Project 1 – Neurodevelopment & Chemical Exposure

Leica image of an alcian blue/alizarin red stained zebrafish. Blue structures are cartilage-derived, while red structures are skeletal-derived.

Overview

Project 1 research aims to understand the mechanisms by which environmental toxicants, such as combustion products, pesticides, and flame retardants, affect neurodevelopment and lead to impacts later in life. We’ll use what we learn to determine which neurobehavioral systems are most important for neurodevelopment and explore potential therapeutic approaches that might decrease the impact of toxicant exposures over the lifespan.

Summary

Cognitive and behavioral dysfunction are prevalent problems associated with exposure to environmental toxicants. Children are especially vulnerable during sensitive windows in their development. Impairments have been seen in children after developmental exposure to various chemicals including pesticides, flame retardants, and components of tobacco smoke. These and other impairments exact significant societal and economic costs. Impact from neurodevelopmental disorders and IQ deficits are estimated to range from tens to hundreds of billions of dollars per year in the U.S. alone.

Our researchers aim to better understand the mechanisms of those impacts using animal models (rats and zebrafish). We are working towards a better understanding of how diverse sets of chemicals target the same final neurotransmitter pathways and lead to health impacts. This is done by studying physiology and biochemistry of signaling in the brain, and by using a battery of tests to assess impacts on specific behavioral and cognitive function. We aim to harness this understanding by evaluating therapeutic approaches.

Our researchers utilize animal models because they can control and limit some of the confounding variables humans experience that make it harder to draw conclusions when studying exposures in people. Also, given our focus on early life exposures and later life health impacts, studying animals with shorter lifespans allows us to do experiments that encompass full lifespans on a much shorter timescale.

We tracked the movement of zebrafish larvae in response to changing light and dark conditions after exposing them to different concentrations of organophosphate flame retardants to understand the impact on normal behavior & development. Glazer et al., 2018

Objective

We aim to use both rats and zebrafish, to determine how a wide range of environmental pollutants, including pesticides, combustion products and flame retardants, affect brain development and cause later life emotional problems, cognitive impairment and movement dysfunction. Our researchers work to understand how environmental pollutants impact specific neural systems so that we can know more about the mechanisms of the chemicals tested and thus more efficiently investigate a broader range of chemicals. We want to understand how and why exposure to these chemicals can impact neurodevelopment, and what, if anything can be done to treat resulting health complications or limit existing exposures.

Importance

Answering the question of how developmental toxicants impact brain functioning, and ultimately development and behavioral outcomes, is important for a variety of reasons. First, developing a mechanistic understanding can help inform the investigation and use of therapeutic treatments to reverse or mitigate associated health effects. Our researchers are looking into the potential for existing therapeutic treatments based on previous and ongoing mechanistic research. Health impacts are not always easy to detect or quantify in broader epidemiological surveys, so this research can also raise the profile of more subtle impacts from low-level exposures.

When we know how a developmental toxicant acts in the body, we can better understand how contaminant mixtures may impact health differently because of interactions between individual contaminants. For example, we have studied how benzo[a]pyrene and nicotine (which are both present in cigarettes) interact and amplify behavioral impacts in rats. These results are important for comparing the relative safety of nicotine-containing products, including vaping, versus smoked tobacco during pregnancy and for assessing potential health concerns of second hand smoke exposure for young children.

Project Aims

  1. Evaluate how exposure to developmental toxicants can lead to impairment of common brain signaling pathways, and cognitive and behavioral dysfunction in rats.
  2. Explore potential for therapeutic interventions targeting these signaling pathways to offset developmental and behavioral health impacts from exposure.
  3. Using zebrafish, study the vulnerability of these same brain signaling pathways to developmental toxicant exposure, and explore the potential for zebrafish to be used for higher-throughput screening of multiple chemicals.

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