| Principal Investigator: Coffman, James A | |
|---|---|
| Institute Receiving Award | Mount Desert Island Biological Lab |
| Location | Salsbury Cove, ME |
| Grant Number | R21ES035818 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 21 Mar 2024 to 28 Feb 2026 |
| DESCRIPTION (provided by applicant): | PROJECT SUMMARY / ABSTRACT Arsenic exposure from well water and food is a major public health concern. Early life (e.g., prenatal) exposure to low level arsenic increases risk of developing psychiatric disorders such as depression and anxiety in adulthood. Arsenic is an endocrine disruptor and available evidence suggests that its psychopathological effects stem from interference with glucocorticoid receptor (GR) signaling; however, gaps remain in our understanding of the underlying mechanisms. Krüppel-like factor 9 (Klf9) is a transcription factor important for neurogenesis and metabolic regulation and is a regulatory hub at the junction of multiple endocrine and cellular stress signaling pathways. KLF9 has been implicated in stress-induced psychopathology and neurodegeneration. We and others have shown that Klf9 is a feedforward regulator of GR signaling. We have obtained preliminary data indicating that the GR-Klf9 gene regulatory pathway is perturbed in zebrafish embryos exposed to low-level arsenic, This exploratory/developmental research project will use zebrafish as a model system to test the hypothesis that chronic early life exposure to low levels of arsenic increases risk of depression and/or other psychiatric disorders by developmentally altering homeostatic setpoints to persistently impede GR- and/or Klf9-dependent stress responsivity, resulting in long-term loss of plasticity and dysfunction. Zebrafish are an ideal model system for the proposed studies as they share all the relevant genes and neuroendocrine signaling pathways with humans, and are social, diurnal animals with complex behaviors that can be measured and related to human psychology and stress-responsive behavior. Moreover, the larvae provide unsurpassed access for experimental manipulation and observation, and transgenic reporter lines for monitoring GR and brain activity by fluorescence microscopy. The proposed research will use those tools, as well as a klf9 and GR-knockout lines that we recently created using CRISPR, to accomplish two specific aims. The first is to determine if chronic exposure to arsenic results in long-term glucocorticoid resistance and increased neuroinflammation. To that end we will assess the effects of chronic arsenic exposure during early development on basal and stress-induced activity of GR target genes and inflammation markers in larvae and adult brain tissue, as well as on larval and adult cortisol levels. The second specific aim is to determine if chronic developmental exposure to low level arsenic results in aberrant brain activity and behaviors. To accomplish this, we will use fluorescence microscopy and automated movement tracking to ask how chronic developmental exposure to low-level arsenic affect brain development, basal and stress-responsive neuronal activity in parts of the larval brain that regulate neuroendocrine stress signaling, and behavior of the exposed larvae across the lifespan. The project will open a new avenue for future research focused on the mechanisms underlying the the pathophysiological effects of early life arsenic exposure on the neuroendocrine stress system. |
| Science Code(s)/Area of Science(s) |
Primary: 61 - Neurodevelopmental Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Jonathan Hollander |